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1.  Adiposity as a cause of cardiovascular disease: a Mendelian randomization study 
Background: Adiposity, as indicated by body mass index (BMI), has been associated with risk of cardiovascular diseases in epidemiological studies. We aimed to investigate if these associations are causal, using Mendelian randomization (MR) methods.
Methods: The associations of BMI with cardiovascular outcomes [coronary heart disease (CHD), heart failure and ischaemic stroke], and associations of a genetic score (32 BMI single nucleotide polymorphisms) with BMI and cardiovascular outcomes were examined in up to 22 193 individuals with 3062 incident cardiovascular events from nine prospective follow-up studies within the ENGAGE consortium. We used random-effects meta-analysis in an MR framework to provide causal estimates of the effect of adiposity on cardiovascular outcomes.
Results: There was a strong association between BMI and incident CHD (HR = 1.20 per SD-increase of BMI, 95% CI, 1.12–1.28, P = 1.9·10−7), heart failure (HR = 1.47, 95% CI, 1.35–1.60, P = 9·10−19) and ischaemic stroke (HR = 1.15, 95% CI, 1.06–1.24, P = 0.0008) in observational analyses. The genetic score was robustly associated with BMI (β = 0.030 SD-increase of BMI per additional allele, 95% CI, 0.028–0.033, P = 3·10−107). Analyses indicated a causal effect of adiposity on development of heart failure (HR = 1.93 per SD-increase of BMI, 95% CI, 1.12–3.30, P = 0.017) and ischaemic stroke (HR = 1.83, 95% CI, 1.05–3.20, P = 0.034). Additional cross-sectional analyses using both ENGAGE and CARDIoGRAMplusC4D data showed a causal effect of adiposity on CHD.
Conclusions: Using MR methods, we provide support for the hypothesis that adiposity causes CHD, heart failure and, previously not demonstrated, ischaemic stroke.
doi:10.1093/ije/dyv094
PMCID: PMC4553708  PMID: 26016847
Cardiovascular disease; epidemiology; body mass index; Mendelian randomization
2.  The impact of low-frequency and rare variants on lipid levels 
Surakka, Ida | Horikoshi, Momoko | Mägi, Reedik | Sarin, Antti-Pekka | Mahajan, Anubha | Lagou, Vasiliki | Marullo, Letizia | Ferreira, Teresa | Miraglio, Benjamin | Timonen, Sanna | Kettunen, Johannes | Pirinen, Matti | Karjalainen, Juha | Thorleifsson, Gudmar | Hägg, Sara | Hottenga, Jouke-Jan | Isaacs, Aaron | Ladenvall, Claes | Beekman, Marian | Esko, Tõnu | Ried, Janina S | Nelson, Christopher P | Willenborg, Christina | Gustafsson, Stefan | Westra, Harm-Jan | Blades, Matthew | de Craen, Anton JM | de Geus, Eco J | Deelen, Joris | Grallert, Harald | Hamsten, Anders | Havulinna, Aki S. | Hengstenberg, Christian | Houwing-Duistermaat, Jeanine J | Hyppönen, Elina | Karssen, Lennart C | Lehtimäki, Terho | Lyssenko, Valeriya | Magnusson, Patrik KE | Mihailov, Evelin | Müller-Nurasyid, Martina | Mpindi, John-Patrick | Pedersen, Nancy L | Penninx, Brenda WJH | Perola, Markus | Pers, Tune H | Peters, Annette | Rung, Johan | Smit, Johannes H | Steinthorsdottir, Valgerdur | Tobin, Martin D | Tsernikova, Natalia | van Leeuwen, Elisabeth M | Viikari, Jorma S | Willems, Sara M | Willemsen, Gonneke | Schunkert, Heribert | Erdmann, Jeanette | Samani, Nilesh J | Kaprio, Jaakko | Lind, Lars | Gieger, Christian | Metspalu, Andres | Slagboom, P Eline | Groop, Leif | van Duijn, Cornelia M | Eriksson, Johan G | Jula, Antti | Salomaa, Veikko | Boomsma, Dorret I | Power, Christine | Raitakari, Olli T | Ingelsson, Erik | Järvelin, Marjo-Riitta | Stefansson, Kari | Franke, Lude | Ikonen, Elina | Kallioniemi, Olli | Pietiäinen, Vilja | Lindgren, Cecilia M | Thorsteinsdottir, Unnur | Palotie, Aarno | McCarthy, Mark I | Morris, Andrew P | Prokopenko, Inga | Ripatti, Samuli
Nature genetics  2015;47(6):589-597.
Using a genome-wide screen of 9.6 million genetic variants achieved through 1000 Genomes imputation in 62,166 samples, we identify association to lipids in 93 loci including 79 previously identified loci with new lead-SNPs, 10 new loci, 15 loci with a low-frequency and 10 loci with missense lead-SNPs, and, 2 loci with an accumulation of rare variants. In six loci, SNPs with established function in lipid genetics (CELSR2, GCKR, LIPC, and APOE), or candidate missense mutations with predicted damaging function (CD300LG and TM6SF2), explained the locus associations. The low-frequency variants increased the proportion of variance explained, particularly for LDL-C and TC. Altogether, our results highlight the impact of low-frequency variants in complex traits and show that imputation offers a cost-effective alternative to re-sequencing.
doi:10.1038/ng.3300
PMCID: PMC4757735  PMID: 25961943
3.  New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk 
Lu, Yingchang | Day, Felix R. | Gustafsson, Stefan | Buchkovich, Martin L. | Na, Jianbo | Bataille, Veronique | Cousminer, Diana L. | Dastani, Zari | Drong, Alexander W. | Esko, Tõnu | Evans, David M. | Falchi, Mario | Feitosa, Mary F. | Ferreira, Teresa | Hedman, Åsa K. | Haring, Robin | Hysi, Pirro G. | Iles, Mark M. | Justice, Anne E. | Kanoni, Stavroula | Lagou, Vasiliki | Li, Rui | Li, Xin | Locke, Adam | Lu, Chen | Mägi, Reedik | Perry, John R. B. | Pers, Tune H. | Qi, Qibin | Sanna, Marianna | Schmidt, Ellen M. | Scott, William R. | Shungin, Dmitry | Teumer, Alexander | Vinkhuyzen, Anna A. E. | Walker, Ryan W. | Westra, Harm-Jan | Zhang, Mingfeng | Zhang, Weihua | Zhao, Jing Hua | Zhu, Zhihong | Afzal, Uzma | Ahluwalia, Tarunveer Singh | Bakker, Stephan J. L. | Bellis, Claire | Bonnefond, Amélie | Borodulin, Katja | Buchman, Aron S. | Cederholm, Tommy | Choh, Audrey C. | Choi, Hyung Jin | Curran, Joanne E. | de Groot, Lisette C. P. G. M. | De Jager, Philip L. | Dhonukshe-Rutten, Rosalie A. M. | Enneman, Anke W. | Eury, Elodie | Evans, Daniel S. | Forsen, Tom | Friedrich, Nele | Fumeron, Frédéric | Garcia, Melissa E. | Gärtner, Simone | Han, Bok-Ghee | Havulinna, Aki S. | Hayward, Caroline | Hernandez, Dena | Hillege, Hans | Ittermann, Till | Kent, Jack W. | Kolcic, Ivana | Laatikainen, Tiina | Lahti, Jari | Leach, Irene Mateo | Lee, Christine G. | Lee, Jong-Young | Liu, Tian | Liu, Youfang | Lobbens, Stéphane | Loh, Marie | Lyytikäinen, Leo-Pekka | Medina-Gomez, Carolina | Michaëlsson, Karl | Nalls, Mike A. | Nielson, Carrie M. | Oozageer, Laticia | Pascoe, Laura | Paternoster, Lavinia | Polašek, Ozren | Ripatti, Samuli | Sarzynski, Mark A. | Shin, Chan Soo | Narančić, Nina Smolej | Spira, Dominik | Srikanth, Priya | Steinhagen-Thiessen, Elisabeth | Sung, Yun Ju | Swart, Karin M. A. | Taittonen, Leena | Tanaka, Toshiko | Tikkanen, Emmi | van der Velde, Nathalie | van Schoor, Natasja M. | Verweij, Niek | Wright, Alan F. | Yu, Lei | Zmuda, Joseph M. | Eklund, Niina | Forrester, Terrence | Grarup, Niels | Jackson, Anne U. | Kristiansson, Kati | Kuulasmaa, Teemu | Kuusisto, Johanna | Lichtner, Peter | Luan, Jian'an | Mahajan, Anubha | Männistö, Satu | Palmer, Cameron D. | Ried, Janina S. | Scott, Robert A. | Stancáková, Alena | Wagner, Peter J. | Demirkan, Ayse | Döring, Angela | Gudnason, Vilmundur | Kiel, Douglas P. | Kühnel, Brigitte | Mangino, Massimo | Mcknight, Barbara | Menni, Cristina | O'Connell, Jeffrey R. | Oostra, Ben A. | Shuldiner, Alan R. | Song, Kijoung | Vandenput, Liesbeth | van Duijn, Cornelia M. | Vollenweider, Peter | White, Charles C. | Boehnke, Michael | Boettcher, Yvonne | Cooper, Richard S. | Forouhi, Nita G. | Gieger, Christian | Grallert, Harald | Hingorani, Aroon | Jørgensen, Torben | Jousilahti, Pekka | Kivimaki, Mika | Kumari, Meena | Laakso, Markku | Langenberg, Claudia | Linneberg, Allan | Luke, Amy | Mckenzie, Colin A. | Palotie, Aarno | Pedersen, Oluf | Peters, Annette | Strauch, Konstantin | Tayo, Bamidele O. | Wareham, Nicholas J. | Bennett, David A. | Bertram, Lars | Blangero, John | Blüher, Matthias | Bouchard, Claude | Campbell, Harry | Cho, Nam H. | Cummings, Steven R. | Czerwinski, Stefan A. | Demuth, Ilja | Eckardt, Rahel | Eriksson, Johan G. | Ferrucci, Luigi | Franco, Oscar H. | Froguel, Philippe | Gansevoort, Ron T. | Hansen, Torben | Harris, Tamara B. | Hastie, Nicholas | Heliövaara, Markku | Hofman, Albert | Jordan, Joanne M. | Jula, Antti | Kähönen, Mika | Kajantie, Eero | Knekt, Paul B. | Koskinen, Seppo | Kovacs, Peter | Lehtimäki, Terho | Lind, Lars | Liu, Yongmei | Orwoll, Eric S. | Osmond, Clive | Perola, Markus | Pérusse, Louis | Raitakari, Olli T. | Rankinen, Tuomo | Rao, D. C. | Rice, Treva K. | Rivadeneira, Fernando | Rudan, Igor | Salomaa, Veikko | Sørensen, Thorkild I. A. | Stumvoll, Michael | Tönjes, Anke | Towne, Bradford | Tranah, Gregory J. | Tremblay, Angelo | Uitterlinden, André G. | van der Harst, Pim | Vartiainen, Erkki | Viikari, Jorma S. | Vitart, Veronique | Vohl, Marie-Claude | Völzke, Henry | Walker, Mark | Wallaschofski, Henri | Wild, Sarah | Wilson, James F. | Yengo, Loïc | Bishop, D. Timothy | Borecki, Ingrid B. | Chambers, John C. | Cupples, L. Adrienne | Dehghan, Abbas | Deloukas, Panos | Fatemifar, Ghazaleh | Fox, Caroline | Furey, Terrence S. | Franke, Lude | Han, Jiali | Hunter, David J. | Karjalainen, Juha | Karpe, Fredrik | Kaplan, Robert C. | Kooner, Jaspal S. | McCarthy, Mark I. | Murabito, Joanne M. | Morris, Andrew P. | Bishop, Julia A. N. | North, Kari E. | Ohlsson, Claes | Ong, Ken K. | Prokopenko, Inga | Richards, J. Brent | Schadt, Eric E. | Spector, Tim D. | Widén, Elisabeth | Willer, Cristen J. | Yang, Jian | Ingelsson, Erik | Mohlke, Karen L. | Hirschhorn, Joel N. | Pospisilik, John Andrew | Zillikens, M. Carola | Lindgren, Cecilia | Kilpeläinen, Tuomas Oskari | Loos, Ruth J. F.
Nature Communications  2016;7:10495.
To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10−8), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.
A genome-wide association meta-analysis study here shows novel genetic loci to be associated to body fat percentage, and describes cross-phenotype association that further demonstrate a close relationship between adiposity and cardiovascular disease risk.
doi:10.1038/ncomms10495
PMCID: PMC4740398  PMID: 26833246
4.  New genetic loci link adipose and insulin biology to body fat distribution 
Shungin, Dmitry | Winkler, Thomas W | Croteau-Chonka, Damien C | Ferreira, Teresa | Locke, Adam E | Mägi, Reedik | Strawbridge, Rona J | Pers, Tune H | Fischer, Krista | Justice, Anne E | Workalemahu, Tsegaselassie | Wu, Joseph M.W. | Buchkovich, Martin L | Heard-Costa, Nancy L | Roman, Tamara S | Drong, Alexander W | Song, Ci | Gustafsson, Stefan | Day, Felix R | Esko, Tonu | Fall, Tove | Kutalik, Zoltán | Luan, Jian’an | Randall, Joshua C | Scherag, André | Vedantam, Sailaja | Wood, Andrew R | Chen, Jin | Fehrmann, Rudolf | Karjalainen, Juha | Kahali, Bratati | Liu, Ching-Ti | Schmidt, Ellen M | Absher, Devin | Amin, Najaf | Anderson, Denise | Beekman, Marian | Bragg-Gresham, Jennifer L | Buyske, Steven | Demirkan, Ayse | Ehret, Georg B | Feitosa, Mary F | Goel, Anuj | Jackson, Anne U | Johnson, Toby | Kleber, Marcus E | Kristiansson, Kati | Mangino, Massimo | Leach, Irene Mateo | Medina-Gomez, Carolina | Palmer, Cameron D | Pasko, Dorota | Pechlivanis, Sonali | Peters, Marjolein J | Prokopenko, Inga | Stančáková, Alena | Sung, Yun Ju | Tanaka, Toshiko | Teumer, Alexander | Van Vliet-Ostaptchouk, Jana V | Yengo, Loïc | Zhang, Weihua | Albrecht, Eva | Ärnlöv, Johan | Arscott, Gillian M | Bandinelli, Stefania | Barrett, Amy | Bellis, Claire | Bennett, Amanda J | Berne, Christian | Blüher, Matthias | Böhringer, Stefan | Bonnet, Fabrice | Böttcher, Yvonne | Bruinenberg, Marcel | Carba, Delia B | Caspersen, Ida H | Clarke, Robert | Daw, E Warwick | Deelen, Joris | Deelman, Ewa | Delgado, Graciela | Doney, Alex SF | Eklund, Niina | Erdos, Michael R | Estrada, Karol | Eury, Elodie | Friedrich, Nele | Garcia, Melissa E | Giedraitis, Vilmantas | Gigante, Bruna | Go, Alan S | Golay, Alain | Grallert, Harald | Grammer, Tanja B | Gräßler, Jürgen | Grewal, Jagvir | Groves, Christopher J | Haller, Toomas | Hallmans, Goran | Hartman, Catharina A | Hassinen, Maija | Hayward, Caroline | Heikkilä, Kauko | Herzig, Karl-Heinz | Helmer, Quinta | Hillege, Hans L | Holmen, Oddgeir | Hunt, Steven C | Isaacs, Aaron | Ittermann, Till | James, Alan L | Johansson, Ingegerd | Juliusdottir, Thorhildur | Kalafati, Ioanna-Panagiota | Kinnunen, Leena | Koenig, Wolfgang | Kooner, Ishminder K | Kratzer, Wolfgang | Lamina, Claudia | Leander, Karin | Lee, Nanette R | Lichtner, Peter | Lind, Lars | Lindström, Jaana | Lobbens, Stéphane | Lorentzon, Mattias | Mach, François | Magnusson, Patrik KE | Mahajan, Anubha | McArdle, Wendy L | Menni, Cristina | Merger, Sigrun | Mihailov, Evelin | Milani, Lili | Mills, Rebecca | Moayyeri, Alireza | Monda, Keri L | Mooijaart, Simon P | Mühleisen, Thomas W | Mulas, Antonella | Müller, Gabriele | Müller-Nurasyid, Martina | Nagaraja, Ramaiah | Nalls, Michael A | Narisu, Narisu | Glorioso, Nicola | Nolte, Ilja M | Olden, Matthias | Rayner, Nigel W | Renstrom, Frida | Ried, Janina S | Robertson, Neil R | Rose, Lynda M | Sanna, Serena | Scharnagl, Hubert | Scholtens, Salome | Sennblad, Bengt | Seufferlein, Thomas | Sitlani, Colleen M | Smith, Albert Vernon | Stirrups, Kathleen | Stringham, Heather M | Sundström, Johan | Swertz, Morris A | Swift, Amy J | Syvänen, Ann-Christine | Tayo, Bamidele O | Thorand, Barbara | Thorleifsson, Gudmar | Tomaschitz, Andreas | Troffa, Chiara | van Oort, Floor VA | Verweij, Niek | Vonk, Judith M | Waite, Lindsay L | Wennauer, Roman | Wilsgaard, Tom | Wojczynski, Mary K | Wong, Andrew | Zhang, Qunyuan | Zhao, Jing Hua | Brennan, Eoin P. | Choi, Murim | Eriksson, Per | Folkersen, Lasse | Franco-Cereceda, Anders | Gharavi, Ali G | Hedman, Åsa K | Hivert, Marie-France | Huang, Jinyan | Kanoni, Stavroula | Karpe, Fredrik | Keildson, Sarah | Kiryluk, Krzysztof | Liang, Liming | Lifton, Richard P | Ma, Baoshan | McKnight, Amy J | McPherson, Ruth | Metspalu, Andres | Min, Josine L | Moffatt, Miriam F | Montgomery, Grant W | Murabito, Joanne M | Nicholson, George | Nyholt, Dale R | Olsson, Christian | Perry, John RB | Reinmaa, Eva | Salem, Rany M | Sandholm, Niina | Schadt, Eric E | Scott, Robert A | Stolk, Lisette | Vallejo, Edgar E. | Westra, Harm-Jan | Zondervan, Krina T | Amouyel, Philippe | Arveiler, Dominique | Bakker, Stephan JL | Beilby, John | Bergman, Richard N | Blangero, John | Brown, Morris J | Burnier, Michel | Campbell, Harry | Chakravarti, Aravinda | Chines, Peter S | Claudi-Boehm, Simone | Collins, Francis S | Crawford, Dana C | Danesh, John | de Faire, Ulf | de Geus, Eco JC | Dörr, Marcus | Erbel, Raimund | Eriksson, Johan G | Farrall, Martin | Ferrannini, Ele | Ferrières, Jean | Forouhi, Nita G | Forrester, Terrence | Franco, Oscar H | Gansevoort, Ron T | Gieger, Christian | Gudnason, Vilmundur | Haiman, Christopher A | Harris, Tamara B | Hattersley, Andrew T | Heliövaara, Markku | Hicks, Andrew A | Hingorani, Aroon D | Hoffmann, Wolfgang | Hofman, Albert | Homuth, Georg | Humphries, Steve E | Hyppönen, Elina | Illig, Thomas | Jarvelin, Marjo-Riitta | Johansen, Berit | Jousilahti, Pekka | Jula, Antti M | Kaprio, Jaakko | Kee, Frank | Keinanen-Kiukaanniemi, Sirkka M | Kooner, Jaspal S | Kooperberg, Charles | Kovacs, Peter | Kraja, Aldi T | Kumari, Meena | Kuulasmaa, Kari | Kuusisto, Johanna | Lakka, Timo A | Langenberg, Claudia | Le Marchand, Loic | Lehtimäki, Terho | Lyssenko, Valeriya | Männistö, Satu | Marette, André | Matise, Tara C | McKenzie, Colin A | McKnight, Barbara | Musk, Arthur W | Möhlenkamp, Stefan | Morris, Andrew D | Nelis, Mari | Ohlsson, Claes | Oldehinkel, Albertine J | Ong, Ken K | Palmer, Lyle J | Penninx, Brenda W | Peters, Annette | Pramstaller, Peter P | Raitakari, Olli T | Rankinen, Tuomo | Rao, DC | Rice, Treva K | Ridker, Paul M | Ritchie, Marylyn D. | Rudan, Igor | Salomaa, Veikko | Samani, Nilesh J | Saramies, Jouko | Sarzynski, Mark A | Schwarz, Peter EH | Shuldiner, Alan R | Staessen, Jan A | Steinthorsdottir, Valgerdur | Stolk, Ronald P | Strauch, Konstantin | Tönjes, Anke | Tremblay, Angelo | Tremoli, Elena | Vohl, Marie-Claude | Völker, Uwe | Vollenweider, Peter | Wilson, James F | Witteman, Jacqueline C | Adair, Linda S | Bochud, Murielle | Boehm, Bernhard O | Bornstein, Stefan R | Bouchard, Claude | Cauchi, Stéphane | Caulfield, Mark J | Chambers, John C | Chasman, Daniel I | Cooper, Richard S | Dedoussis, George | Ferrucci, Luigi | Froguel, Philippe | Grabe, Hans-Jörgen | Hamsten, Anders | Hui, Jennie | Hveem, Kristian | Jöckel, Karl-Heinz | Kivimaki, Mika | Kuh, Diana | Laakso, Markku | Liu, Yongmei | März, Winfried | Munroe, Patricia B | Njølstad, Inger | Oostra, Ben A | Palmer, Colin NA | Pedersen, Nancy L | Perola, Markus | Pérusse, Louis | Peters, Ulrike | Power, Chris | Quertermous, Thomas | Rauramaa, Rainer | Rivadeneira, Fernando | Saaristo, Timo E | Saleheen, Danish | Sinisalo, Juha | Slagboom, P Eline | Snieder, Harold | Spector, Tim D | Stefansson, Kari | Stumvoll, Michael | Tuomilehto, Jaakko | Uitterlinden, André G | Uusitupa, Matti | van der Harst, Pim | Veronesi, Giovanni | Walker, Mark | Wareham, Nicholas J | Watkins, Hugh | Wichmann, H-Erich | Abecasis, Goncalo R | Assimes, Themistocles L | Berndt, Sonja I | Boehnke, Michael | Borecki, Ingrid B | Deloukas, Panos | Franke, Lude | Frayling, Timothy M | Groop, Leif C | Hunter, David J. | Kaplan, Robert C | O’Connell, Jeffrey R | Qi, Lu | Schlessinger, David | Strachan, David P | Thorsteinsdottir, Unnur | van Duijn, Cornelia M | Willer, Cristen J | Visscher, Peter M | Yang, Jian | Hirschhorn, Joel N | Zillikens, M Carola | McCarthy, Mark I | Speliotes, Elizabeth K | North, Kari E | Fox, Caroline S | Barroso, Inês | Franks, Paul W | Ingelsson, Erik | Heid, Iris M | Loos, Ruth JF | Cupples, L Adrienne | Morris, Andrew P | Lindgren, Cecilia M | Mohlke, Karen L
Nature  2015;518(7538):187-196.
Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, we conducted genome-wide association meta-analyses of waist and hip circumference-related traits in up to 224,459 individuals. We identified 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (WHRadjBMI) and an additional 19 loci newly associated with related waist and hip circumference measures (P<5×10−8). Twenty of the 49 WHRadjBMI loci showed significant sexual dimorphism, 19 of which displayed a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation, and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
doi:10.1038/nature14132
PMCID: PMC4338562  PMID: 25673412
5.  Pleiotropic genes for metabolic syndrome and inflammation 
Molecular genetics and metabolism  2014;112(4):317-338.
Metabolic syndrome (MetS) has become a health and financial burden worldwide. The MetS definition captures clustering of risk factors that predict higher risk for diabetes mellitus and cardiovascular disease. Our study hypothesis is that additional to genes influencing individual MetS risk factors, genetic variants exist that influence MetS and inflammatory markers forming a predisposing MetS genetic network. To test this hypothesis a staged approach was undertaken. (a) We analyzed 17 metabolic and inflammatory traits in more than 85,500 participants from 14 large epidemiological studies within the Cross Consortia Pleiotropy Group. Individuals classified with MetS (NCEP definition), versus those without, showed on average significantly different levels for most inflammatory markers studied. (b) Paired average correlations between 8 metabolic traits and 9 inflammatory markers from the same studies as above, estimated with two methods, and factor analyses on large simulated data, helped in identifying 8 combinations of traits for follow-up in meta-analyses, out of 130,305 possible combinations between metabolic traits and inflammatory markers studied. (c) We performed correlated meta-analyses for 8 metabolic traits and 6 inflammatory markers by using existing GWAS published genetic summary results, with about 2.5 million SNPs from twelve predominantly largest GWAS consortia. These analyses yielded 130 unique SNPs/genes with pleiotropic associations (a SNP/gene associating at least one metabolic trait and one inflammatory marker). Of them twenty-five variants (seven loci newly reported) are proposed as MetS candidates. They map to genes MACF1, KIAA0754, GCKR, GRB14, COBLL1, LOC646736-IRS1, SLC39A8, NELFE, SKIV2L, STK19, TFAP2B, BAZ1B, BCL7B, TBL2, MLXIPL, LPL, TRIB1, ATXN2, HECTD4, PTPN11, ZNF664, PDXDC1, FTO, MC4R and TOMM40. Based on large data evidence, we conclude that inflammation is a feature of MetS and several gene variants show pleiotropic genetic associations across phenotypes and might explain a part of MetS correlated genetic architecture. These findings warrant further functional investigation.
doi:10.1016/j.ymgme.2014.04.007
PMCID: PMC4122618  PMID: 24981077
6.  Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation 
Horikoshi, Momoko | Mӓgi, Reedik | van de Bunt, Martijn | Surakka, Ida | Sarin, Antti-Pekka | Mahajan, Anubha | Marullo, Letizia | Thorleifsson, Gudmar | Hӓgg, Sara | Hottenga, Jouke-Jan | Ladenvall, Claes | Ried, Janina S. | Winkler, Thomas W. | Willems, Sara M. | Pervjakova, Natalia | Esko, Tõnu | Beekman, Marian | Nelson, Christopher P. | Willenborg, Christina | Wiltshire, Steven | Ferreira, Teresa | Fernandez, Juan | Gaulton, Kyle J. | Steinthorsdottir, Valgerdur | Hamsten, Anders | Magnusson, Patrik K. E. | Willemsen, Gonneke | Milaneschi, Yuri | Robertson, Neil R. | Groves, Christopher J. | Bennett, Amanda J. | Lehtimӓki, Terho | Viikari, Jorma S. | Rung, Johan | Lyssenko, Valeriya | Perola, Markus | Heid, Iris M. | Herder, Christian | Grallert, Harald | Müller-Nurasyid, Martina | Roden, Michael | Hypponen, Elina | Isaacs, Aaron | van Leeuwen, Elisabeth M. | Karssen, Lennart C. | Mihailov, Evelin | Houwing-Duistermaat, Jeanine J. | de Craen, Anton J. M. | Deelen, Joris | Havulinna, Aki S. | Blades, Matthew | Hengstenberg, Christian | Erdmann, Jeanette | Schunkert, Heribert | Kaprio, Jaakko | Tobin, Martin D. | Samani, Nilesh J. | Lind, Lars | Salomaa, Veikko | Lindgren, Cecilia M. | Slagboom, P. Eline | Metspalu, Andres | van Duijn, Cornelia M. | Eriksson, Johan G. | Peters, Annette | Gieger, Christian | Jula, Antti | Groop, Leif | Raitakari, Olli T. | Power, Chris | Penninx, Brenda W. J. H. | de Geus, Eco | Smit, Johannes H. | Boomsma, Dorret I. | Pedersen, Nancy L. | Ingelsson, Erik | Thorsteinsdottir, Unnur | Stefansson, Kari | Ripatti, Samuli | Prokopenko, Inga | McCarthy, Mark I. | Morris, Andrew P.
PLoS Genetics  2015;11(7):e1005230.
Reference panels from the 1000 Genomes (1000G) Project Consortium provide near complete coverage of common and low-frequency genetic variation with minor allele frequency ≥0.5% across European ancestry populations. Within the European Network for Genetic and Genomic Epidemiology (ENGAGE) Consortium, we have undertaken the first large-scale meta-analysis of genome-wide association studies (GWAS), supplemented by 1000G imputation, for four quantitative glycaemic and obesity-related traits, in up to 87,048 individuals of European ancestry. We identified two loci for body mass index (BMI) at genome-wide significance, and two for fasting glucose (FG), none of which has been previously reported in larger meta-analysis efforts to combine GWAS of European ancestry. Through conditional analysis, we also detected multiple distinct signals of association mapping to established loci for waist-hip ratio adjusted for BMI (RSPO3) and FG (GCK and G6PC2). The index variant for one association signal at the G6PC2 locus is a low-frequency coding allele, H177Y, which has recently been demonstrated to have a functional role in glucose regulation. Fine-mapping analyses revealed that the non-coding variants most likely to drive association signals at established and novel loci were enriched for overlap with enhancer elements, which for FG mapped to promoter and transcription factor binding sites in pancreatic islets, in particular. Our study demonstrates that 1000G imputation and genetic fine-mapping of common and low-frequency variant association signals at GWAS loci, integrated with genomic annotation in relevant tissues, can provide insight into the functional and regulatory mechanisms through which their effects on glycaemic and obesity-related traits are mediated.
Author Summary
Human genetic studies have demonstrated that quantitative human anthropometric and metabolic traits, including body mass index, waist-hip ratio, and plasma concentrations of glucose and insulin, are highly heritable, and are established risk factors for type 2 diabetes and cardiovascular diseases. Although many regions of the genome have been associated with these traits, the specific genes responsible have not yet been identified. By making use of advanced statistical “imputation” techniques applied to more than 87,000 individuals of European ancestry, and publicly available “reference panels” of more than 37 million genetic variants, we have been able to identify novel regions of the genome associated with these glycaemic and obesity-related traits and localise genes within these regions that are most likely to be causal. This improved understanding of the biological mechanisms underlying glycaemic and obesity-related traits is extremely important because it may advance drug development for downstream disease endpoints, ultimately leading to public health benefits.
doi:10.1371/journal.pgen.1005230
PMCID: PMC4488845  PMID: 26132169
7.  Impact of Type 2 Diabetes Susceptibility Variants on Quantitative Glycemic Traits Reveals Mechanistic Heterogeneity 
Diabetes  2014;63(6):2158-2171.
Patients with established type 2 diabetes display both β-cell dysfunction and insulin resistance. To define fundamental processes leading to the diabetic state, we examined the relationship between type 2 diabetes risk variants at 37 established susceptibility loci, and indices of proinsulin processing, insulin secretion, and insulin sensitivity. We included data from up to 58,614 nondiabetic subjects with basal measures and 17,327 with dynamic measures. We used additive genetic models with adjustment for sex, age, and BMI, followed by fixed-effects, inverse-variance meta-analyses. Cluster analyses grouped risk loci into five major categories based on their relationship to these continuous glycemic phenotypes. The first cluster (PPARG, KLF14, IRS1, GCKR) was characterized by primary effects on insulin sensitivity. The second cluster (MTNR1B, GCK) featured risk alleles associated with reduced insulin secretion and fasting hyperglycemia. ARAP1 constituted a third cluster characterized by defects in insulin processing. A fourth cluster (TCF7L2, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without a detectable change in fasting glucose levels. The final group contained 20 risk loci with no clear-cut associations to continuous glycemic traits. By assembling extensive data on continuous glycemic traits, we have exposed the diverse mechanisms whereby type 2 diabetes risk variants impact disease predisposition.
doi:10.2337/db13-0949
PMCID: PMC4030103  PMID: 24296717
8.  Defining the role of common variation in the genomic and biological architecture of adult human height 
Wood, Andrew R | Esko, Tonu | Yang, Jian | Vedantam, Sailaja | Pers, Tune H | Gustafsson, Stefan | Chu, Audrey Y | Estrada, Karol | Luan, Jian’an | Kutalik, Zoltán | Amin, Najaf | Buchkovich, Martin L | Croteau-Chonka, Damien C | Day, Felix R | Duan, Yanan | Fall, Tove | Fehrmann, Rudolf | Ferreira, Teresa | Jackson, Anne U | Karjalainen, Juha | Lo, Ken Sin | Locke, Adam E | Mägi, Reedik | Mihailov, Evelin | Porcu, Eleonora | Randall, Joshua C | Scherag, André | Vinkhuyzen, Anna AE | Westra, Harm-Jan | Winkler, Thomas W | Workalemahu, Tsegaselassie | Zhao, Jing Hua | Absher, Devin | Albrecht, Eva | Anderson, Denise | Baron, Jeffrey | Beekman, Marian | Demirkan, Ayse | Ehret, Georg B | Feenstra, Bjarke | Feitosa, Mary F | Fischer, Krista | Fraser, Ross M | Goel, Anuj | Gong, Jian | Justice, Anne E | Kanoni, Stavroula | Kleber, Marcus E | Kristiansson, Kati | Lim, Unhee | Lotay, Vaneet | Lui, Julian C | Mangino, Massimo | Leach, Irene Mateo | Medina-Gomez, Carolina | Nalls, Michael A | Nyholt, Dale R | Palmer, Cameron D | Pasko, Dorota | Pechlivanis, Sonali | Prokopenko, Inga | Ried, Janina S | Ripke, Stephan | Shungin, Dmitry | Stancáková, Alena | Strawbridge, Rona J | Sung, Yun Ju | Tanaka, Toshiko | Teumer, Alexander | Trompet, Stella | van der Laan, Sander W | van Setten, Jessica | Van Vliet-Ostaptchouk, Jana V | Wang, Zhaoming | Yengo, Loïc | Zhang, Weihua | Afzal, Uzma | Ärnlöv, Johan | Arscott, Gillian M | Bandinelli, Stefania | Barrett, Amy | Bellis, Claire | Bennett, Amanda J | Berne, Christian | Blüher, Matthias | Bolton, Jennifer L | Böttcher, Yvonne | Boyd, Heather A | Bruinenberg, Marcel | Buckley, Brendan M | Buyske, Steven | Caspersen, Ida H | Chines, Peter S | Clarke, Robert | Claudi-Boehm, Simone | Cooper, Matthew | Daw, E Warwick | De Jong, Pim A | Deelen, Joris | Delgado, Graciela | Denny, Josh C | Dhonukshe-Rutten, Rosalie | Dimitriou, Maria | Doney, Alex SF | Dörr, Marcus | Eklund, Niina | Eury, Elodie | Folkersen, Lasse | Garcia, Melissa E | Geller, Frank | Giedraitis, Vilmantas | Go, Alan S | Grallert, Harald | Grammer, Tanja B | Gräßler, Jürgen | Grönberg, Henrik | de Groot, Lisette C.P.G.M. | Groves, Christopher J | Haessler, Jeffrey | Hall, Per | Haller, Toomas | Hallmans, Goran | Hannemann, Anke | Hartman, Catharina A | Hassinen, Maija | Hayward, Caroline | Heard-Costa, Nancy L | Helmer, Quinta | Hemani, Gibran | Henders, Anjali K | Hillege, Hans L | Hlatky, Mark A | Hoffmann, Wolfgang | Hoffmann, Per | Holmen, Oddgeir | Houwing-Duistermaat, Jeanine J | Illig, Thomas | Isaacs, Aaron | James, Alan L | Jeff, Janina | Johansen, Berit | Johansson, Åsa | Jolley, Jennifer | Juliusdottir, Thorhildur | Junttila, Juhani | Kho, Abel N | Kinnunen, Leena | Klopp, Norman | Kocher, Thomas | Kratzer, Wolfgang | Lichtner, Peter | Lind, Lars | Lindström, Jaana | Lobbens, Stéphane | Lorentzon, Mattias | Lu, Yingchang | Lyssenko, Valeriya | Magnusson, Patrik KE | Mahajan, Anubha | Maillard, Marc | McArdle, Wendy L | McKenzie, Colin A | McLachlan, Stela | McLaren, Paul J | Menni, Cristina | Merger, Sigrun | Milani, Lili | Moayyeri, Alireza | Monda, Keri L | Morken, Mario A | Müller, Gabriele | Müller-Nurasyid, Martina | Musk, Arthur W | Narisu, Narisu | Nauck, Matthias | Nolte, Ilja M | Nöthen, Markus M | Oozageer, Laticia | Pilz, Stefan | Rayner, Nigel W | Renstrom, Frida | Robertson, Neil R | Rose, Lynda M | Roussel, Ronan | Sanna, Serena | Scharnagl, Hubert | Scholtens, Salome | Schumacher, Fredrick R | Schunkert, Heribert | Scott, Robert A | Sehmi, Joban | Seufferlein, Thomas | Shi, Jianxin | Silventoinen, Karri | Smit, Johannes H | Smith, Albert Vernon | Smolonska, Joanna | Stanton, Alice V | Stirrups, Kathleen | Stott, David J | Stringham, Heather M | Sundström, Johan | Swertz, Morris A | Syvänen, Ann-Christine | Tayo, Bamidele O | Thorleifsson, Gudmar | Tyrer, Jonathan P | van Dijk, Suzanne | van Schoor, Natasja M | van der Velde, Nathalie | van Heemst, Diana | van Oort, Floor VA | Vermeulen, Sita H | Verweij, Niek | Vonk, Judith M | Waite, Lindsay L | Waldenberger, Melanie | Wennauer, Roman | Wilkens, Lynne R | Willenborg, Christina | Wilsgaard, Tom | Wojczynski, Mary K | Wong, Andrew | Wright, Alan F | Zhang, Qunyuan | Arveiler, Dominique | Bakker, Stephan JL | Beilby, John | Bergman, Richard N | Bergmann, Sven | Biffar, Reiner | Blangero, John | Boomsma, Dorret I | Bornstein, Stefan R | Bovet, Pascal | Brambilla, Paolo | Brown, Morris J | Campbell, Harry | Caulfield, Mark J | Chakravarti, Aravinda | Collins, Rory | Collins, Francis S | Crawford, Dana C | Cupples, L Adrienne | Danesh, John | de Faire, Ulf | den Ruijter, Hester M | Erbel, Raimund | Erdmann, Jeanette | Eriksson, Johan G | Farrall, Martin | Ferrannini, Ele | Ferrières, Jean | Ford, Ian | Forouhi, Nita G | Forrester, Terrence | Gansevoort, Ron T | Gejman, Pablo V | Gieger, Christian | Golay, Alain | Gottesman, Omri | Gudnason, Vilmundur | Gyllensten, Ulf | Haas, David W | Hall, Alistair S | Harris, Tamara B | Hattersley, Andrew T | Heath, Andrew C | Hengstenberg, Christian | Hicks, Andrew A | Hindorff, Lucia A | Hingorani, Aroon D | Hofman, Albert | Hovingh, G Kees | Humphries, Steve E | Hunt, Steven C | Hypponen, Elina | Jacobs, Kevin B | Jarvelin, Marjo-Riitta | Jousilahti, Pekka | Jula, Antti M | Kaprio, Jaakko | Kastelein, John JP | Kayser, Manfred | Kee, Frank | Keinanen-Kiukaanniemi, Sirkka M | Kiemeney, Lambertus A | Kooner, Jaspal S | Kooperberg, Charles | Koskinen, Seppo | Kovacs, Peter | Kraja, Aldi T | Kumari, Meena | Kuusisto, Johanna | Lakka, Timo A | Langenberg, Claudia | Le Marchand, Loic | Lehtimäki, Terho | Lupoli, Sara | Madden, Pamela AF | Männistö, Satu | Manunta, Paolo | Marette, André | Matise, Tara C | McKnight, Barbara | Meitinger, Thomas | Moll, Frans L | Montgomery, Grant W | Morris, Andrew D | Morris, Andrew P | Murray, Jeffrey C | Nelis, Mari | Ohlsson, Claes | Oldehinkel, Albertine J | Ong, Ken K | Ouwehand, Willem H | Pasterkamp, Gerard | Peters, Annette | Pramstaller, Peter P | Price, Jackie F | Qi, Lu | Raitakari, Olli T | Rankinen, Tuomo | Rao, DC | Rice, Treva K | Ritchie, Marylyn | Rudan, Igor | Salomaa, Veikko | Samani, Nilesh J | Saramies, Jouko | Sarzynski, Mark A | Schwarz, Peter EH | Sebert, Sylvain | Sever, Peter | Shuldiner, Alan R | Sinisalo, Juha | Steinthorsdottir, Valgerdur | Stolk, Ronald P | Tardif, Jean-Claude | Tönjes, Anke | Tremblay, Angelo | Tremoli, Elena | Virtamo, Jarmo | Vohl, Marie-Claude | Amouyel, Philippe | Asselbergs, Folkert W | Assimes, Themistocles L | Bochud, Murielle | Boehm, Bernhard O | Boerwinkle, Eric | Bottinger, Erwin P | Bouchard, Claude | Cauchi, Stéphane | Chambers, John C | Chanock, Stephen J | Cooper, Richard S | de Bakker, Paul IW | Dedoussis, George | Ferrucci, Luigi | Franks, Paul W | Froguel, Philippe | Groop, Leif C | Haiman, Christopher A | Hamsten, Anders | Hayes, M Geoffrey | Hui, Jennie | Hunter, David J. | Hveem, Kristian | Jukema, J Wouter | Kaplan, Robert C | Kivimaki, Mika | Kuh, Diana | Laakso, Markku | Liu, Yongmei | Martin, Nicholas G | März, Winfried | Melbye, Mads | Moebus, Susanne | Munroe, Patricia B | Njølstad, Inger | Oostra, Ben A | Palmer, Colin NA | Pedersen, Nancy L | Perola, Markus | Pérusse, Louis | Peters, Ulrike | Powell, Joseph E | Power, Chris | Quertermous, Thomas | Rauramaa, Rainer | Reinmaa, Eva | Ridker, Paul M | Rivadeneira, Fernando | Rotter, Jerome I | Saaristo, Timo E | Saleheen, Danish | Schlessinger, David | Slagboom, P Eline | Snieder, Harold | Spector, Tim D | Strauch, Konstantin | Stumvoll, Michael | Tuomilehto, Jaakko | Uusitupa, Matti | van der Harst, Pim | Völzke, Henry | Walker, Mark | Wareham, Nicholas J | Watkins, Hugh | Wichmann, H-Erich | Wilson, James F | Zanen, Pieter | Deloukas, Panos | Heid, Iris M | Lindgren, Cecilia M | Mohlke, Karen L | Speliotes, Elizabeth K | Thorsteinsdottir, Unnur | Barroso, Inês | Fox, Caroline S | North, Kari E | Strachan, David P | Beckmann, Jacques S. | Berndt, Sonja I | Boehnke, Michael | Borecki, Ingrid B | McCarthy, Mark I | Metspalu, Andres | Stefansson, Kari | Uitterlinden, André G | van Duijn, Cornelia M | Franke, Lude | Willer, Cristen J | Price, Alkes L. | Lettre, Guillaume | Loos, Ruth JF | Weedon, Michael N | Ingelsson, Erik | O’Connell, Jeffrey R | Abecasis, Goncalo R | Chasman, Daniel I | Goddard, Michael E | Visscher, Peter M | Hirschhorn, Joel N | Frayling, Timothy M
Nature genetics  2014;46(11):1173-1186.
Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explain one-fifth of heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ~2,000, ~3,700 and ~9,500 SNPs explained ~21%, ~24% and ~29% of phenotypic variance. Furthermore, all common variants together captured the majority (60%) of heritability. The 697 variants clustered in 423 loci enriched for genes, pathways, and tissue-types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/beta-catenin, and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
doi:10.1038/ng.3097
PMCID: PMC4250049  PMID: 25282103
9.  Defining the role of common variation in the genomic and biological architecture of adult human height 
Wood, Andrew R | Esko, Tonu | Yang, Jian | Vedantam, Sailaja | Pers, Tune H | Gustafsson, Stefan | Chu, Audrey Y | Estrada, Karol | Luan, Jian’an | Kutalik, Zoltán | Amin, Najaf | Buchkovich, Martin L | Croteau-Chonka, Damien C | Day, Felix R | Duan, Yanan | Fall, Tove | Fehrmann, Rudolf | Ferreira, Teresa | Jackson, Anne U | Karjalainen, Juha | Lo, Ken Sin | Locke, Adam E | Mägi, Reedik | Mihailov, Evelin | Porcu, Eleonora | Randall, Joshua C | Scherag, André | Vinkhuyzen, Anna AE | Westra, Harm-Jan | Winkler, Thomas W | Workalemahu, Tsegaselassie | Zhao, Jing Hua | Absher, Devin | Albrecht, Eva | Anderson, Denise | Baron, Jeffrey | Beekman, Marian | Demirkan, Ayse | Ehret, Georg B | Feenstra, Bjarke | Feitosa, Mary F | Fischer, Krista | Fraser, Ross M | Goel, Anuj | Gong, Jian | Justice, Anne E | Kanoni, Stavroula | Kleber, Marcus E | Kristiansson, Kati | Lim, Unhee | Lotay, Vaneet | Lui, Julian C | Mangino, Massimo | Leach, Irene Mateo | Medina-Gomez, Carolina | Nalls, Michael A | Nyholt, Dale R | Palmer, Cameron D | Pasko, Dorota | Pechlivanis, Sonali | Prokopenko, Inga | Ried, Janina S | Ripke, Stephan | Shungin, Dmitry | Stancáková, Alena | Strawbridge, Rona J | Sung, Yun Ju | Tanaka, Toshiko | Teumer, Alexander | Trompet, Stella | van der Laan, Sander W | van Setten, Jessica | Van Vliet-Ostaptchouk, Jana V | Wang, Zhaoming | Yengo, Loïc | Zhang, Weihua | Afzal, Uzma | Ärnlöv, Johan | Arscott, Gillian M | Bandinelli, Stefania | Barrett, Amy | Bellis, Claire | Bennett, Amanda J | Berne, Christian | Blüher, Matthias | Bolton, Jennifer L | Böttcher, Yvonne | Boyd, Heather A | Bruinenberg, Marcel | Buckley, Brendan M | Buyske, Steven | Caspersen, Ida H | Chines, Peter S | Clarke, Robert | Claudi-Boehm, Simone | Cooper, Matthew | Daw, E Warwick | De Jong, Pim A | Deelen, Joris | Delgado, Graciela | Denny, Josh C | Dhonukshe-Rutten, Rosalie | Dimitriou, Maria | Doney, Alex SF | Dörr, Marcus | Eklund, Niina | Eury, Elodie | Folkersen, Lasse | Garcia, Melissa E | Geller, Frank | Giedraitis, Vilmantas | Go, Alan S | Grallert, Harald | Grammer, Tanja B | Gräßler, Jürgen | Grönberg, Henrik | de Groot, Lisette C.P.G.M. | Groves, Christopher J | Haessler, Jeffrey | Hall, Per | Haller, Toomas | Hallmans, Goran | Hannemann, Anke | Hartman, Catharina A | Hassinen, Maija | Hayward, Caroline | Heard-Costa, Nancy L | Helmer, Quinta | Hemani, Gibran | Henders, Anjali K | Hillege, Hans L | Hlatky, Mark A | Hoffmann, Wolfgang | Hoffmann, Per | Holmen, Oddgeir | Houwing-Duistermaat, Jeanine J | Illig, Thomas | Isaacs, Aaron | James, Alan L | Jeff, Janina | Johansen, Berit | Johansson, Åsa | Jolley, Jennifer | Juliusdottir, Thorhildur | Junttila, Juhani | Kho, Abel N | Kinnunen, Leena | Klopp, Norman | Kocher, Thomas | Kratzer, Wolfgang | Lichtner, Peter | Lind, Lars | Lindström, Jaana | Lobbens, Stéphane | Lorentzon, Mattias | Lu, Yingchang | Lyssenko, Valeriya | Magnusson, Patrik KE | Mahajan, Anubha | Maillard, Marc | McArdle, Wendy L | McKenzie, Colin A | McLachlan, Stela | McLaren, Paul J | Menni, Cristina | Merger, Sigrun | Milani, Lili | Moayyeri, Alireza | Monda, Keri L | Morken, Mario A | Müller, Gabriele | Müller-Nurasyid, Martina | Musk, Arthur W | Narisu, Narisu | Nauck, Matthias | Nolte, Ilja M | Nöthen, Markus M | Oozageer, Laticia | Pilz, Stefan | Rayner, Nigel W | Renstrom, Frida | Robertson, Neil R | Rose, Lynda M | Roussel, Ronan | Sanna, Serena | Scharnagl, Hubert | Scholtens, Salome | Schumacher, Fredrick R | Schunkert, Heribert | Scott, Robert A | Sehmi, Joban | Seufferlein, Thomas | Shi, Jianxin | Silventoinen, Karri | Smit, Johannes H | Smith, Albert Vernon | Smolonska, Joanna | Stanton, Alice V | Stirrups, Kathleen | Stott, David J | Stringham, Heather M | Sundström, Johan | Swertz, Morris A | Syvänen, Ann-Christine | Tayo, Bamidele O | Thorleifsson, Gudmar | Tyrer, Jonathan P | van Dijk, Suzanne | van Schoor, Natasja M | van der Velde, Nathalie | van Heemst, Diana | van Oort, Floor VA | Vermeulen, Sita H | Verweij, Niek | Vonk, Judith M | Waite, Lindsay L | Waldenberger, Melanie | Wennauer, Roman | Wilkens, Lynne R | Willenborg, Christina | Wilsgaard, Tom | Wojczynski, Mary K | Wong, Andrew | Wright, Alan F | Zhang, Qunyuan | Arveiler, Dominique | Bakker, Stephan JL | Beilby, John | Bergman, Richard N | Bergmann, Sven | Biffar, Reiner | Blangero, John | Boomsma, Dorret I | Bornstein, Stefan R | Bovet, Pascal | Brambilla, Paolo | Brown, Morris J | Campbell, Harry | Caulfield, Mark J | Chakravarti, Aravinda | Collins, Rory | Collins, Francis S | Crawford, Dana C | Cupples, L Adrienne | Danesh, John | de Faire, Ulf | den Ruijter, Hester M | Erbel, Raimund | Erdmann, Jeanette | Eriksson, Johan G | Farrall, Martin | Ferrannini, Ele | Ferrières, Jean | Ford, Ian | Forouhi, Nita G | Forrester, Terrence | Gansevoort, Ron T | Gejman, Pablo V | Gieger, Christian | Golay, Alain | Gottesman, Omri | Gudnason, Vilmundur | Gyllensten, Ulf | Haas, David W | Hall, Alistair S | Harris, Tamara B | Hattersley, Andrew T | Heath, Andrew C | Hengstenberg, Christian | Hicks, Andrew A | Hindorff, Lucia A | Hingorani, Aroon D | Hofman, Albert | Hovingh, G Kees | Humphries, Steve E | Hunt, Steven C | Hypponen, Elina | Jacobs, Kevin B | Jarvelin, Marjo-Riitta | Jousilahti, Pekka | Jula, Antti M | Kaprio, Jaakko | Kastelein, John JP | Kayser, Manfred | Kee, Frank | Keinanen-Kiukaanniemi, Sirkka M | Kiemeney, Lambertus A | Kooner, Jaspal S | Kooperberg, Charles | Koskinen, Seppo | Kovacs, Peter | Kraja, Aldi T | Kumari, Meena | Kuusisto, Johanna | Lakka, Timo A | Langenberg, Claudia | Le Marchand, Loic | Lehtimäki, Terho | Lupoli, Sara | Madden, Pamela AF | Männistö, Satu | Manunta, Paolo | Marette, André | Matise, Tara C | McKnight, Barbara | Meitinger, Thomas | Moll, Frans L | Montgomery, Grant W | Morris, Andrew D | Morris, Andrew P | Murray, Jeffrey C | Nelis, Mari | Ohlsson, Claes | Oldehinkel, Albertine J | Ong, Ken K | Ouwehand, Willem H | Pasterkamp, Gerard | Peters, Annette | Pramstaller, Peter P | Price, Jackie F | Qi, Lu | Raitakari, Olli T | Rankinen, Tuomo | Rao, DC | Rice, Treva K | Ritchie, Marylyn | Rudan, Igor | Salomaa, Veikko | Samani, Nilesh J | Saramies, Jouko | Sarzynski, Mark A | Schwarz, Peter EH | Sebert, Sylvain | Sever, Peter | Shuldiner, Alan R | Sinisalo, Juha | Steinthorsdottir, Valgerdur | Stolk, Ronald P | Tardif, Jean-Claude | Tönjes, Anke | Tremblay, Angelo | Tremoli, Elena | Virtamo, Jarmo | Vohl, Marie-Claude | Amouyel, Philippe | Asselbergs, Folkert W | Assimes, Themistocles L | Bochud, Murielle | Boehm, Bernhard O | Boerwinkle, Eric | Bottinger, Erwin P | Bouchard, Claude | Cauchi, Stéphane | Chambers, John C | Chanock, Stephen J | Cooper, Richard S | de Bakker, Paul IW | Dedoussis, George | Ferrucci, Luigi | Franks, Paul W | Froguel, Philippe | Groop, Leif C | Haiman, Christopher A | Hamsten, Anders | Hayes, M Geoffrey | Hui, Jennie | Hunter, David J. | Hveem, Kristian | Jukema, J Wouter | Kaplan, Robert C | Kivimaki, Mika | Kuh, Diana | Laakso, Markku | Liu, Yongmei | Martin, Nicholas G | März, Winfried | Melbye, Mads | Moebus, Susanne | Munroe, Patricia B | Njølstad, Inger | Oostra, Ben A | Palmer, Colin NA | Pedersen, Nancy L | Perola, Markus | Pérusse, Louis | Peters, Ulrike | Powell, Joseph E | Power, Chris | Quertermous, Thomas | Rauramaa, Rainer | Reinmaa, Eva | Ridker, Paul M | Rivadeneira, Fernando | Rotter, Jerome I | Saaristo, Timo E | Saleheen, Danish | Schlessinger, David | Slagboom, P Eline | Snieder, Harold | Spector, Tim D | Strauch, Konstantin | Stumvoll, Michael | Tuomilehto, Jaakko | Uusitupa, Matti | van der Harst, Pim | Völzke, Henry | Walker, Mark | Wareham, Nicholas J | Watkins, Hugh | Wichmann, H-Erich | Wilson, James F | Zanen, Pieter | Deloukas, Panos | Heid, Iris M | Lindgren, Cecilia M | Mohlke, Karen L | Speliotes, Elizabeth K | Thorsteinsdottir, Unnur | Barroso, Inês | Fox, Caroline S | North, Kari E | Strachan, David P | Beckmann, Jacques S. | Berndt, Sonja I | Boehnke, Michael | Borecki, Ingrid B | McCarthy, Mark I | Metspalu, Andres | Stefansson, Kari | Uitterlinden, André G | van Duijn, Cornelia M | Franke, Lude | Willer, Cristen J | Price, Alkes L. | Lettre, Guillaume | Loos, Ruth JF | Weedon, Michael N | Ingelsson, Erik | O’Connell, Jeffrey R | Abecasis, Goncalo R | Chasman, Daniel I | Goddard, Michael E | Visscher, Peter M | Hirschhorn, Joel N | Frayling, Timothy M
Nature genetics  2014;46(11):1173-1186.
Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explain one-fifth of heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ~2,000, ~3,700 and ~9,500 SNPs explained ~21%, ~24% and ~29% of phenotypic variance. Furthermore, all common variants together captured the majority (60%) of heritability. The 697 variants clustered in 423 loci enriched for genes, pathways, and tissue-types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/beta-catenin, and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
doi:10.1038/ng.3097
PMCID: PMC4250049  PMID: 25282103
10.  Genetic studies of body mass index yield new insights for obesity biology 
Locke, Adam E. | Kahali, Bratati | Berndt, Sonja I. | Justice, Anne E. | Pers, Tune H. | Day, Felix R. | Powell, Corey | Vedantam, Sailaja | Buchkovich, Martin L. | Yang, Jian | Croteau-Chonka, Damien C. | Esko, Tonu | Fall, Tove | Ferreira, Teresa | Gustafsson, Stefan | Kutalik, Zoltán | Luan, Jian’an | Mägi, Reedik | Randall, Joshua C. | Winkler, Thomas W. | Wood, Andrew R. | Workalemahu, Tsegaselassie | Faul, Jessica D. | Smith, Jennifer A. | Zhao, Jing Hua | Zhao, Wei | Chen, Jin | Fehrmann, Rudolf | Hedman, Åsa K. | Karjalainen, Juha | Schmidt, Ellen M. | Absher, Devin | Amin, Najaf | Anderson, Denise | Beekman, Marian | Bolton, Jennifer L. | Bragg-Gresham, Jennifer L. | Buyske, Steven | Demirkan, Ayse | Deng, Guohong | Ehret, Georg B. | Feenstra, Bjarke | Feitosa, Mary F. | Fischer, Krista | Goel, Anuj | Gong, Jian | Jackson, Anne U. | Kanoni, Stavroula | Kleber, Marcus E. | Kristiansson, Kati | Lim, Unhee | Lotay, Vaneet | Mangino, Massimo | Leach, Irene Mateo | Medina-Gomez, Carolina | Medland, Sarah E. | Nalls, Michael A. | Palmer, Cameron D. | Pasko, Dorota | Pechlivanis, Sonali | Peters, Marjolein J. | Prokopenko, Inga | Shungin, Dmitry | Stančáková, Alena | Strawbridge, Rona J. | Sung, Yun Ju | Tanaka, Toshiko | Teumer, Alexander | Trompet, Stella | van der Laan, Sander W. | van Setten, Jessica | Van Vliet-Ostaptchouk, Jana V. | Wang, Zhaoming | Yengo, Loïc | Zhang, Weihua | Isaacs, Aaron | Albrecht, Eva | Ärnlöv, Johan | Arscott, Gillian M. | Attwood, Antony P. | Bandinelli, Stefania | Barrett, Amy | Bas, Isabelita N. | Bellis, Claire | Bennett, Amanda J. | Berne, Christian | Blagieva, Roza | Blüher, Matthias | Böhringer, Stefan | Bonnycastle, Lori L. | Böttcher, Yvonne | Boyd, Heather A. | Bruinenberg, Marcel | Caspersen, Ida H. | Chen, Yii-Der Ida | Clarke, Robert | Daw, E. Warwick | de Craen, Anton J. M. | Delgado, Graciela | Dimitriou, Maria | Doney, Alex S. F. | Eklund, Niina | Estrada, Karol | Eury, Elodie | Folkersen, Lasse | Fraser, Ross M. | Garcia, Melissa E. | Geller, Frank | Giedraitis, Vilmantas | Gigante, Bruna | Go, Alan S. | Golay, Alain | Goodall, Alison H. | Gordon, Scott D. | Gorski, Mathias | Grabe, Hans-Jörgen | Grallert, Harald | Grammer, Tanja B. | Gräßler, Jürgen | Grönberg, Henrik | Groves, Christopher J. | Gusto, Gaëlle | Haessler, Jeffrey | Hall, Per | Haller, Toomas | Hallmans, Goran | Hartman, Catharina A. | Hassinen, Maija | Hayward, Caroline | Heard-Costa, Nancy L. | Helmer, Quinta | Hengstenberg, Christian | Holmen, Oddgeir | Hottenga, Jouke-Jan | James, Alan L. | Jeff, Janina M. | Johansson, Åsa | Jolley, Jennifer | Juliusdottir, Thorhildur | Kinnunen, Leena | Koenig, Wolfgang | Koskenvuo, Markku | Kratzer, Wolfgang | Laitinen, Jaana | Lamina, Claudia | Leander, Karin | Lee, Nanette R. | Lichtner, Peter | Lind, Lars | Lindström, Jaana | Lo, Ken Sin | Lobbens, Stéphane | Lorbeer, Roberto | Lu, Yingchang | Mach, François | Magnusson, Patrik K. E. | Mahajan, Anubha | McArdle, Wendy L. | McLachlan, Stela | Menni, Cristina | Merger, Sigrun | Mihailov, Evelin | Milani, Lili | Moayyeri, Alireza | Monda, Keri L. | Morken, Mario A. | Mulas, Antonella | Müller, Gabriele | Müller-Nurasyid, Martina | Musk, Arthur W. | Nagaraja, Ramaiah | Nöthen, Markus M. | Nolte, Ilja M. | Pilz, Stefan | Rayner, Nigel W. | Renstrom, Frida | Rettig, Rainer | Ried, Janina S. | Ripke, Stephan | Robertson, Neil R. | Rose, Lynda M. | Sanna, Serena | Scharnagl, Hubert | Scholtens, Salome | Schumacher, Fredrick R. | Scott, William R. | Seufferlein, Thomas | Shi, Jianxin | Smith, Albert Vernon | Smolonska, Joanna | Stanton, Alice V. | Steinthorsdottir, Valgerdur | Stirrups, Kathleen | Stringham, Heather M. | Sundström, Johan | Swertz, Morris A. | Swift, Amy J. | Syvänen, Ann-Christine | Tan, Sian-Tsung | Tayo, Bamidele O. | Thorand, Barbara | Thorleifsson, Gudmar | Tyrer, Jonathan P. | Uh, Hae-Won | Vandenput, Liesbeth | Verhulst, Frank C. | Vermeulen, Sita H. | Verweij, Niek | Vonk, Judith M. | Waite, Lindsay L. | Warren, Helen R. | Waterworth, Dawn | Weedon, Michael N. | Wilkens, Lynne R. | Willenborg, Christina | Wilsgaard, Tom | Wojczynski, Mary K. | Wong, Andrew | Wright, Alan F. | Zhang, Qunyuan | Brennan, Eoin P. | Choi, Murim | Dastani, Zari | Drong, Alexander W. | Eriksson, Per | Franco-Cereceda, Anders | Gådin, Jesper R. | Gharavi, Ali G. | Goddard, Michael E. | Handsaker, Robert E. | Huang, Jinyan | Karpe, Fredrik | Kathiresan, Sekar | Keildson, Sarah | Kiryluk, Krzysztof | Kubo, Michiaki | Lee, Jong-Young | Liang, Liming | Lifton, Richard P. | Ma, Baoshan | McCarroll, Steven A. | McKnight, Amy J. | Min, Josine L. | Moffatt, Miriam F. | Montgomery, Grant W. | Murabito, Joanne M. | Nicholson, George | Nyholt, Dale R. | Okada, Yukinori | Perry, John R. B. | Dorajoo, Rajkumar | Reinmaa, Eva | Salem, Rany M. | Sandholm, Niina | Scott, Robert A. | Stolk, Lisette | Takahashi, Atsushi | Tanaka, Toshihiro | van ’t Hooft, Ferdinand M. | Vinkhuyzen, Anna A. E. | Westra, Harm-Jan | Zheng, Wei | Zondervan, Krina T. | Heath, Andrew C. | Arveiler, Dominique | Bakker, Stephan J. L. | Beilby, John | Bergman, Richard N. | Blangero, John | Bovet, Pascal | Campbell, Harry | Caulfield, Mark J. | Cesana, Giancarlo | Chakravarti, Aravinda | Chasman, Daniel I. | Chines, Peter S. | Collins, Francis S. | Crawford, Dana C. | Cupples, L. Adrienne | Cusi, Daniele | Danesh, John | de Faire, Ulf | den Ruijter, Hester M. | Dominiczak, Anna F. | Erbel, Raimund | Erdmann, Jeanette | Eriksson, Johan G. | Farrall, Martin | Felix, Stephan B. | Ferrannini, Ele | Ferrières, Jean | Ford, Ian | Forouhi, Nita G. | Forrester, Terrence | Franco, Oscar H. | Gansevoort, Ron T. | Gejman, Pablo V. | Gieger, Christian | Gottesman, Omri | Gudnason, Vilmundur | Gyllensten, Ulf | Hall, Alistair S. | Harris, Tamara B. | Hattersley, Andrew T. | Hicks, Andrew A. | Hindorff, Lucia A. | Hingorani, Aroon D. | Hofman, Albert | Homuth, Georg | Hovingh, G. Kees | Humphries, Steve E. | Hunt, Steven C. | Hyppönen, Elina | Illig, Thomas | Jacobs, Kevin B. | Jarvelin, Marjo-Riitta | Jöckel, Karl-Heinz | Johansen, Berit | Jousilahti, Pekka | Jukema, J. Wouter | Jula, Antti M. | Kaprio, Jaakko | Kastelein, John J. P. | Keinanen-Kiukaanniemi, Sirkka M. | Kiemeney, Lambertus A. | Knekt, Paul | Kooner, Jaspal S. | Kooperberg, Charles | Kovacs, Peter | Kraja, Aldi T. | Kumari, Meena | Kuusisto, Johanna | Lakka, Timo A. | Langenberg, Claudia | Marchand, Loic Le | Lehtimäki, Terho | Lyssenko, Valeriya | Männistö, Satu | Marette, André | Matise, Tara C. | McKenzie, Colin A. | McKnight, Barbara | Moll, Frans L. | Morris, Andrew D. | Morris, Andrew P. | Murray, Jeffrey C. | Nelis, Mari | Ohlsson, Claes | Oldehinkel, Albertine J. | Ong, Ken K. | Madden, Pamela A. F. | Pasterkamp, Gerard | Peden, John F. | Peters, Annette | Postma, Dirkje S. | Pramstaller, Peter P. | Price, Jackie F. | Qi, Lu | Raitakari, Olli T. | Rankinen, Tuomo | Rao, D. C. | Rice, Treva K. | Ridker, Paul M. | Rioux, John D. | Ritchie, Marylyn D. | Rudan, Igor | Salomaa, Veikko | Samani, Nilesh J. | Saramies, Jouko | Sarzynski, Mark A. | Schunkert, Heribert | Schwarz, Peter E. H. | Sever, Peter | Shuldiner, Alan R. | Sinisalo, Juha | Stolk, Ronald P. | Strauch, Konstantin | Tönjes, Anke | Trégouët, David-Alexandre | Tremblay, Angelo | Tremoli, Elena | Virtamo, Jarmo | Vohl, Marie-Claude | Völker, Uwe | Waeber, Gérard | Willemsen, Gonneke | Witteman, Jacqueline C. | Zillikens, M. Carola | Adair, Linda S. | Amouyel, Philippe | Asselbergs, Folkert W. | Assimes, Themistocles L. | Bochud, Murielle | Boehm, Bernhard O. | Boerwinkle, Eric | Bornstein, Stefan R. | Bottinger, Erwin P. | Bouchard, Claude | Cauchi, Stéphane | Chambers, John C. | Chanock, Stephen J. | Cooper, Richard S. | de Bakker, Paul I. W. | Dedoussis, George | Ferrucci, Luigi | Franks, Paul W. | Froguel, Philippe | Groop, Leif C. | Haiman, Christopher A. | Hamsten, Anders | Hui, Jennie | Hunter, David J. | Hveem, Kristian | Kaplan, Robert C. | Kivimaki, Mika | Kuh, Diana | Laakso, Markku | Liu, Yongmei | Martin, Nicholas G. | März, Winfried | Melbye, Mads | Metspalu, Andres | Moebus, Susanne | Munroe, Patricia B. | Njølstad, Inger | Oostra, Ben A. | Palmer, Colin N. A. | Pedersen, Nancy L. | Perola, Markus | Pérusse, Louis | Peters, Ulrike | Power, Chris | Quertermous, Thomas | Rauramaa, Rainer | Rivadeneira, Fernando | Saaristo, Timo E. | Saleheen, Danish | Sattar, Naveed | Schadt, Eric E. | Schlessinger, David | Slagboom, P. Eline | Snieder, Harold | Spector, Tim D. | Thorsteinsdottir, Unnur | Stumvoll, Michael | Tuomilehto, Jaakko | Uitterlinden, André G. | Uusitupa, Matti | van der Harst, Pim | Walker, Mark | Wallaschofski, Henri | Wareham, Nicholas J. | Watkins, Hugh | Weir, David R. | Wichmann, H-Erich | Wilson, James F. | Zanen, Pieter | Borecki, Ingrid B. | Deloukas, Panos | Fox, Caroline S. | Heid, Iris M. | O’Connell, Jeffrey R. | Strachan, David P. | Stefansson, Kari | van Duijn, Cornelia M. | Abecasis, Gonçalo R. | Franke, Lude | Frayling, Timothy M. | McCarthy, Mark I. | Visscher, Peter M. | Scherag, André | Willer, Cristen J. | Boehnke, Michael | Mohlke, Karen L. | Lindgren, Cecilia M. | Beckmann, Jacques S. | Barroso, Inês | North, Kari E. | Ingelsson, Erik | Hirschhorn, Joel N. | Loos, Ruth J. F. | Speliotes, Elizabeth K.
Nature  2015;518(7538):197-206.
Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10−8), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ~2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
doi:10.1038/nature14177
PMCID: PMC4382211  PMID: 25673413
11.  Expression of Phosphofructokinase in Skeletal Muscle Is Influenced by Genetic Variation and Associated With Insulin Sensitivity 
Diabetes  2014;63(3):1154-1165.
Using an integrative approach in which genetic variation, gene expression, and clinical phenotypes are assessed in relevant tissues may help functionally characterize the contribution of genetics to disease susceptibility. We sought to identify genetic variation influencing skeletal muscle gene expression (expression quantitative trait loci [eQTLs]) as well as expression associated with measures of insulin sensitivity. We investigated associations of 3,799,401 genetic variants in expression of >7,000 genes from three cohorts (n = 104). We identified 287 genes with cis-acting eQTLs (false discovery rate [FDR] <5%; P < 1.96 × 10−5) and 49 expression–insulin sensitivity phenotype associations (i.e., fasting insulin, homeostasis model assessment–insulin resistance, and BMI) (FDR <5%; P = 1.34 × 10−4). One of these associations, fasting insulin/phosphofructokinase (PFKM), overlaps with an eQTL. Furthermore, the expression of PFKM, a rate-limiting enzyme in glycolysis, was nominally associated with glucose uptake in skeletal muscle (P = 0.026; n = 42) and overexpressed (Bonferroni-corrected P = 0.03) in skeletal muscle of patients with T2D (n = 102) compared with normoglycemic controls (n = 87). The PFKM eQTL (rs4547172; P = 7.69 × 10−6) was nominally associated with glucose uptake, glucose oxidation rate, intramuscular triglyceride content, and metabolic flexibility (P = 0.016–0.048; n = 178). We explored eQTL results using published data from genome-wide association studies (DIAGRAM and MAGIC), and a proxy for the PFKM eQTL (rs11168327; r2 = 0.75) was nominally associated with T2D (DIAGRAM P = 2.7 × 10−3). Taken together, our analysis highlights PFKM as a potential regulator of skeletal muscle insulin sensitivity.
doi:10.2337/db13-1301
PMCID: PMC3931395  PMID: 24306210
12.  Identification and Functional Characterization of G6PC2 Coding Variants Influencing Glycemic Traits Define an Effector Transcript at the G6PC2-ABCB11 Locus 
Mahajan, Anubha | Sim, Xueling | Ng, Hui Jin | Manning, Alisa | Rivas, Manuel A. | Highland, Heather M. | Locke, Adam E. | Grarup, Niels | Im, Hae Kyung | Cingolani, Pablo | Flannick, Jason | Fontanillas, Pierre | Fuchsberger, Christian | Gaulton, Kyle J. | Teslovich, Tanya M. | Rayner, N. William | Robertson, Neil R. | Beer, Nicola L. | Rundle, Jana K. | Bork-Jensen, Jette | Ladenvall, Claes | Blancher, Christine | Buck, David | Buck, Gemma | Burtt, Noël P. | Gabriel, Stacey | Gjesing, Anette P. | Groves, Christopher J. | Hollensted, Mette | Huyghe, Jeroen R. | Jackson, Anne U. | Jun, Goo | Justesen, Johanne Marie | Mangino, Massimo | Murphy, Jacquelyn | Neville, Matt | Onofrio, Robert | Small, Kerrin S. | Stringham, Heather M. | Syvänen, Ann-Christine | Trakalo, Joseph | Abecasis, Goncalo | Bell, Graeme I. | Blangero, John | Cox, Nancy J. | Duggirala, Ravindranath | Hanis, Craig L. | Seielstad, Mark | Wilson, James G. | Christensen, Cramer | Brandslund, Ivan | Rauramaa, Rainer | Surdulescu, Gabriela L. | Doney, Alex S. F. | Lannfelt, Lars | Linneberg, Allan | Isomaa, Bo | Tuomi, Tiinamaija | Jørgensen, Marit E. | Jørgensen, Torben | Kuusisto, Johanna | Uusitupa, Matti | Salomaa, Veikko | Spector, Timothy D. | Morris, Andrew D. | Palmer, Colin N. A. | Collins, Francis S. | Mohlke, Karen L. | Bergman, Richard N. | Ingelsson, Erik | Lind, Lars | Tuomilehto, Jaakko | Hansen, Torben | Watanabe, Richard M. | Prokopenko, Inga | Dupuis, Josee | Karpe, Fredrik | Groop, Leif | Laakso, Markku | Pedersen, Oluf | Florez, Jose C. | Morris, Andrew P. | Altshuler, David | Meigs, James B. | Boehnke, Michael | McCarthy, Mark I. | Lindgren, Cecilia M. | Gloyn, Anna L.
PLoS Genetics  2015;11(1):e1004876.
Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P<5×10-7) evidence for two loci not previously highlighted by common variant GWAS: GLP1R (p.Ala316Thr, minor allele frequency (MAF)=1.5%) influencing FG levels, and URB2 (p.Glu594Val, MAF = 0.1%) influencing FI levels. Coding variant associations can highlight potential effector genes at (non-coding) GWAS signals. At the G6PC2/ABCB11 locus, we identified multiple coding variants in G6PC2 (p.Val219Leu, p.His177Tyr, and p.Tyr207Ser) influencing FG levels, conditionally independent of each other and the non-coding GWAS signal. In vitro assays demonstrate that these associated coding alleles result in reduced protein abundance via proteasomal degradation, establishing G6PC2 as an effector gene at this locus. Reconciliation of single-variant associations and functional effects was only possible when haplotype phase was considered. In contrast to earlier reports suggesting that, paradoxically, glucose-raising alleles at this locus are protective against type 2 diabetes (T2D), the p.Val219Leu G6PC2 variant displayed a modest but directionally consistent association with T2D risk. Coding variant associations for glycemic traits in GWAS signals highlight PCSK1, RREB1, and ZHX3 as likely effector transcripts. These coding variant association signals do not have a major impact on the trait variance explained, but they do provide valuable biological insights.
Author Summary
Understanding how FI and FG levels are regulated is important because their derangement is a feature of T2D. Despite recent success from GWAS in identifying regions of the genome influencing glycemic traits, collectively these loci explain only a small proportion of trait variance. Unlocking the biological mechanisms driving these associations has been challenging because the vast majority of variants map to non-coding sequence, and the genes through which they exert their impact are largely unknown. In the current study, we sought to increase our understanding of the physiological pathways influencing both traits using exome-array genotyping in up to 33,231 non-diabetic individuals to identify coding variants and consequently genes associated with either FG or FI levels. We identified novel association signals for both traits including the receptor for GLP-1 agonists which are a widely used therapy for T2D. Furthermore, we identified coding variants at several GWAS loci which point to the genes underlying these association signals. Importantly, we found that multiple coding variants in G6PC2 result in a loss of protein function and lower fasting glucose levels.
doi:10.1371/journal.pgen.1004876
PMCID: PMC4307976  PMID: 25625282
13.  Genome Wide Meta-analysis Highlights the Role of Genetic Variation in RARRES2 in the Regulation of Circulating Serum Chemerin 
PLoS Genetics  2014;10(12):e1004854.
Chemerin is an adipokine proposed to link obesity and chronic inflammation of adipose tissue. Genetic factors determining chemerin release from adipose tissue are yet unknown. We conducted a meta-analysis of genome-wide association studies (GWAS) for serum chemerin in three independent cohorts from Europe: Sorbs and KORA from Germany and PPP-Botnia from Finland (total N = 2,791). In addition, we measured mRNA expression of genes within the associated loci in peripheral mononuclear cells by micro-arrays, and within adipose tissue by quantitative RT-PCR and performed mRNA expression quantitative trait and expression-chemerin association studies to functionally substantiate our loci. Heritability estimate of circulating chemerin levels was 16.2% in the Sorbs cohort. Thirty single nucleotide polymorphisms (SNPs) at chromosome 7 within the retinoic acid receptor responder 2 (RARRES2)/Leucine Rich Repeat Containing (LRRC61) locus reached genome-wide significance (p<5.0×10−8) in the meta-analysis (the strongest evidence for association at rs7806429 with p = 7.8×10−14, beta = −0.067, explained variance 2.0%). All other SNPs within the cluster were in linkage disequilibrium with rs7806429 (minimum r2 = 0.43 in the Sorbs cohort). The results of the subgroup analyses of males and females were consistent with the results found in the total cohort. No significant SNP-sex interaction was observed. rs7806429 was associated with mRNA expression of RARRES2 in visceral adipose tissue in women (p<0.05 after adjusting for age and body mass index). In conclusion, the present meta-GWAS combined with mRNA expression studies highlights the role of genetic variation in the RARRES2 locus in the regulation of circulating chemerin concentrations.
Author Summary
Chemerin is an adipokine proposed to link obesity and chronic inflammation of adipose tissue. In the present study we show that circulating chemerin is a heritable trait. In a meta-analysis of genome-wide association studies (GWAS) of 2,791 individuals from Germany and Finland, we identified common genetic variants which associate with serum chemerin levels. The variants map within the retinoic acid receptor responder 2 (RARRES2)/Leucine Rich Repeat Containing (LRRC61) at chromosome 7. To better understand the potential functionality of the identified variants, we also provide insights into the mRNA expression of RARRES2 (encoding chemerin) in blood and adipose tissue. Our results highlight the role and function of genetic variation in the RARRES2 locus in the regulation of circulating chemerin concentrations.
doi:10.1371/journal.pgen.1004854
PMCID: PMC4270463  PMID: 25521368
14.  Genome-wide association and longitudinal analyses reveal genetic loci linking pubertal height growth, pubertal timing and childhood adiposity 
Human Molecular Genetics  2013;22(13):2735-2747.
The pubertal height growth spurt is a distinctive feature of childhood growth reflecting both the central onset of puberty and local growth factors. Although little is known about the underlying genetics, growth variability during puberty correlates with adult risks for hormone-dependent cancer and adverse cardiometabolic health. The only gene so far associated with pubertal height growth, LIN28B, pleiotropically influences childhood growth, puberty and cancer progression, pointing to shared underlying mechanisms. To discover genetic loci influencing pubertal height and growth and to place them in context of overall growth and maturation, we performed genome-wide association meta-analyses in 18 737 European samples utilizing longitudinally collected height measurements. We found significant associations (P < 1.67 × 10−8) at 10 loci, including LIN28B. Five loci associated with pubertal timing, all impacting multiple aspects of growth. In particular, a novel variant correlated with expression of MAPK3, and associated both with increased prepubertal growth and earlier menarche. Another variant near ADCY3-POMC associated with increased body mass index, reduced pubertal growth and earlier puberty. Whereas epidemiological correlations suggest that early puberty marks a pathway from rapid prepubertal growth to reduced final height and adult obesity, our study shows that individual loci associating with pubertal growth have variable longitudinal growth patterns that may differ from epidemiological observations. Overall, this study uncovers part of the complex genetic architecture linking pubertal height growth, the timing of puberty and childhood obesity and provides new information to pinpoint processes linking these traits.
doi:10.1093/hmg/ddt104
PMCID: PMC3674797  PMID: 23449627
15.  Identification of seven loci affecting mean telomere length and their association with disease 
Codd, Veryan | Nelson, Christopher P. | Albrecht, Eva | Mangino, Massimo | Deelen, Joris | Buxton, Jessica L. | Jan Hottenga, Jouke | Fischer, Krista | Esko, Tõnu | Surakka, Ida | Broer, Linda | Nyholt, Dale R. | Mateo Leach, Irene | Salo, Perttu | Hägg, Sara | Matthews, Mary K. | Palmen, Jutta | Norata, Giuseppe D. | O’Reilly, Paul F. | Saleheen, Danish | Amin, Najaf | Balmforth, Anthony J. | Beekman, Marian | de Boer, Rudolf A. | Böhringer, Stefan | Braund, Peter S. | Burton, Paul R. | de Craen, Anton J. M. | Denniff, Matthew | Dong, Yanbin | Douroudis, Konstantinos | Dubinina, Elena | Eriksson, Johan G. | Garlaschelli, Katia | Guo, Dehuang | Hartikainen, Anna-Liisa | Henders, Anjali K. | Houwing-Duistermaat, Jeanine J. | Kananen, Laura | Karssen, Lennart C. | Kettunen, Johannes | Klopp, Norman | Lagou, Vasiliki | van Leeuwen, Elisabeth M. | Madden, Pamela A. | Mägi, Reedik | Magnusson, Patrik K.E. | Männistö, Satu | McCarthy, Mark I. | Medland, Sarah E. | Mihailov, Evelin | Montgomery, Grant W. | Oostra, Ben A. | Palotie, Aarno | Peters, Annette | Pollard, Helen | Pouta, Anneli | Prokopenko, Inga | Ripatti, Samuli | Salomaa, Veikko | Suchiman, H. Eka D. | Valdes, Ana M. | Verweij, Niek | Viñuela, Ana | Wang, Xiaoling | Wichmann, H.-Erich | Widen, Elisabeth | Willemsen, Gonneke | Wright, Margaret J. | Xia, Kai | Xiao, Xiangjun | van Veldhuisen, Dirk J. | Catapano, Alberico L. | Tobin, Martin D. | Hall, Alistair S. | Blakemore, Alexandra I.F. | van Gilst, Wiek H. | Zhu, Haidong | Erdmann, Jeanette | Reilly, Muredach P. | Kathiresan, Sekar | Schunkert, Heribert | Talmud, Philippa J. | Pedersen, Nancy L. | Perola, Markus | Ouwehand, Willem | Kaprio, Jaakko | Martin, Nicholas G. | van Duijn, Cornelia M. | Hovatta, Iiris | Gieger, Christian | Metspalu, Andres | Boomsma, Dorret I. | Jarvelin, Marjo-Riitta | Slagboom, P. Eline | Thompson, John R. | Spector, Tim D. | van der Harst, Pim | Samani, Nilesh J.
Nature genetics  2013;45(4):422-427e2.
Inter-individual variation in mean leukocyte telomere length (LTL) is associated with cancer and several age-associated diseases. Here, in a genome-wide meta-analysis of 37,684 individuals with replication of selected variants in a further 10,739 individuals, we identified seven loci, including five novel loci, associated with mean LTL (P<5x10−8). Five of the loci contain genes (TERC, TERT, NAF1, OBFC1, RTEL1) that are known to be involved in telomere biology. Lead SNPs at two loci (TERC and TERT) associate with several cancers and other diseases, including idiopathic pulmonary fibrosis. Moreover, a genetic risk score analysis combining lead variants at all seven loci in 22,233 coronary artery disease cases and 64,762 controls showed an association of the alleles associated with shorter LTL with increased risk of CAD (21% (95% CI: 5–35%) per standard deviation in LTL, p=0.014). Our findings support a causal role of telomere length variation in some age-related diseases.
doi:10.1038/ng.2528
PMCID: PMC4006270  PMID: 23535734
16.  A Central Role for GRB10 in Regulation of Islet Function in Man 
PLoS Genetics  2014;10(4):e1004235.
Variants in the growth factor receptor-bound protein 10 (GRB10) gene were in a GWAS meta-analysis associated with reduced glucose-stimulated insulin secretion and increased risk of type 2 diabetes (T2D) if inherited from the father, but inexplicably reduced fasting glucose when inherited from the mother. GRB10 is a negative regulator of insulin signaling and imprinted in a parent-of-origin fashion in different tissues. GRB10 knock-down in human pancreatic islets showed reduced insulin and glucagon secretion, which together with changes in insulin sensitivity may explain the paradoxical reduction of glucose despite a decrease in insulin secretion. Together, these findings suggest that tissue-specific methylation and possibly imprinting of GRB10 can influence glucose metabolism and contribute to T2D pathogenesis. The data also emphasize the need in genetic studies to consider whether risk alleles are inherited from the mother or the father.
Author Summary
In this paper, we report the first large genome-wide association study in man for glucose-stimulated insulin secretion (GSIS) indices during an oral glucose tolerance test. We identify seven genetic loci and provide effects on GSIS for all previously reported glycemic traits and obesity genetic loci in a large-scale sample. We observe paradoxical effects of genetic variants in the growth factor receptor-bound protein 10 (GRB10) gene yielding both reduced GSIS and reduced fasting plasma glucose concentrations, specifically showing a parent-of-origin effect of GRB10 on lower fasting plasma glucose and enhanced insulin sensitivity for maternal and elevated glucose and decreased insulin sensitivity for paternal transmissions of the risk allele. We also observe tissue-specific differences in DNA methylation and allelic imbalance in expression of GRB10 in human pancreatic islets. We further disrupt GRB10 by shRNA in human islets, showing reduction of both insulin and glucagon expression and secretion. In conclusion, we provide evidence for complex regulation of GRB10 in human islets. Our data suggest that tissue-specific methylation and imprinting of GRB10 can influence glucose metabolism and contribute to T2D pathogenesis. The data also emphasize the need in genetic studies to consider whether risk alleles are inherited from the mother or the father.
doi:10.1371/journal.pgen.1004235
PMCID: PMC3974640  PMID: 24699409
17.  Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture 
Berndt, Sonja I. | Gustafsson, Stefan | Mägi, Reedik | Ganna, Andrea | Wheeler, Eleanor | Feitosa, Mary F. | Justice, Anne E. | Monda, Keri L. | Croteau-Chonka, Damien C. | Day, Felix R. | Esko, Tõnu | Fall, Tove | Ferreira, Teresa | Gentilini, Davide | Jackson, Anne U. | Luan, Jian’an | Randall, Joshua C. | Vedantam, Sailaja | Willer, Cristen J. | Winkler, Thomas W. | Wood, Andrew R. | Workalemahu, Tsegaselassie | Hu, Yi-Juan | Lee, Sang Hong | Liang, Liming | Lin, Dan-Yu | Min, Josine L. | Neale, Benjamin M. | Thorleifsson, Gudmar | Yang, Jian | Albrecht, Eva | Amin, Najaf | Bragg-Gresham, Jennifer L. | Cadby, Gemma | den Heijer, Martin | Eklund, Niina | Fischer, Krista | Goel, Anuj | Hottenga, Jouke-Jan | Huffman, Jennifer E. | Jarick, Ivonne | Johansson, Åsa | Johnson, Toby | Kanoni, Stavroula | Kleber, Marcus E. | König, Inke R. | Kristiansson, Kati | Kutalik, Zoltán | Lamina, Claudia | Lecoeur, Cecile | Li, Guo | Mangino, Massimo | McArdle, Wendy L. | Medina-Gomez, Carolina | Müller-Nurasyid, Martina | Ngwa, Julius S. | Nolte, Ilja M. | Paternoster, Lavinia | Pechlivanis, Sonali | Perola, Markus | Peters, Marjolein J. | Preuss, Michael | Rose, Lynda M. | Shi, Jianxin | Shungin, Dmitry | Smith, Albert Vernon | Strawbridge, Rona J. | Surakka, Ida | Teumer, Alexander | Trip, Mieke D. | Tyrer, Jonathan | Van Vliet-Ostaptchouk, Jana V. | Vandenput, Liesbeth | Waite, Lindsay L. | Zhao, Jing Hua | Absher, Devin | Asselbergs, Folkert W. | Atalay, Mustafa | Attwood, Antony P. | Balmforth, Anthony J. | Basart, Hanneke | Beilby, John | Bonnycastle, Lori L. | Brambilla, Paolo | Bruinenberg, Marcel | Campbell, Harry | Chasman, Daniel I. | Chines, Peter S. | Collins, Francis S. | Connell, John M. | Cookson, William | de Faire, Ulf | de Vegt, Femmie | Dei, Mariano | Dimitriou, Maria | Edkins, Sarah | Estrada, Karol | Evans, David M. | Farrall, Martin | Ferrario, Marco M. | Ferrières, Jean | Franke, Lude | Frau, Francesca | Gejman, Pablo V. | Grallert, Harald | Grönberg, Henrik | Gudnason, Vilmundur | Hall, Alistair S. | Hall, Per | Hartikainen, Anna-Liisa | Hayward, Caroline | Heard-Costa, Nancy L. | Heath, Andrew C. | Hebebrand, Johannes | Homuth, Georg | Hu, Frank B. | Hunt, Sarah E. | Hyppönen, Elina | Iribarren, Carlos | Jacobs, Kevin B. | Jansson, John-Olov | Jula, Antti | Kähönen, Mika | Kathiresan, Sekar | Kee, Frank | Khaw, Kay-Tee | Kivimaki, Mika | Koenig, Wolfgang | Kraja, Aldi T. | Kumari, Meena | Kuulasmaa, Kari | Kuusisto, Johanna | Laitinen, Jaana H. | Lakka, Timo A. | Langenberg, Claudia | Launer, Lenore J. | Lind, Lars | Lindström, Jaana | Liu, Jianjun | Liuzzi, Antonio | Lokki, Marja-Liisa | Lorentzon, Mattias | Madden, Pamela A. | Magnusson, Patrik K. | Manunta, Paolo | Marek, Diana | März, Winfried | Mateo Leach, Irene | McKnight, Barbara | Medland, Sarah E. | Mihailov, Evelin | Milani, Lili | Montgomery, Grant W. | Mooser, Vincent | Mühleisen, Thomas W. | Munroe, Patricia B. | Musk, Arthur W. | Narisu, Narisu | Navis, Gerjan | Nicholson, George | Nohr, Ellen A. | Ong, Ken K. | Oostra, Ben A. | Palmer, Colin N.A. | Palotie, Aarno | Peden, John F. | Pedersen, Nancy | Peters, Annette | Polasek, Ozren | Pouta, Anneli | Pramstaller, Peter P. | Prokopenko, Inga | Pütter, Carolin | Radhakrishnan, Aparna | Raitakari, Olli | Rendon, Augusto | Rivadeneira, Fernando | Rudan, Igor | Saaristo, Timo E. | Sambrook, Jennifer G. | Sanders, Alan R. | Sanna, Serena | Saramies, Jouko | Schipf, Sabine | Schreiber, Stefan | Schunkert, Heribert | Shin, So-Youn | Signorini, Stefano | Sinisalo, Juha | Skrobek, Boris | Soranzo, Nicole | Stančáková, Alena | Stark, Klaus | Stephens, Jonathan C. | Stirrups, Kathleen | Stolk, Ronald P. | Stumvoll, Michael | Swift, Amy J. | Theodoraki, Eirini V. | Thorand, Barbara | Tregouet, David-Alexandre | Tremoli, Elena | Van der Klauw, Melanie M. | van Meurs, Joyce B.J. | Vermeulen, Sita H. | Viikari, Jorma | Virtamo, Jarmo | Vitart, Veronique | Waeber, Gérard | Wang, Zhaoming | Widén, Elisabeth | Wild, Sarah H. | Willemsen, Gonneke | Winkelmann, Bernhard R. | Witteman, Jacqueline C.M. | Wolffenbuttel, Bruce H.R. | Wong, Andrew | Wright, Alan F. | Zillikens, M. Carola | Amouyel, Philippe | Boehm, Bernhard O. | Boerwinkle, Eric | Boomsma, Dorret I. | Caulfield, Mark J. | Chanock, Stephen J. | Cupples, L. Adrienne | Cusi, Daniele | Dedoussis, George V. | Erdmann, Jeanette | Eriksson, Johan G. | Franks, Paul W. | Froguel, Philippe | Gieger, Christian | Gyllensten, Ulf | Hamsten, Anders | Harris, Tamara B. | Hengstenberg, Christian | Hicks, Andrew A. | Hingorani, Aroon | Hinney, Anke | Hofman, Albert | Hovingh, Kees G. | Hveem, Kristian | Illig, Thomas | Jarvelin, Marjo-Riitta | Jöckel, Karl-Heinz | Keinanen-Kiukaanniemi, Sirkka M. | Kiemeney, Lambertus A. | Kuh, Diana | Laakso, Markku | Lehtimäki, Terho | Levinson, Douglas F. | Martin, Nicholas G. | Metspalu, Andres | Morris, Andrew D. | Nieminen, Markku S. | Njølstad, Inger | Ohlsson, Claes | Oldehinkel, Albertine J. | Ouwehand, Willem H. | Palmer, Lyle J. | Penninx, Brenda | Power, Chris | Province, Michael A. | Psaty, Bruce M. | Qi, Lu | Rauramaa, Rainer | Ridker, Paul M. | Ripatti, Samuli | Salomaa, Veikko | Samani, Nilesh J. | Snieder, Harold | Sørensen, Thorkild I.A. | Spector, Timothy D. | Stefansson, Kari | Tönjes, Anke | Tuomilehto, Jaakko | Uitterlinden, André G. | Uusitupa, Matti | van der Harst, Pim | Vollenweider, Peter | Wallaschofski, Henri | Wareham, Nicholas J. | Watkins, Hugh | Wichmann, H.-Erich | Wilson, James F. | Abecasis, Goncalo R. | Assimes, Themistocles L. | Barroso, Inês | Boehnke, Michael | Borecki, Ingrid B. | Deloukas, Panos | Fox, Caroline S. | Frayling, Timothy | Groop, Leif C. | Haritunian, Talin | Heid, Iris M. | Hunter, David | Kaplan, Robert C. | Karpe, Fredrik | Moffatt, Miriam | Mohlke, Karen L. | O’Connell, Jeffrey R. | Pawitan, Yudi | Schadt, Eric E. | Schlessinger, David | Steinthorsdottir, Valgerdur | Strachan, David P. | Thorsteinsdottir, Unnur | van Duijn, Cornelia M. | Visscher, Peter M. | Di Blasio, Anna Maria | Hirschhorn, Joel N. | Lindgren, Cecilia M. | Morris, Andrew P. | Meyre, David | Scherag, André | McCarthy, Mark I. | Speliotes, Elizabeth K. | North, Kari E. | Loos, Ruth J.F. | Ingelsson, Erik
Nature genetics  2013;45(5):501-512.
Approaches exploiting extremes of the trait distribution may reveal novel loci for common traits, but it is unknown whether such loci are generalizable to the general population. In a genome-wide search for loci associated with upper vs. lower 5th percentiles of body mass index, height and waist-hip ratio, as well as clinical classes of obesity including up to 263,407 European individuals, we identified four new loci (IGFBP4, H6PD, RSRC1, PPP2R2A) influencing height detected in the tails and seven new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3, ZZZ3) for clinical classes of obesity. Further, we show that there is large overlap in terms of genetic structure and distribution of variants between traits based on extremes and the general population and little etiologic heterogeneity between obesity subgroups.
doi:10.1038/ng.2606
PMCID: PMC3973018  PMID: 23563607
18.  Meta-Analysis Investigating Associations Between Healthy Diet and Fasting Glucose and Insulin Levels and Modification by Loci Associated With Glucose Homeostasis in Data From 15 Cohorts 
American Journal of Epidemiology  2012;177(2):103-115.
Whether loci that influence fasting glucose (FG) and fasting insulin (FI) levels, as identified by genome-wide association studies, modify associations of diet with FG or FI is unknown. We utilized data from 15 US and European cohort studies comprising 51,289 persons without diabetes to test whether genotype and diet interact to influence FG or FI concentration. We constructed a diet score using study-specific quartile rankings for intakes of whole grains, fish, fruits, vegetables, and nuts/seeds (favorable) and red/processed meats, sweets, sugared beverages, and fried potatoes (unfavorable). We used linear regression within studies, followed by inverse-variance-weighted meta-analysis, to quantify 1) associations of diet score with FG and FI levels and 2) interactions of diet score with 16 FG-associated loci and 2 FI-associated loci. Diet score (per unit increase) was inversely associated with FG (β = −0.004 mmol/L, 95% confidence interval: −0.005, −0.003) and FI (β = −0.008 ln-pmol/L, 95% confidence interval: −0.009, −0.007) levels after adjustment for demographic factors, lifestyle, and body mass index. Genotype variation at the studied loci did not modify these associations. Healthier diets were associated with lower FG and FI concentrations regardless of genotype at previously replicated FG- and FI-associated loci. Studies focusing on genomic regions that do not yield highly statistically significant associations from main-effect genome-wide association studies may be more fruitful in identifying diet-gene interactions.
doi:10.1093/aje/kws297
PMCID: PMC3707424  PMID: 23255780
diabetes; dietary pattern; gene-environment interaction; glucose; insulin
19.  Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function 
Chasman, Daniel I. | Fuchsberger, Christian | Pattaro, Cristian | Teumer, Alexander | Böger, Carsten A. | Endlich, Karlhans | Olden, Matthias | Chen, Ming-Huei | Tin, Adrienne | Taliun, Daniel | Li, Man | Gao, Xiaoyi | Gorski, Mathias | Yang, Qiong | Hundertmark, Claudia | Foster, Meredith C. | O'Seaghdha, Conall M. | Glazer, Nicole | Isaacs, Aaron | Liu, Ching-Ti | Smith, Albert V. | O'Connell, Jeffrey R. | Struchalin, Maksim | Tanaka, Toshiko | Li, Guo | Johnson, Andrew D. | Gierman, Hinco J. | Feitosa, Mary F. | Hwang, Shih-Jen | Atkinson, Elizabeth J. | Lohman, Kurt | Cornelis, Marilyn C. | Johansson, Åsa | Tönjes, Anke | Dehghan, Abbas | Lambert, Jean-Charles | Holliday, Elizabeth G. | Sorice, Rossella | Kutalik, Zoltan | Lehtimäki, Terho | Esko, Tõnu | Deshmukh, Harshal | Ulivi, Sheila | Chu, Audrey Y. | Murgia, Federico | Trompet, Stella | Imboden, Medea | Coassin, Stefan | Pistis, Giorgio | Harris, Tamara B. | Launer, Lenore J. | Aspelund, Thor | Eiriksdottir, Gudny | Mitchell, Braxton D. | Boerwinkle, Eric | Schmidt, Helena | Cavalieri, Margherita | Rao, Madhumathi | Hu, Frank | Demirkan, Ayse | Oostra, Ben A. | de Andrade, Mariza | Turner, Stephen T. | Ding, Jingzhong | Andrews, Jeanette S. | Freedman, Barry I. | Giulianini, Franco | Koenig, Wolfgang | Illig, Thomas | Meisinger, Christa | Gieger, Christian | Zgaga, Lina | Zemunik, Tatijana | Boban, Mladen | Minelli, Cosetta | Wheeler, Heather E. | Igl, Wilmar | Zaboli, Ghazal | Wild, Sarah H. | Wright, Alan F. | Campbell, Harry | Ellinghaus, David | Nöthlings, Ute | Jacobs, Gunnar | Biffar, Reiner | Ernst, Florian | Homuth, Georg | Kroemer, Heyo K. | Nauck, Matthias | Stracke, Sylvia | Völker, Uwe | Völzke, Henry | Kovacs, Peter | Stumvoll, Michael | Mägi, Reedik | Hofman, Albert | Uitterlinden, Andre G. | Rivadeneira, Fernando | Aulchenko, Yurii S. | Polasek, Ozren | Hastie, Nick | Vitart, Veronique | Helmer, Catherine | Wang, Jie Jin | Stengel, Bénédicte | Ruggiero, Daniela | Bergmann, Sven | Kähönen, Mika | Viikari, Jorma | Nikopensius, Tiit | Province, Michael | Ketkar, Shamika | Colhoun, Helen | Doney, Alex | Robino, Antonietta | Krämer, Bernhard K. | Portas, Laura | Ford, Ian | Buckley, Brendan M. | Adam, Martin | Thun, Gian-Andri | Paulweber, Bernhard | Haun, Margot | Sala, Cinzia | Mitchell, Paul | Ciullo, Marina | Kim, Stuart K. | Vollenweider, Peter | Raitakari, Olli | Metspalu, Andres | Palmer, Colin | Gasparini, Paolo | Pirastu, Mario | Jukema, J. Wouter | Probst-Hensch, Nicole M. | Kronenberg, Florian | Toniolo, Daniela | Gudnason, Vilmundur | Shuldiner, Alan R. | Coresh, Josef | Schmidt, Reinhold | Ferrucci, Luigi | Siscovick, David S. | van Duijn, Cornelia M. | Borecki, Ingrid B. | Kardia, Sharon L.R. | Liu, Yongmei | Curhan, Gary C. | Rudan, Igor | Gyllensten, Ulf | Wilson, James F. | Franke, Andre | Pramstaller, Peter P. | Rettig, Rainer | Prokopenko, Inga | Witteman, Jacqueline | Hayward, Caroline | Ridker, Paul M | Parsa, Afshin | Bochud, Murielle | Heid, Iris M. | Kao, W.H. Linda | Fox, Caroline S. | Köttgen, Anna
Human Molecular Genetics  2012;21(24):5329-5343.
In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 × 10−9) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 × 10−4–2.2 × 10−7. Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.
doi:10.1093/hmg/dds369
PMCID: PMC3607468  PMID: 22962313
20.  Common variants at 12q15 and 12q24 are associated with infant head circumference 
Taal, H Rob | Pourcain, Beate St | Thiering, Elisabeth | Das, Shikta | Mook-Kanamori, Dennis O | Warrington, Nicole M | Kaakinen, Marika | Kreiner-Møller, Eskil | Bradfield, Jonathan P | Freathy, Rachel M | Geller, Frank | Guxens, Mònica | Cousminer, Diana L | Kerkhof, Marjan | Timpson, Nicholas J | Ikram, M Arfan | Beilin, Lawrence J | Bønnelykke, Klaus | Buxton, Jessica L | Charoen, Pimphen | Chawes, Bo Lund Krogsgaard | Eriksson, Johan | Evans, David M | Hofman, Albert | Kemp, John P | Kim, Cecilia E | Klopp, Norman | Lahti, Jari | Lye, Stephen J | McMahon, George | Mentch, Frank D | Müller, Martina | O’Reilly, Paul F | Prokopenko, Inga | Rivadeneira, Fernando | Steegers, Eric A P | Sunyer, Jordi | Tiesler, Carla | Yaghootkar, Hanieh | Breteler, Monique M B | Debette, Stephanie | Fornage, Myriam | Gudnason, Vilmundur | Launer, Lenore J | van der Lugt, Aad | Mosley, Thomas H | Seshadri, Sudha | Smith, Albert V | Vernooij, Meike W | Blakemore, Alexandra IF | Chiavacci, Rosetta M | Feenstra, Bjarke | Fernandez-Benet, Julio | Grant, Struan F A | Hartikainen, Anna-Liisa | van der Heijden, Albert J | Iñiguez, Carmen | Lathrop, Mark | McArdle, Wendy L | Mølgaard, Anne | Newnham, John P | Palmer, Lyle J | Palotie, Aarno | Pouta, Annneli | Ring, Susan M | Sovio, Ulla | Standl, Marie | Uitterlinden, Andre G | Wichmann, H-Erich | Vissing, Nadja Hawwa | DeCarli, Charles | van Duijn, Cornelia M | McCarthy, Mark I | Koppelman, Gerard H. | Estivill, Xavier | Hattersley, Andrew T | Melbye, Mads | Bisgaard, Hans | Pennell, Craig E | Widen, Elisabeth | Hakonarson, Hakon | Smith, George Davey | Heinrich, Joachim | Jarvelin, Marjo-Riitta | Jaddoe, Vincent W V
Nature genetics  2012;44(5):532-538.
To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association (GWA) studies (N=10,768 from European ancestry enrolled in pregnancy/birth cohorts) and followed up three lead signals in six replication studies (combined N=19,089). Rs7980687 on chromosome 12q24 (P=8.1×10−9), and rs1042725 on chromosome 12q15 (P=2.8×10−10) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height1, their effects on infant head circumference were largely independent of height (P=3.8×10−7 for rs7980687, P=1.3×10−7 for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P=3.9×10−6). SNPs correlated to the 17q21 signal show genome-wide association with adult intra cranial volume2, Parkinson’s disease and other neurodegenerative diseases3-5, indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.
doi:10.1038/ng.2238
PMCID: PMC3773913  PMID: 22504419
21.  Genome-wide association study in people of South Asian ancestry identifies six novel susceptibility loci for type 2 diabetes 
Nature genetics  2011;43(10):984-989.
We carried out a genome wide association study of type-2 diabetes (T2D) amongst 20,119 people of South Asian ancestry (5,561 with T2D); we identified 20 independent SNPs associated with T2D at P<10−4 for testing amongst a further 38,568 South Asians (13,170 with T2D). In combined analysis, common genetic variants at six novel loci (GRB14, ST6GAL1, VPS26A, HMG20A, AP3S2 and HNF4A) were associated with T2D (P=4.1×10−8 to P=1.9×10−11); SNPs at GRB14 were also associated with insulin sensitivity, and at ST6GAL1 and HNF4A with pancreatic beta-cell function respectively. Our findings provide additional insight into mechanisms underlying T2D, and demonstrate the potential for new discovery from genetic association studies in South Asians who have increased susceptibility to T2D.
doi:10.1038/ng.921
PMCID: PMC3773920  PMID: 21874001
22.  Genetic loci influencing kidney function and chronic kidney disease in man 
Chambers, John C | Zhang, Weihua | Lord, Graham M | van der Harst, Pim | Lawlor, Debbie A | Sehmi, Joban S | Gale, Daniel P | Wass, Mark N | Ahmadi, Kourosh R | Bakker, Stephan JL | Beckmann, Jacqui | Bilo, Henk JG | Bochud, Murielle | Brown, Morris J | Caulfield, Mark J | Connell, John M C | Cook, Terence | Cotlarciuc, Ioana | Smith, George Davey | de Silva, Ranil | Deng, Guohong | Devuyst, Olivier | Dikkeschei, Lambert D. | Dimkovic, Nada | Dockrell, Mark | Dominiczak, Anna | Ebrahim, Shah | Eggermann, Thomas | Farrall, Martin | Ferrucci, Luigi | Floege, Jurgen | Forouhi, Nita G | Gansevoort, Ron T | Han, Xijin | Hedblad, Bo | van der Heide, Jaap J Homan | Hepkema, Bouke G | Hernandez-Fuentes, Maria | Hypponen, Elina | Johnson, Toby | de Jong, Paul E | Kleefstra, Nanne | Lagou, Vasiliki | Lapsley, Marta | Li, Yun | Loos, Ruth J F | Luan, Jian'an | Luttropp, Karin | Maréchal, Céline | Melander, Olle | Munroe, Patricia B | Nordfors, Louise | Parsa, Afshin | Penninx, Brenda W. | Perucha, Esperanza | Pouta, Anneli | Prokopenko, Inga | Roderick, Paul J | Ruokonen, Aimo | Samani, Nilesh | Sanna, Serena | Schalling, Martin | Schlessinger, David | Schlieper, Georg | Seelen, Marc AJ | Shuldiner, Alan R | Sjögren, Marketa | Smit, Johannes H. | Snieder, Harold | Soranzo, Nicole | Spector, Timothy D | Stenvinkel, Peter | Sternberg, Michael JE | Swaminathan, Ramasamyiyer | Tanaka, Toshiko | Ubink-Veltmaat, Lielith J. | Uda, Manuela | Vollenweider, Peter | Wallace, Chris | Waterworth, Dawn | Zerres, Klaus | Waeber, Gerard | Wareham, Nicholas J | Maxwell, Patrick H | McCarthy, Mark I | Jarvelin, Marjo-Riitta | Mooser, Vincent | Abecasis, Goncalo R | Lightstone, Liz | Scott, James | Navis, Gerjan | Elliott, Paul | Kooner., Jaspal S
Nature genetics  2010;42(5):373-375.
Chronic kidney disease (CKD), the result of permanent loss of kidney function, is a major global problem. We identify common genetic variants at chr2p12-p13, chr6q26, chr17q23 and chr19q13 associated with serum creatinine, a marker of kidney function (P=10−10 to 10−15). SNPs rs10206899 (near NAT8, chr2p12-p13) and rs4805834 (near SLC7A9, chr19q13) were also associated with CKD. Our findings provide new insight into metabolic, solute and drug-transport pathways underlying susceptibility to CKD.
doi:10.1038/ng.566
PMCID: PMC3748585  PMID: 20383145
23.  Genome-wide association analyses identify 18 new loci associated with serum urate concentrations 
Köttgen, Anna | Albrecht, Eva | Teumer, Alexander | Vitart, Veronique | Krumsiek, Jan | Hundertmark, Claudia | Pistis, Giorgio | Ruggiero, Daniela | O’Seaghdha, Conall M | Haller, Toomas | Yang, Qiong | Tanaka, Toshiko | Johnson, Andrew D | Kutalik, Zoltán | Smith, Albert V | Shi, Julia | Struchalin, Maksim | Middelberg, Rita P S | Brown, Morris J | Gaffo, Angelo L | Pirastu, Nicola | Li, Guo | Hayward, Caroline | Zemunik, Tatijana | Huffman, Jennifer | Yengo, Loic | Zhao, Jing Hua | Demirkan, Ayse | Feitosa, Mary F | Liu, Xuan | Malerba, Giovanni | Lopez, Lorna M | van der Harst, Pim | Li, Xinzhong | Kleber, Marcus E | Hicks, Andrew A | Nolte, Ilja M | Johansson, Asa | Murgia, Federico | Wild, Sarah H | Bakker, Stephan J L | Peden, John F | Dehghan, Abbas | Steri, Maristella | Tenesa, Albert | Lagou, Vasiliki | Salo, Perttu | Mangino, Massimo | Rose, Lynda M | Lehtimäki, Terho | Woodward, Owen M | Okada, Yukinori | Tin, Adrienne | Müller, Christian | Oldmeadow, Christopher | Putku, Margus | Czamara, Darina | Kraft, Peter | Frogheri, Laura | Thun, Gian Andri | Grotevendt, Anne | Gislason, Gauti Kjartan | Harris, Tamara B | Launer, Lenore J | McArdle, Patrick | Shuldiner, Alan R | Boerwinkle, Eric | Coresh, Josef | Schmidt, Helena | Schallert, Michael | Martin, Nicholas G | Montgomery, Grant W | Kubo, Michiaki | Nakamura, Yusuke | Tanaka, Toshihiro | Munroe, Patricia B | Samani, Nilesh J | Jacobs, David R | Liu, Kiang | D’Adamo, Pio | Ulivi, Sheila | Rotter, Jerome I | Psaty, Bruce M | Vollenweider, Peter | Waeber, Gerard | Campbell, Susan | Devuyst, Olivier | Navarro, Pau | Kolcic, Ivana | Hastie, Nicholas | Balkau, Beverley | Froguel, Philippe | Esko, Tõnu | Salumets, Andres | Khaw, Kay Tee | Langenberg, Claudia | Wareham, Nicholas J | Isaacs, Aaron | Kraja, Aldi | Zhang, Qunyuan | Wild, Philipp S | Scott, Rodney J | Holliday, Elizabeth G | Org, Elin | Viigimaa, Margus | Bandinelli, Stefania | Metter, Jeffrey E | Lupo, Antonio | Trabetti, Elisabetta | Sorice, Rossella | Döring, Angela | Lattka, Eva | Strauch, Konstantin | Theis, Fabian | Waldenberger, Melanie | Wichmann, H-Erich | Davies, Gail | Gow, Alan J | Bruinenberg, Marcel | Study, LifeLines Cohort | Stolk, Ronald P | Kooner, Jaspal S | Zhang, Weihua | Winkelmann, Bernhard R | Boehm, Bernhard O | Lucae, Susanne | Penninx, Brenda W | Smit, Johannes H | Curhan, Gary | Mudgal, Poorva | Plenge, Robert M | Portas, Laura | Persico, Ivana | Kirin, Mirna | Wilson, James F | Leach, Irene Mateo | van Gilst, Wiek H | Goel, Anuj | Ongen, Halit | Hofman, Albert | Rivadeneira, Fernando | Uitterlinden, Andre G | Imboden, Medea | von Eckardstein, Arnold | Cucca, Francesco | Nagaraja, Ramaiah | Piras, Maria Grazia | Nauck, Matthias | Schurmann, Claudia | Budde, Kathrin | Ernst, Florian | Farrington, Susan M | Theodoratou, Evropi | Prokopenko, Inga | Stumvoll, Michael | Jula, Antti | Perola, Markus | Salomaa, Veikko | Shin, So-Youn | Spector, Tim D | Sala, Cinzia | Ridker, Paul M | Kähönen, Mika | Viikari, Jorma | Hengstenberg, Christian | Nelson, Christopher P | Consortium, CARDIoGRAM | Consortium, DIAGRAM | Consortium, ICBP | Consortium, MAGIC | Meschia, James F | Nalls, Michael A | Sharma, Pankaj | Singleton, Andrew B | Kamatani, Naoyuki | Zeller, Tanja | Burnier, Michel | Attia, John | Laan, Maris | Klopp, Norman | Hillege, Hans L | Kloiber, Stefan | Choi, Hyon | Pirastu, Mario | Tore, Silvia | Probst-Hensch, Nicole M | Völzke, Henry | Gudnason, Vilmundur | Parsa, Afshin | Schmidt, Reinhold | Whitfield, John B | Fornage, Myriam | Gasparini, Paolo | Siscovick, David S | Polašek, Ozren | Campbell, Harry | Rudan, Igor | Bouatia-Naji, Nabila | Metspalu, Andres | Loos, Ruth J F | van Duijn, Cornelia M | Borecki, Ingrid B | Ferrucci, Luigi | Gambaro, Giovanni | Deary, Ian J | Wolffenbuttel, Bruce H R | Chambers, John C | März, Winfried | Pramstaller, Peter P | Snieder, Harold | Gyllensten, Ulf | Wright, Alan F | Navis, Gerjan | Watkins, Hugh | Witteman, Jacqueline C M | Sanna, Serena | Schipf, Sabine | Dunlop, Malcolm G | Tönjes, Anke | Ripatti, Samuli | Soranzo, Nicole | Toniolo, Daniela | Chasman, Daniel I | Raitakari, Olli | Kao, W H Linda | Ciullo, Marina | Fox, Caroline S | Caulfield, Mark | Bochud, Murielle | Gieger, Christian
Nature genetics  2012;45(2):145-154.
Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
doi:10.1038/ng.2500
PMCID: PMC3663712  PMID: 23263486
24.  New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism 
Horikoshi, Momoko | Yaghootkar, Hanieh | Mook-Kanamori, Dennis O. | Sovio, Ulla | Taal, H. Rob | Hennig, Branwen J. | Bradfield, Jonathan P. | St. Pourcain, Beate | Evans, David M. | Charoen, Pimphen | Kaakinen, Marika | Cousminer, Diana L. | Lehtimäki, Terho | Kreiner-Møller, Eskil | Warrington, Nicole M. | Bustamante, Mariona | Feenstra, Bjarke | Berry, Diane J. | Thiering, Elisabeth | Pfab, Thiemo | Barton, Sheila J. | Shields, Beverley M. | Kerkhof, Marjan | van Leeuwen, Elisabeth M. | Fulford, Anthony J. | Kutalik, Zoltán | Zhao, Jing Hua | den Hoed, Marcel | Mahajan, Anubha | Lindi, Virpi | Goh, Liang-Kee | Hottenga, Jouke-Jan | Wu, Ying | Raitakari, Olli T. | Harder, Marie N. | Meirhaeghe, Aline | Ntalla, Ioanna | Salem, Rany M. | Jameson, Karen A. | Zhou, Kaixin | Monies, Dorota M. | Lagou, Vasiliki | Kirin, Mirna | Heikkinen, Jani | Adair, Linda S. | Alkuraya, Fowzan S. | Al-Odaib, Ali | Amouyel, Philippe | Andersson, Ehm Astrid | Bennett, Amanda J. | Blakemore, Alexandra I.F. | Buxton, Jessica L. | Dallongeville, Jean | Das, Shikta | de Geus, Eco J. C. | Estivill, Xavier | Flexeder, Claudia | Froguel, Philippe | Geller, Frank | Godfrey, Keith M. | Gottrand, Frédéric | Groves, Christopher J. | Hansen, Torben | Hirschhorn, Joel N. | Hofman, Albert | Hollegaard, Mads V. | Hougaard, David M. | Hyppönen, Elina | Inskip, Hazel M. | Isaacs, Aaron | Jørgensen, Torben | Kanaka-Gantenbein, Christina | Kemp, John P. | Kiess, Wieland | Kilpeläinen, Tuomas O. | Klopp, Norman | Knight, Bridget A. | Kuzawa, Christopher W. | McMahon, George | Newnham, John P. | Niinikoski, Harri | Oostra, Ben A. | Pedersen, Louise | Postma, Dirkje S. | Ring, Susan M. | Rivadeneira, Fernando | Robertson, Neil R. | Sebert, Sylvain | Simell, Olli | Slowinski, Torsten | Tiesler, Carla M.T. | Tönjes, Anke | Vaag, Allan | Viikari, Jorma S. | Vink, Jacqueline M. | Vissing, Nadja Hawwa | Wareham, Nicholas J. | Willemsen, Gonneke | Witte, Daniel R. | Zhang, Haitao | Zhao, Jianhua | Wilson, James F. | Stumvoll, Michael | Prentice, Andrew M. | Meyer, Brian F. | Pearson, Ewan R. | Boreham, Colin A.G. | Cooper, Cyrus | Gillman, Matthew W. | Dedoussis, George V. | Moreno, Luis A | Pedersen, Oluf | Saarinen, Maiju | Mohlke, Karen L. | Boomsma, Dorret I. | Saw, Seang-Mei | Lakka, Timo A. | Körner, Antje | Loos, Ruth J.F. | Ong, Ken K. | Vollenweider, Peter | van Duijn, Cornelia M. | Koppelman, Gerard H. | Hattersley, Andrew T. | Holloway, John W. | Hocher, Berthold | Heinrich, Joachim | Power, Chris | Melbye, Mads | Guxens, Mònica | Pennell, Craig E. | Bønnelykke, Klaus | Bisgaard, Hans | Eriksson, Johan G. | Widén, Elisabeth | Hakonarson, Hakon | Uitterlinden, André G. | Pouta, Anneli | Lawlor, Debbie A. | Smith, George Davey | Frayling, Timothy M. | McCarthy, Mark I. | Grant, Struan F.A. | Jaddoe, Vincent W.V. | Jarvelin, Marjo-Riitta | Timpson, Nicholas J. | Prokopenko, Inga | Freathy, Rachel M.
Nature genetics  2012;45(1):76-82.
Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood1. Previous genome-wide association studies identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes, and a second variant, near CCNL1, with no obvious link to adult traits2. In an expanded genome-wide association meta-analysis and follow-up study (up to 69,308 individuals of European descent from 43 studies), we have now extended the number of genome-wide significant loci to seven, accounting for a similar proportion of variance to maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes; ADRB1 with adult blood pressure; and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.
doi:10.1038/ng.2477
PMCID: PMC3605762  PMID: 23202124
25.  The Role of Adiposity in Cardiometabolic Traits: A Mendelian Randomization Analysis 
Fall, Tove | Hägg, Sara | Mägi, Reedik | Ploner, Alexander | Fischer, Krista | Horikoshi, Momoko | Sarin, Antti-Pekka | Thorleifsson, Gudmar | Ladenvall, Claes | Kals, Mart | Kuningas, Maris | Draisma, Harmen H. M. | Ried, Janina S. | van Zuydam, Natalie R. | Huikari, Ville | Mangino, Massimo | Sonestedt, Emily | Benyamin, Beben | Nelson, Christopher P. | Rivera, Natalia V. | Kristiansson, Kati | Shen, Huei-yi | Havulinna, Aki S. | Dehghan, Abbas | Donnelly, Louise A. | Kaakinen, Marika | Nuotio, Marja-Liisa | Robertson, Neil | de Bruijn, Renée F. A. G. | Ikram, M. Arfan | Amin, Najaf | Balmforth, Anthony J. | Braund, Peter S. | Doney, Alexander S. F. | Döring, Angela | Elliott, Paul | Esko, Tõnu | Franco, Oscar H. | Gretarsdottir, Solveig | Hartikainen, Anna-Liisa | Heikkilä, Kauko | Herzig, Karl-Heinz | Holm, Hilma | Hottenga, Jouke Jan | Hyppönen, Elina | Illig, Thomas | Isaacs, Aaron | Isomaa, Bo | Karssen, Lennart C. | Kettunen, Johannes | Koenig, Wolfgang | Kuulasmaa, Kari | Laatikainen, Tiina | Laitinen, Jaana | Lindgren, Cecilia | Lyssenko, Valeriya | Läärä, Esa | Rayner, Nigel W. | Männistö, Satu | Pouta, Anneli | Rathmann, Wolfgang | Rivadeneira, Fernando | Ruokonen, Aimo | Savolainen, Markku J. | Sijbrands, Eric J. G. | Small, Kerrin S. | Smit, Jan H. | Steinthorsdottir, Valgerdur | Syvänen, Ann-Christine | Taanila, Anja | Tobin, Martin D. | Uitterlinden, Andre G. | Willems, Sara M. | Willemsen, Gonneke | Witteman, Jacqueline | Perola, Markus | Evans, Alun | Ferrières, Jean | Virtamo, Jarmo | Kee, Frank | Tregouet, David-Alexandre | Arveiler, Dominique | Amouyel, Philippe | Ferrario, Marco M. | Brambilla, Paolo | Hall, Alistair S. | Heath, Andrew C. | Madden, Pamela A. F. | Martin, Nicholas G. | Montgomery, Grant W. | Whitfield, John B. | Jula, Antti | Knekt, Paul | Oostra, Ben | van Duijn, Cornelia M. | Penninx, Brenda W. J. H. | Davey Smith, George | Kaprio, Jaakko | Samani, Nilesh J. | Gieger, Christian | Peters, Annette | Wichmann, H.-Erich | Boomsma, Dorret I. | de Geus, Eco J. C. | Tuomi, TiinaMaija | Power, Chris | Hammond, Christopher J. | Spector, Tim D. | Lind, Lars |