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author:("Ruokonen, aim")
1.  Discovery and Refinement of Loci Associated with Lipid Levels 
Willer, Cristen J. | Schmidt, Ellen M. | Sengupta, Sebanti | Peloso, Gina M. | Gustafsson, Stefan | Kanoni, Stavroula | Ganna, Andrea | Chen, Jin | Buchkovich, Martin L. | Mora, Samia | Beckmann, Jacques S. | Bragg-Gresham, Jennifer L. | Chang, Hsing-Yi | Demirkan, Ayşe | Den Hertog, Heleen M. | Do, Ron | Donnelly, Louise A. | Ehret, Georg B. | Esko, Tõnu | Feitosa, Mary F. | Ferreira, Teresa | Fischer, Krista | Fontanillas, Pierre | Fraser, Ross M. | Freitag, Daniel F. | Gurdasani, Deepti | Heikkilä, Kauko | Hyppönen, Elina | Isaacs, Aaron | Jackson, Anne U. | Johansson, Åsa | Johnson, Toby | Kaakinen, Marika | Kettunen, Johannes | Kleber, Marcus E. | Li, Xiaohui | Luan, Jian’an | Lyytikäinen, Leo-Pekka | Magnusson, Patrik K.E. | Mangino, Massimo | Mihailov, Evelin | Montasser, May E. | Müller-Nurasyid, Martina | Nolte, Ilja M. | O’Connell, Jeffrey R. | Palmer, Cameron D. | Perola, Markus | Petersen, Ann-Kristin | Sanna, Serena | Saxena, Richa | Service, Susan K. | Shah, Sonia | Shungin, Dmitry | Sidore, Carlo | Song, Ci | Strawbridge, Rona J. | Surakka, Ida | Tanaka, Toshiko | Teslovich, Tanya M. | Thorleifsson, Gudmar | Van den Herik, Evita G. | Voight, Benjamin F. | Volcik, Kelly A. | Waite, Lindsay L. | Wong, Andrew | Wu, Ying | Zhang, Weihua | Absher, Devin | Asiki, Gershim | Barroso, Inês | Been, Latonya F. | Bolton, Jennifer L. | Bonnycastle, Lori L | Brambilla, Paolo | Burnett, Mary S. | Cesana, Giancarlo | Dimitriou, Maria | Doney, Alex S.F. | Döring, Angela | Elliott, Paul | Epstein, Stephen E. | Ingi Eyjolfsson, Gudmundur | Gigante, Bruna | Goodarzi, Mark O. | Grallert, Harald | Gravito, Martha L. | Groves, Christopher J. | Hallmans, Göran | Hartikainen, Anna-Liisa | Hayward, Caroline | Hernandez, Dena | Hicks, Andrew A. | Holm, Hilma | Hung, Yi-Jen | Illig, Thomas | Jones, Michelle R. | Kaleebu, Pontiano | Kastelein, John J.P. | Khaw, Kay-Tee | Kim, Eric | Klopp, Norman | Komulainen, Pirjo | Kumari, Meena | Langenberg, Claudia | Lehtimäki, Terho | Lin, Shih-Yi | Lindström, Jaana | Loos, Ruth J.F. | Mach, François | McArdle, Wendy L | Meisinger, Christa | Mitchell, Braxton D. | Müller, Gabrielle | Nagaraja, Ramaiah | Narisu, Narisu | Nieminen, Tuomo V.M. | Nsubuga, Rebecca N. | Olafsson, Isleifur | Ong, Ken K. | Palotie, Aarno | Papamarkou, Theodore | Pomilla, Cristina | Pouta, Anneli | Rader, Daniel J. | Reilly, Muredach P. | Ridker, Paul M. | Rivadeneira, Fernando | Rudan, Igor | Ruokonen, Aimo | Samani, Nilesh | Scharnagl, Hubert | Seeley, Janet | Silander, Kaisa | Stančáková, Alena | Stirrups, Kathleen | Swift, Amy J. | Tiret, Laurence | Uitterlinden, Andre G. | van Pelt, L. Joost | Vedantam, Sailaja | Wainwright, Nicholas | Wijmenga, Cisca | Wild, Sarah H. | Willemsen, Gonneke | Wilsgaard, Tom | Wilson, James F. | Young, Elizabeth H. | Zhao, Jing Hua | Adair, Linda S. | Arveiler, Dominique | Assimes, Themistocles L. | Bandinelli, Stefania | Bennett, Franklyn | Bochud, Murielle | Boehm, Bernhard O. | Boomsma, Dorret I. | Borecki, Ingrid B. | Bornstein, Stefan R. | Bovet, Pascal | Burnier, Michel | Campbell, Harry | Chakravarti, Aravinda | Chambers, John C. | Chen, Yii-Der Ida | Collins, Francis S. | Cooper, Richard S. | Danesh, John | Dedoussis, George | de Faire, Ulf | Feranil, Alan B. | Ferrières, Jean | Ferrucci, Luigi | Freimer, Nelson B. | Gieger, Christian | Groop, Leif C. | Gudnason, Vilmundur | Gyllensten, Ulf | Hamsten, Anders | Harris, Tamara B. | Hingorani, Aroon | Hirschhorn, Joel N. | Hofman, Albert | Hovingh, G. Kees | Hsiung, Chao Agnes | Humphries, Steve E. | Hunt, Steven C. | Hveem, Kristian | Iribarren, Carlos | Järvelin, Marjo-Riitta | Jula, Antti | Kähönen, Mika | Kaprio, Jaakko | Kesäniemi, Antero | Kivimaki, Mika | Kooner, Jaspal S. | Koudstaal, Peter J. | Krauss, Ronald M. | Kuh, Diana | Kuusisto, Johanna | Kyvik, Kirsten O. | Laakso, Markku | Lakka, Timo A. | Lind, Lars | Lindgren, Cecilia M. | Martin, Nicholas G. | März, Winfried | McCarthy, Mark I. | McKenzie, Colin A. | Meneton, Pierre | Metspalu, Andres | Moilanen, Leena | Morris, Andrew D. | Munroe, Patricia B. | Njølstad, Inger | Pedersen, Nancy L. | Power, Chris | Pramstaller, Peter P. | Price, Jackie F. | Psaty, Bruce M. | Quertermous, Thomas | Rauramaa, Rainer | Saleheen, Danish | Salomaa, Veikko | Sanghera, Dharambir K. | Saramies, Jouko | Schwarz, Peter E.H. | Sheu, Wayne H-H | Shuldiner, Alan R. | Siegbahn, Agneta | Spector, Tim D. | Stefansson, Kari | Strachan, David P. | Tayo, Bamidele O. | Tremoli, Elena | Tuomilehto, Jaakko | Uusitupa, Matti | van Duijn, Cornelia M. | Vollenweider, Peter | Wallentin, Lars | Wareham, Nicholas J. | Whitfield, John B. | Wolffenbuttel, Bruce H.R. | Ordovas, Jose M. | Boerwinkle, Eric | Palmer, Colin N.A. | Thorsteinsdottir, Unnur | Chasman, Daniel I. | Rotter, Jerome I. | Franks, Paul W. | Ripatti, Samuli | Cupples, L. Adrienne | Sandhu, Manjinder S. | Rich, Stephen S. | Boehnke, Michael | Deloukas, Panos | Kathiresan, Sekar | Mohlke, Karen L. | Ingelsson, Erik | Abecasis, Gonçalo R.
Nature genetics  2013;45(11):10.1038/ng.2797.
Low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, and total cholesterol are heritable, modifiable, risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,578 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5×10−8, including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian, and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipids are often associated with cardiovascular and metabolic traits including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio, and body mass index. Our results illustrate the value of genetic data from individuals of diverse ancestries and provide insights into biological mechanisms regulating blood lipids to guide future genetic, biological, and therapeutic research.
doi:10.1038/ng.2797
PMCID: PMC3838666  PMID: 24097068
2.  Common variants associated with plasma triglycerides and risk for coronary artery disease 
Do, Ron | Willer, Cristen J. | Schmidt, Ellen M. | Sengupta, Sebanti | Gao, Chi | Peloso, Gina M. | Gustafsson, Stefan | Kanoni, Stavroula | Ganna, Andrea | Chen, Jin | Buchkovich, Martin L. | Mora, Samia | Beckmann, Jacques S. | Bragg-Gresham, Jennifer L. | Chang, Hsing-Yi | Demirkan, Ayşe | Den Hertog, Heleen M. | Donnelly, Louise A. | Ehret, Georg B. | Esko, Tõnu | Feitosa, Mary F. | Ferreira, Teresa | Fischer, Krista | Fontanillas, Pierre | Fraser, Ross M. | Freitag, Daniel F. | Gurdasani, Deepti | Heikkilä, Kauko | Hyppönen, Elina | Isaacs, Aaron | Jackson, Anne U. | Johansson, Åsa | Johnson, Toby | Kaakinen, Marika | Kettunen, Johannes | Kleber, Marcus E. | Li, Xiaohui | Luan, Jian'an | Lyytikäinen, Leo-Pekka | Magnusson, Patrik K.E. | Mangino, Massimo | Mihailov, Evelin | Montasser, May E. | Müller-Nurasyid, Martina | Nolte, Ilja M. | O'Connell, Jeffrey R. | Palmer, Cameron D. | Perola, Markus | Petersen, Ann-Kristin | Sanna, Serena | Saxena, Richa | Service, Susan K. | Shah, Sonia | Shungin, Dmitry | Sidore, Carlo | Song, Ci | Strawbridge, Rona J. | Surakka, Ida | Tanaka, Toshiko | Teslovich, Tanya M. | Thorleifsson, Gudmar | Van den Herik, Evita G. | Voight, Benjamin F. | Volcik, Kelly A. | Waite, Lindsay L. | Wong, Andrew | Wu, Ying | Zhang, Weihua | Absher, Devin | Asiki, Gershim | Barroso, Inês | Been, Latonya F. | Bolton, Jennifer L. | Bonnycastle, Lori L | Brambilla, Paolo | Burnett, Mary S. | Cesana, Giancarlo | Dimitriou, Maria | Doney, Alex S.F. | Döring, Angela | Elliott, Paul | Epstein, Stephen E. | Eyjolfsson, Gudmundur Ingi | Gigante, Bruna | Goodarzi, Mark O. | Grallert, Harald | Gravito, Martha L. | Groves, Christopher J. | Hallmans, Göran | Hartikainen, Anna-Liisa | Hayward, Caroline | Hernandez, Dena | Hicks, Andrew A. | Holm, Hilma | Hung, Yi-Jen | Illig, Thomas | Jones, Michelle R. | Kaleebu, Pontiano | Kastelein, John J.P. | Khaw, Kay-Tee | Kim, Eric | Klopp, Norman | Komulainen, Pirjo | Kumari, Meena | Langenberg, Claudia | Lehtimäki, Terho | Lin, Shih-Yi | Lindström, Jaana | Loos, Ruth J.F. | Mach, François | McArdle, Wendy L | Meisinger, Christa | Mitchell, Braxton D. | Müller, Gabrielle | Nagaraja, Ramaiah | Narisu, Narisu | Nieminen, Tuomo V.M. | Nsubuga, Rebecca N. | Olafsson, Isleifur | Ong, Ken K. | Palotie, Aarno | Papamarkou, Theodore | Pomilla, Cristina | Pouta, Anneli | Rader, Daniel J. | Reilly, Muredach P. | Ridker, Paul M. | Rivadeneira, Fernando | Rudan, Igor | Ruokonen, Aimo | Samani, Nilesh | Scharnagl, Hubert | Seeley, Janet | Silander, Kaisa | Stančáková, Alena | Stirrups, Kathleen | Swift, Amy J. | Tiret, Laurence | Uitterlinden, Andre G. | van Pelt, L. Joost | Vedantam, Sailaja | Wainwright, Nicholas | Wijmenga, Cisca | Wild, Sarah H. | Willemsen, Gonneke | Wilsgaard, Tom | Wilson, James F. | Young, Elizabeth H. | Zhao, Jing Hua | Adair, Linda S. | Arveiler, Dominique | Assimes, Themistocles L. | Bandinelli, Stefania | Bennett, Franklyn | Bochud, Murielle | Boehm, Bernhard O. | Boomsma, Dorret I. | Borecki, Ingrid B. | Bornstein, Stefan R. | Bovet, Pascal | Burnier, Michel | Campbell, Harry | Chakravarti, Aravinda | Chambers, John C. | Chen, Yii-Der Ida | Collins, Francis S. | Cooper, Richard S. | Danesh, John | Dedoussis, George | de Faire, Ulf | Feranil, Alan B. | Ferrières, Jean | Ferrucci, Luigi | Freimer, Nelson B. | Gieger, Christian | Groop, Leif C. | Gudnason, Vilmundur | Gyllensten, Ulf | Hamsten, Anders | Harris, Tamara B. | Hingorani, Aroon | Hirschhorn, Joel N. | Hofman, Albert | Hovingh, G. Kees | Hsiung, Chao Agnes | Humphries, Steve E. | Hunt, Steven C. | Hveem, Kristian | Iribarren, Carlos | Järvelin, Marjo-Riitta | Jula, Antti | Kähönen, Mika | Kaprio, Jaakko | Kesäniemi, Antero | Kivimaki, Mika | Kooner, Jaspal S. | Koudstaal, Peter J. | Krauss, Ronald M. | Kuh, Diana | Kuusisto, Johanna | Kyvik, Kirsten O. | Laakso, Markku | Lakka, Timo A. | Lind, Lars | Lindgren, Cecilia M. | Martin, Nicholas G. | März, Winfried | McCarthy, Mark I. | McKenzie, Colin A. | Meneton, Pierre | Metspalu, Andres | Moilanen, Leena | Morris, Andrew D. | Munroe, Patricia B. | Njølstad, Inger | Pedersen, Nancy L. | Power, Chris | Pramstaller, Peter P. | Price, Jackie F. | Psaty, Bruce M. | Quertermous, Thomas | Rauramaa, Rainer | Saleheen, Danish | Salomaa, Veikko | Sanghera, Dharambir K. | Saramies, Jouko | Schwarz, Peter E.H. | Sheu, Wayne H-H | Shuldiner, Alan R. | Siegbahn, Agneta | Spector, Tim D. | Stefansson, Kari | Strachan, David P. | Tayo, Bamidele O. | Tremoli, Elena | Tuomilehto, Jaakko | Uusitupa, Matti | van Duijn, Cornelia M. | Vollenweider, Peter | Wallentin, Lars | Wareham, Nicholas J. | Whitfield, John B. | Wolffenbuttel, Bruce H.R. | Altshuler, David | Ordovas, Jose M. | Boerwinkle, Eric | Palmer, Colin N.A. | Thorsteinsdottir, Unnur | Chasman, Daniel I. | Rotter, Jerome I. | Franks, Paul W. | Ripatti, Samuli | Cupples, L. Adrienne | Sandhu, Manjinder S. | Rich, Stephen S. | Boehnke, Michael | Deloukas, Panos | Mohlke, Karen L. | Ingelsson, Erik | Abecasis, Goncalo R. | Daly, Mark J. | Neale, Benjamin M. | Kathiresan, Sekar
Nature genetics  2013;45(11):1345-1352.
Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiologic studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P<5×10−8 for each) to examine the role of triglycerides on risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglycerides, and show that the direction and magnitude of both are factors in determining CAD risk. Second, we consider loci with only a strong magnitude of association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol, a polymorphism's strength of effect on triglycerides is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
doi:10.1038/ng.2795
PMCID: PMC3904346  PMID: 24097064
3.  Preeclampsia, gestational hypertension and subsequent hypothyroidism 
Pregnancy hypertension  2012;3(1):21-27.
Objectives
To evaluate the effect of preeclampsia (PE) and gestational hypertension (GH) on subsequent hypothyroidism. Recent studies suggest that women with PE have increased risk for reduced thyroid function, but the association between PE and GH with overt hypothyroidism has not been examined.
Study design
Two prospective population-based cohort studies, the Northern Finland Birth Cohorts 1966 and 1986, followed women who had PE (N=955), GH (N=1449) or were normotensive (N=13531) during pregnancy. Finnish national registers were used to confirm subsequent hypothyroidism. Adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) estimated hypothyroidism risk when comparing women with PE or GH with normotensive women.
Main outcome measures
Primary hypothyroidism during follow-up of 20–40 years.
Results
The subsequent prevalence of hypothyroidism was higher among women with PE (4.0%) and GH (4.5%) compared with normotensive women (3.5%), but the risk increase was not significant (aHR for PE 1.13, 95%CI 0.80–1.59 and aHR for GH 1.11, 95%CI 0.85–1.45).
Subgroup analysis among nulliparous women revealed a significant association between late PE and subsequent hypothyroidism (aHR 1.82, 95%CI 1.04–3.19).
Early or recurrent PE were not associated with hypothyroidism (aHR 0.93, 95%CI 0.46–1.81 and aHR 1.35, 95%CI 0.63–2.88, respectively).
Conclusions
Overall, PE or GH during pregnancy was not significantly associated with subsequent hypothyroidism in Finnish women after 20–40 years of follow-up. However, late PE in nulliparous women was associated with a 1.8-fold increased risk of subsequent hypothyroidism, a finding that merits further study in other populations.
doi:10.1016/j.preghy.2012.09.001
PMCID: PMC3578699  PMID: 23439671
preeclampsia; gestational hypertension; thyroid; hypothyroidism
4.  Smoking and Early Pregnancy Thyroid Hormone and Anti-Thyroid Antibody Levels in Euthyroid Mothers of the Northern Finland Birth Cohort 1986 
Thyroid  2012;22(9):944-950.
Background
Smokers in the general population have lower thyrotropin (TSH) and higher free triiodothyronine (fT3) and free thyroxine (fT4) concentrations, but the results in pregnant population vary from no effect to a decrease in TSH and fT4 concentrations and an increase in fT3 levels. Our objective was to further evaluate the question of whether there is an association between smoking, before and during pregnancy, with maternal thyroid function during pregnancy and with the risk for subsequent hypothyroidism.
Methods
Our study population was a prospective population-based cohort (N=9362), the Northern Finland Birth Cohort 1986, with extensive data throughout gestation. The mothers underwent serum sampling in early pregnancy. The samples were assayed for TSH, fT3, fT4, thyroid-peroxidase antibodies (TPO-Ab), and thyroglobulin antibodies (TG-Abs) (n=5805). Mothers with thyroid dysfunction diagnosed before or during pregnancy were excluded, leaving 4837 euthyroid mothers. The smoking status of mothers and fathers were requested by questionnaires during pregnancy. Subsequent maternal morbidity relating to hypothyroidism 20 years after the index pregnancy was evaluated using national registers.
Results
Euthyroid mothers who smoked before, or continued smoking during first trimester of pregnancy, had higher serum fT3 (p<0.001) and lower fT4 (p=0.023) concentrations than nonsmokers. Smoking in the second trimester was associated with higher fT3 (p<0.001) concentrations, but no difference in fT4 concentrations compared with nonsmokers. TG-Abs were less common among smoking than nonsmoking mothers (2.5% vs. 4.7%, p<0.001), but the prevalence of TPO-Ab was similar. Paternal smoking had no independent effect on maternal early pregnancy thyroid hormone or antibody concentrations. The risk of subsequent maternal hypothyroidism after follow-up of 20 years was similar among prepregnancy smokers and nonsmokers.
Conclusions
In euthyroid women, smoking during pregnancy was associated with higher fT3 levels and lower fT4 levels; possibly reflecting smoking-induced changes in peripheral metabolism of thyroid hormones. No differences were found in TSH concentrations between smokers and nonsmokers. Our results differ from those of the general population, which usually have shown smoking-induced thyroidal stimulation. This is possibly due to pregnancy-induced changes in thyroid function. Decreases in fT4 levels among smokers might predispose to hypothyroidism or hypothyroxinemia during pregnancy. Despite these changes in thyroid function, smoking did not increase the woman's risk of subsequent hypothyroidism.
doi:10.1089/thy.2011.0377
PMCID: PMC3429279  PMID: 22873201
5.  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
6.  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 | Orho-Melander, Marju | Palmer, Colin Neil Alexander | Morris, Andrew D. | Groop, Leif | Järvelin, Marjo-Riitta | Salomaa, Veikko | Vartiainen, Erkki | Hofman, Albert | Ripatti, Samuli | Metspalu, Andres | Thorsteinsdottir, Unnur | Stefansson, Kari | Pedersen, Nancy L. | McCarthy, Mark I. | Ingelsson, Erik | Prokopenko, Inga
PLoS Medicine  2013;10(6):e1001474.
In this study, Prokopenko and colleagues provide novel evidence for causal relationship between adiposity and heart failure and increased liver enzymes using a Mendelian randomization study design.
Please see later in the article for the Editors' Summary
Background
The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach.
Methods and Findings
We used the adiposity-associated variant rs9939609 at the FTO locus as an instrumental variable (IV) for body mass index (BMI) in a Mendelian randomization design. Thirty-six population-based studies of individuals of European descent contributed to the analyses.
Age- and sex-adjusted regression models were fitted to test for association between (i) rs9939609 and BMI (n = 198,502), (ii) rs9939609 and 24 traits, and (iii) BMI and 24 traits. The causal effect of BMI on the outcome measures was quantified by IV estimators. The estimators were compared to the BMI–trait associations derived from the same individuals. In the IV analysis, we demonstrated novel evidence for a causal relationship between adiposity and incident heart failure (hazard ratio, 1.19 per BMI-unit increase; 95% CI, 1.03–1.39) and replicated earlier reports of a causal association with type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension (odds ratio for IV estimator, 1.1–1.4; all p<0.05). For quantitative traits, our results provide novel evidence for a causal effect of adiposity on the liver enzymes alanine aminotransferase and gamma-glutamyl transferase and confirm previous reports of a causal effect of adiposity on systolic and diastolic blood pressure, fasting insulin, 2-h post-load glucose from the oral glucose tolerance test, C-reactive protein, triglycerides, and high-density lipoprotein cholesterol levels (all p<0.05). The estimated causal effects were in agreement with traditional observational measures in all instances except for type 2 diabetes, where the causal estimate was larger than the observational estimate (p = 0.001).
Conclusions
We provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.
Please see later in the article for the Editors' Summary
Editors' Summary
Cardiovascular disease (CVD)—disease that affects the heart and/or the blood vessels—is a major cause of illness and death worldwide. In the US, for example, coronary heart disease—a CVD in which narrowing of the heart's blood vessels by fatty deposits slows the blood supply to the heart and may eventually cause a heart attack—is the leading cause of death, and stroke—a CVD in which the brain's blood supply is interrupted—is the fourth leading cause of death. Globally, both the incidence of CVD (the number of new cases in a population every year) and its prevalence (the proportion of the population with CVD) are increasing, particularly in low- and middle-income countries. This increasing burden of CVD is occurring in parallel with a global increase in the incidence and prevalence of obesity—having an unhealthy amount of body fat (adiposity)—and of metabolic diseases—conditions such as diabetes in which metabolism (the processes that the body uses to make energy from food) is disrupted, with resulting high blood sugar and damage to the blood vessels.
Why Was This Study Done?
Epidemiological studies—investigations that record the patterns and causes of disease in populations—have reported an association between adiposity (indicated by an increased body mass index [BMI], which is calculated by dividing body weight in kilograms by height in meters squared) and cardiometabolic traits such as coronary heart disease, stroke, heart failure (a condition in which the heart is incapable of pumping sufficient amounts of blood around the body), diabetes, high blood pressure (hypertension), and high blood cholesterol (dyslipidemia). However, observational studies cannot prove that adiposity causes any particular cardiometabolic trait because overweight individuals may share other characteristics (confounding factors) that are the real causes of both obesity and the cardiometabolic disease. Moreover, it is possible that having CVD or a metabolic disease causes obesity (reverse causation). For example, individuals with heart failure cannot do much exercise, so heart failure may cause obesity rather than vice versa. Here, the researchers use “Mendelian randomization” to examine whether adiposity is causally related to various cardiometabolic traits. Because gene variants are inherited randomly, they are not prone to confounding and are free from reverse causation. It is known that a genetic variant (rs9939609) within the genome region that encodes the fat-mass- and obesity-associated gene (FTO) is associated with increased BMI. Thus, an investigation of the associations between rs9939609 and cardiometabolic traits can indicate whether obesity is causally related to these traits.
What Did the Researchers Do and Find?
The researchers analyzed the association between rs9939609 (the “instrumental variable,” or IV) and BMI, between rs9939609 and 24 cardiometabolic traits, and between BMI and the same traits using genetic and health data collected in 36 population-based studies of nearly 200,000 individuals of European descent. They then quantified the strength of the causal association between BMI and the cardiometabolic traits by calculating “IV estimators.” Higher BMI showed a causal relationship with heart failure, metabolic syndrome (a combination of medical disorders that increases the risk of developing CVD), type 2 diabetes, dyslipidemia, hypertension, increased blood levels of liver enzymes (an indicator of liver damage; some metabolic disorders involve liver damage), and several other cardiometabolic traits. All the IV estimators were similar to the BMI–cardiovascular trait associations (observational estimates) derived from the same individuals, with the exception of diabetes, where the causal estimate was higher than the observational estimate, probably because the observational estimate is based on a single BMI measurement, whereas the causal estimate considers lifetime changes in BMI.
What Do These Findings Mean?
Like all Mendelian randomization studies, the reliability of the causal associations reported here depends on several assumptions made by the researchers. Nevertheless, these findings provide support for many previously suspected and biologically plausible causal relationships, such as that between adiposity and hypertension. They also provide new insights into the causal effect of obesity on liver enzyme levels and on heart failure. In the latter case, these findings suggest that a one-unit increase in BMI might increase the incidence of heart failure by 17%. In the US, this corresponds to 113,000 additional cases of heart failure for every unit increase in BMI at the population level. Although additional studies are needed to confirm and extend these findings, these results suggest that global efforts to reduce the burden of obesity will likely also reduce the occurrence of CVD and metabolic disorders.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001474.
The American Heart Association provides information on all aspects of cardiovascular disease and tips on keeping the heart healthy, including weight management (in several languages); its website includes personal stories about stroke and heart attacks
The US Centers for Disease Control and Prevention has information on heart disease, stroke, and all aspects of overweight and obesity (in English and Spanish)
The UK National Health Service Choices website provides information about cardiovascular disease and obesity, including a personal story about losing weight
The World Health Organization provides information on obesity (in several languages)
The International Obesity Taskforce provides information about the global obesity epidemic
Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
MedlinePlus provides links to other sources of information on heart disease, on vascular disease, on obesity, and on metabolic disorders (in English and Spanish)
The International Association for the Study of Obesity provides maps and information about obesity worldwide
The International Diabetes Federation has a web page that describes types, complications, and risk factors of diabetes
doi:10.1371/journal.pmed.1001474
PMCID: PMC3692470  PMID: 23824655
7.  Seventy-five genetic loci influencing the human red blood cell 
van der Harst, Pim | Zhang, Weihua | Leach, Irene Mateo | Rendon, Augusto | Verweij, Niek | Sehmi, Joban | Paul, Dirk S. | Elling, Ulrich | Allayee, Hooman | Li, Xinzhong | Radhakrishnan, Aparna | Tan, Sian-Tsung | Voss, Katrin | Weichenberger, Christian X. | Albers, Cornelis A. | Al-Hussani, Abtehale | Asselbergs, Folkert W. | Ciullo, Marina | Danjou, Fabrice | Dina, Christian | Esko, Tõnu | Evans, David M. | Franke, Lude | Gögele, Martin | Hartiala, Jaana | Hersch, Micha | Holm, Hilma | Hottenga, Jouke-Jan | Kanoni, Stavroula | Kleber, Marcus E. | Lagou, Vasiliki | Langenberg, Claudia | Lopez, Lorna M. | Lyytikäinen, Leo-Pekka | Melander, Olle | Murgia, Federico | Nolte, Ilja M. | O’Reilly, Paul F. | Padmanabhan, Sandosh | Parsa, Afshin | Pirastu, Nicola | Porcu, Eleonora | Portas, Laura | Prokopenko, Inga | Ried, Janina S. | Shin, So-Youn | Tang, Clara S. | Teumer, Alexander | Traglia, Michela | Ulivi, Sheila | Westra, Harm-Jan | Yang, Jian | Zhao, Jing Hua | Anni, Franco | Abdellaoui, Abdel | Attwood, Antony | Balkau, Beverley | Bandinelli, Stefania | Bastardot, François | Benyamin, Beben | Boehm, Bernhard O. | Cookson, William O. | Das, Debashish | de Bakker, Paul I. W. | de Boer, Rudolf A. | de Geus, Eco J. C. | de Moor, Marleen H. | Dimitriou, Maria | Domingues, Francisco S. | Döring, Angela | Engström, Gunnar | Eyjolfsson, Gudmundur Ingi | Ferrucci, Luigi | Fischer, Krista | Galanello, Renzo | Garner, Stephen F. | Genser, Bernd | Gibson, Quince D. | Girotto, Giorgia | Gudbjartsson, Daniel Fannar | Harris, Sarah E. | Hartikainen, Anna-Liisa | Hastie, Claire E. | Hedblad, Bo | Illig, Thomas | Jolley, Jennifer | Kähönen, Mika | Kema, Ido P. | Kemp, John P. | Liang, Liming | Lloyd-Jones, Heather | Loos, Ruth J. F. | Meacham, Stuart | Medland, Sarah E. | Meisinger, Christa | Memari, Yasin | Mihailov, Evelin | Miller, Kathy | Moffatt, Miriam F. | Nauck, Matthias | Novatchkova, Maria | Nutile, Teresa | Olafsson, Isleifur | Onundarson, Pall T. | Parracciani, Debora | Penninx, Brenda W. | Perseu, Lucia | Piga, Antonio | Pistis, Giorgio | Pouta, Anneli | Puc, Ursula | Raitakari, Olli | Ring, Susan M. | Robino, Antonietta | Ruggiero, Daniela | Ruokonen, Aimo | Saint-Pierre, Aude | Sala, Cinzia | Salumets, Andres | Sambrook, Jennifer | Schepers, Hein | Schmidt, Carsten Oliver | Silljé, Herman H. W. | Sladek, Rob | Smit, Johannes H. | Starr, John M. | Stephens, Jonathan | Sulem, Patrick | Tanaka, Toshiko | Thorsteinsdottir, Unnur | Tragante, Vinicius | van Gilst, Wiek H. | van Pelt, L. Joost | van Veldhuisen, Dirk J. | Völker, Uwe | Whitfield, John B. | Willemsen, Gonneke | Winkelmann, Bernhard R. | Wirnsberger, Gerald | Algra, Ale | Cucca, Francesco | d’Adamo, Adamo Pio | Danesh, John | Deary, Ian J. | Dominiczak, Anna F. | Elliott, Paul | Fortina, Paolo | Froguel, Philippe | Gasparini, Paolo | Greinacher, Andreas | Hazen, Stanley L. | Jarvelin, Marjo-Riitta | Khaw, Kay Tee | Lehtimäki, Terho | Maerz, Winfried | Martin, Nicholas G. | Metspalu, Andres | Mitchell, Braxton D. | Montgomery, Grant W. | Moore, Carmel | Navis, Gerjan | Pirastu, Mario | Pramstaller, Peter P. | Ramirez-Solis, Ramiro | Schadt, Eric | Scott, James | Shuldiner, Alan R. | Smith, George Davey | Smith, J. Gustav | Snieder, Harold | Sorice, Rossella | Spector, Tim D. | Stefansson, Kari | Stumvoll, Michael | Wilson Tang, W. H. | Toniolo, Daniela | Tönjes, Anke | Visscher, Peter M. | Vollenweider, Peter | Wareham, Nicholas J. | Wolffenbuttel, Bruce H. R. | Boomsma, Dorret I. | Beckmann, Jacques S. | Dedoussis, George V. | Deloukas, Panos | Ferreira, Manuel A. | Sanna, Serena | Uda, Manuela | Hicks, Andrew A. | Penninger, Josef Martin | Gieger, Christian | Kooner, Jaspal S. | Ouwehand, Willem H. | Soranzo, Nicole | Chambers, John C
Nature  2012;492(7429):369-375.
Anaemia is a chief determinant of globalill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P <10−8, which together explain 4–9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.
doi:10.1038/nature11677
PMCID: PMC3623669  PMID: 23222517
8.  A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance 
Manning, Alisa K. | Hivert, Marie-France | Scott, Robert A. | Grimsby, Jonna L. | Bouatia-Naji, Nabila | Chen, Han | Rybin, Denis | Liu, Ching-Ti | Bielak, Lawrence F. | Prokopenko, Inga | Amin, Najaf | Barnes, Daniel | Cadby, Gemma | Hottenga, Jouke-Jan | Ingelsson, Erik | Jackson, Anne U. | Johnson, Toby | Kanoni, Stavroula | Ladenvall, Claes | Lagou, Vasiliki | Lahti, Jari | Lecoeur, Cecile | Liu, Yongmei | Martinez-Larrad, Maria Teresa | Montasser, May E. | Navarro, Pau | Perry, John R. B. | Rasmussen-Torvik, Laura J. | Salo, Perttu | Sattar, Naveed | Shungin, Dmitry | Strawbridge, Rona J. | Tanaka, Toshiko | van Duijn, Cornelia M. | An, Ping | de Andrade, Mariza | Andrews, Jeanette S. | Aspelund, Thor | Atalay, Mustafa | Aulchenko, Yurii | Balkau, Beverley | Bandinelli, Stefania | Beckmann, Jacques S. | Beilby, John P. | Bellis, Claire | Bergman, Richard N. | Blangero, John | Boban, Mladen | Boehnke, Michael | Boerwinkle, Eric | Bonnycastle, Lori L. | Boomsma, Dorret I. | Borecki, Ingrid B. | Böttcher, Yvonne | Bouchard, Claude | Brunner, Eric | Budimir, Danijela | Campbell, Harry | Carlson, Olga | Chines, Peter S. | Clarke, Robert | Collins, Francis S. | Corbatón-Anchuelo, Arturo | Couper, David | de Faire, Ulf | Dedoussis, George V | Deloukas, Panos | Dimitriou, Maria | Egan, Josephine M | Eiriksdottir, Gudny | Erdos, Michael R. | Eriksson, Johan G. | Eury, Elodie | Ferrucci, Luigi | Ford, Ian | Forouhi, Nita G. | Fox, Caroline S | Franzosi, Maria Grazia | Franks, Paul W | Frayling, Timothy M | Froguel, Philippe | Galan, Pilar | de Geus, Eco | Gigante, Bruna | Glazer, Nicole L. | Goel, Anuj | Groop, Leif | Gudnason, Vilmundur | Hallmans, Göran | Hamsten, Anders | Hansson, Ola | Harris, Tamara B. | Hayward, Caroline | Heath, Simon | Hercberg, Serge | Hicks, Andrew A. | Hingorani, Aroon | Hofman, Albert | Hui, Jennie | Hung, Joseph | Jarvelin, Marjo Riitta | Jhun, Min A. | Johnson, Paul C.D. | Jukema, J Wouter | Jula, Antti | Kao, W.H. | Kaprio, Jaakko | Kardia, Sharon L. R. | Keinanen-Kiukaanniemi, Sirkka | Kivimaki, Mika | Kolcic, Ivana | Kovacs, Peter | Kumari, Meena | Kuusisto, Johanna | Kyvik, Kirsten Ohm | Laakso, Markku | Lakka, Timo | Lannfelt, Lars | Lathrop, G Mark | Launer, Lenore J. | Leander, Karin | Li, Guo | Lind, Lars | Lindstrom, Jaana | Lobbens, Stéphane | Loos, Ruth J. F. | Luan, Jian’an | Lyssenko, Valeriya | Mägi, Reedik | Magnusson, Patrik K. E. | Marmot, Michael | Meneton, Pierre | Mohlke, Karen L. | Mooser, Vincent | Morken, Mario A. | Miljkovic, Iva | Narisu, Narisu | O’Connell, Jeff | Ong, Ken K. | Oostra, Ben A. | Palmer, Lyle J. | Palotie, Aarno | Pankow, James S. | Peden, John F. | Pedersen, Nancy L. | Pehlic, Marina | Peltonen, Leena | Penninx, Brenda | Pericic, Marijana | Perola, Markus | Perusse, Louis | Peyser, Patricia A | Polasek, Ozren | Pramstaller, Peter P. | Province, Michael A. | Räikkönen, Katri | Rauramaa, Rainer | Rehnberg, Emil | Rice, Ken | Rotter, Jerome I. | Rudan, Igor | Ruokonen, Aimo | Saaristo, Timo | Sabater-Lleal, Maria | Salomaa, Veikko | Savage, David B. | Saxena, Richa | Schwarz, Peter | Seedorf, Udo | Sennblad, Bengt | Serrano-Rios, Manuel | Shuldiner, Alan R. | Sijbrands, Eric J.G. | Siscovick, David S. | Smit, Johannes H. | Small, Kerrin S. | Smith, Nicholas L. | Smith, Albert Vernon | Stančáková, Alena | Stirrups, Kathleen | Stumvoll, Michael | Sun, Yan V. | Swift, Amy J. | Tönjes, Anke | Tuomilehto, Jaakko | Trompet, Stella | Uitterlinden, Andre G. | Uusitupa, Matti | Vikström, Max | Vitart, Veronique | Vohl, Marie-Claude | Voight, Benjamin F. | Vollenweider, Peter | Waeber, Gerard | Waterworth, Dawn M | Watkins, Hugh | Wheeler, Eleanor | Widen, Elisabeth | Wild, Sarah H. | Willems, Sara M. | Willemsen, Gonneke | Wilson, James F. | Witteman, Jacqueline C.M. | Wright, Alan F. | Yaghootkar, Hanieh | Zelenika, Diana | Zemunik, Tatijana | Zgaga, Lina | Wareham, Nicholas J. | McCarthy, Mark I. | Barroso, Ines | Watanabe, Richard M. | Florez, Jose C. | Dupuis, Josée | Meigs, James B. | Langenberg, Claudia
Nature genetics  2012;44(6):659-669.
Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and beta-cell dysfunction, but contributed little to our understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways may be uncovered by accounting for differences in body mass index (BMI) and potential interaction between BMI and genetic variants. We applied a novel joint meta-analytical approach to test associations with fasting insulin (FI) and glucose (FG) on a genome-wide scale. We present six previously unknown FI loci at P<5×10−8 in combined discovery and follow-up analyses of 52 studies comprising up to 96,496non-diabetic individuals. Risk variants were associated with higher triglyceride and lower HDL cholesterol levels, suggestive of a role for these FI loci in insulin resistance pathways. The localization of these additional loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.
doi:10.1038/ng.2274
PMCID: PMC3613127  PMID: 22581228
9.  Rare Genomic Structural Variants in Complex Disease: Lessons from the Replication of Associations with Obesity 
PLoS ONE  2013;8(3):e58048.
The limited ability of common variants to account for the genetic contribution to complex disease has prompted searches for rare variants of large effect, to partly explain the ‘missing heritability’. Analyses of genome-wide genotyping data have identified genomic structural variants (GSVs) as a source of such rare causal variants. Recent studies have reported multiple GSV loci associated with risk of obesity. We attempted to replicate these associations by similar analysis of two familial-obesity case-control cohorts and a population cohort, and detected GSVs at 11 out of 18 loci, at frequencies similar to those previously reported. Based on their reported frequencies and effect sizes (OR≥25), we had sufficient statistical power to detect the large majority (80%) of genuine associations at these loci. However, only one obesity association was replicated. Deletion of a 220 kb region on chromosome 16p11.2 has a carrier population frequency of 2×10−4 (95% confidence interval [9.6×10−5–3.1×10−4]); accounts overall for 0.5% [0.19%–0.82%] of severe childhood obesity cases (P = 3.8×10−10; odds ratio = 25.0 [9.9–60.6]); and results in a mean body mass index (BMI) increase of 5.8 kg.m−2 [1.8–10.3] in adults from the general population. We also attempted replication using BMI as a quantitative trait in our population cohort; associations with BMI at or near nominal significance were detected at two further loci near KIF2B and within FOXP2, but these did not survive correction for multiple testing. These findings emphasise several issues of importance when conducting rare GSV association, including the need for careful cohort selection and replication strategy, accurate GSV identification, and appropriate correction for multiple testing and/or control of false discovery rate. Moreover, they highlight the potential difficulty in replicating rare CNV associations across different populations. Nevertheless, we show that such studies are potentially valuable for the identification of variants making an appreciable contribution to complex disease.
doi:10.1371/journal.pone.0058048
PMCID: PMC3595275  PMID: 23554873
10.  Estimation of Newborn Risk for Child or Adolescent Obesity: Lessons from Longitudinal Birth Cohorts 
PLoS ONE  2012;7(11):e49919.
Objectives
Prevention of obesity should start as early as possible after birth. We aimed to build clinically useful equations estimating the risk of later obesity in newborns, as a first step towards focused early prevention against the global obesity epidemic.
Methods
We analyzed the lifetime Northern Finland Birth Cohort 1986 (NFBC1986) (N = 4,032) to draw predictive equations for childhood and adolescent obesity from traditional risk factors (parental BMI, birth weight, maternal gestational weight gain, behaviour and social indicators), and a genetic score built from 39 BMI/obesity-associated polymorphisms. We performed validation analyses in a retrospective cohort of 1,503 Italian children and in a prospective cohort of 1,032 U.S. children.
Results
In the NFBC1986, the cumulative accuracy of traditional risk factors predicting childhood obesity, adolescent obesity, and childhood obesity persistent into adolescence was good: AUROC = 0·78[0·74–0.82], 0·75[0·71–0·79] and 0·85[0·80–0·90] respectively (all p<0·001). Adding the genetic score produced discrimination improvements ≤1%. The NFBC1986 equation for childhood obesity remained acceptably accurate when applied to the Italian and the U.S. cohort (AUROC = 0·70[0·63–0·77] and 0·73[0·67–0·80] respectively) and the two additional equations for childhood obesity newly drawn from the Italian and the U.S. datasets showed good accuracy in respective cohorts (AUROC = 0·74[0·69–0·79] and 0·79[0·73–0·84]) (all p<0·001). The three equations for childhood obesity were converted into simple Excel risk calculators for potential clinical use.
Conclusion
This study provides the first example of handy tools for predicting childhood obesity in newborns by means of easily recorded information, while it shows that currently known genetic variants have very little usefulness for such prediction.
doi:10.1371/journal.pone.0049919
PMCID: PMC3509134  PMID: 23209618
11.  Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma 
Chambers, John C | Zhang, Weihua | Sehmi, Joban | Li, Xinzhong | Wass, Mark N | Van der Harst, Pim | Holm, Hilma | Sanna, Serena | Kavousi, Maryam | Baumeister, Sebastian E | Coin, Lachlan J | Deng, Guohong | Gieger, Christian | Heard-Costa, Nancy L | Hottenga, Jouke-Jan | Kühnel, Brigitte | Kumar, Vinod | Lagou, Vasiliki | Liang, Liming | Luan, Jian’an | Vidal, Pedro Marques | Leach, Irene Mateo | O’Reilly, Paul F | Peden, John F | Rahmioglu, Nilufer | Soininen, Pasi | Speliotes, Elizabeth K | Yuan, Xin | Thorleifsson, Gudmar | Alizadeh, Behrooz Z | Atwood, Larry D | Borecki, Ingrid B | Brown, Morris J | Charoen, Pimphen | Cucca, Francesco | Das, Debashish | de Geus, Eco J C | Dixon, Anna L | Döring, Angela | Ehret, Georg | Eyjolfsson, Gudmundur I | Farrall, Martin | Forouhi, Nita G | Friedrich, Nele | Goessling, Wolfram | Gudbjartsson, Daniel F | Harris, Tamara B | Hartikainen, Anna-Liisa | Heath, Simon | Hirschfield, Gideon M | Hofman, Albert | Homuth, Georg | Hyppönen, Elina | Janssen, Harry L A | Johnson, Toby | Kangas, Antti J | Kema, Ido P | Kühn, Jens P | Lai, Sandra | Lathrop, Mark | Lerch, Markus M | Li, Yun | Liang, T Jake | Lin, Jing-Ping | Loos, Ruth J F | Martin, Nicholas G | Moffatt, Miriam F | Montgomery, Grant W | Munroe, Patricia B | Musunuru, Kiran | Nakamura, Yusuke | O’Donnell, Christopher J | Olafsson, Isleifur | Penninx, Brenda W | Pouta, Anneli | Prins, Bram P | Prokopenko, Inga | Puls, Ralf | Ruokonen, Aimo | Savolainen, Markku J | Schlessinger, David | Schouten, Jeoffrey N L | Seedorf, Udo | Sen-Chowdhry, Srijita | Siminovitch, Katherine A | Smit, Johannes H | Spector, Timothy D | Tan, Wenting | Teslovich, Tanya M | Tukiainen, Taru | Uitterlinden, Andre G | Van der Klauw, Melanie M | Vasan, Ramachandran S | Wallace, Chris | Wallaschofski, Henri | Wichmann, H-Erich | Willemsen, Gonneke | Würtz, Peter | Xu, Chun | Yerges-Armstrong, Laura M | Abecasis, Goncalo R | Ahmadi, Kourosh R | Boomsma, Dorret I | Caulfield, Mark | Cookson, William O | van Duijn, Cornelia M | Froguel, Philippe | Matsuda, Koichi | McCarthy, Mark I | Meisinger, Christa | Mooser, Vincent | Pietiläinen, Kirsi H | Schumann, Gunter | Snieder, Harold | Sternberg, Michael J E | Stolk, Ronald P | Thomas, Howard C | Thorsteinsdottir, Unnur | Uda, Manuela | Waeber, Gérard | Wareham, Nicholas J | Waterworth, Dawn M | Watkins, Hugh | Whitfield, John B | Witteman, Jacqueline C M | Wolffenbuttel, Bruce H R | Fox, Caroline S | Ala-Korpela, Mika | Stefansson, Kari | Vollenweider, Peter | Völzke, Henry | Schadt, Eric E | Scott, James | Järvelin, Marjo-Riitta | Elliott, Paul | Kooner, Jaspal S
Nature genetics  2011;43(11):1131-1138.
Concentrations of liver enzymes in plasma are widely used as indicators of liver disease. We carried out a genome-wide association study in 61,089 individuals, identifying 42 loci associated with concentrations of liver enzymes in plasma, of which 32 are new associations (P = 10−8 to P = 10−190). We used functional genomic approaches including metabonomic profiling and gene expression analyses to identify probable candidate genes at these regions. We identified 69 candidate genes, including genes involved in biliary transport (ATP8B1 and ABCB11), glucose, carbohydrate and lipid metabolism (FADS1, FADS2, GCKR, JMJD1C, HNF1A, MLXIPL, PNPLA3, PPP1R3B, SLC2A2 and TRIB1), glycoprotein biosynthesis and cell surface glycobiology (ABO, ASGR1, FUT2, GPLD1 and ST3GAL4), inflammation and immunity (CD276, CDH6, GCKR, HNF1A, HPR, ITGA1, RORA and STAT4) and glutathione metabolism (GSTT1, GSTT2 and GGT), as well as several genes of uncertain or unknown function (including ABHD12, EFHD1, EFNA1, EPHA2, MICAL3 and ZNF827). Our results provide new insight into genetic mechanisms and pathways influencing markers of liver function.
doi:10.1038/ng.970
PMCID: PMC3482372  PMID: 22001757
12.  Genome-Wide Screen for Metabolic Syndrome Susceptibility Loci Reveals Strong Lipid Gene Contribution but No Evidence for Common Genetic Basis for Clustering of Metabolic Syndrome Traits 
Background
Genome-wide association (GWA) studies have identified several susceptibility loci for metabolic syndrome (MetS) component traits, but have had variable success in identifying susceptibility loci to the syndrome as an entity. We conducted a GWA study on MetS and its component traits in four Finnish cohorts consisting of 2637 MetS cases and 7927 controls, both free of diabetes, and followed the top loci in an independent sample with transcriptome and NMR-based metabonomics data. Furthermore, we tested for loci associated with multiple MetS component traits using factor analysis and built a genetic risk score for MetS.
Methods and Results
A previously known lipid locus, APOA1/C3/A4/A5 gene cluster region (SNP rs964184), was associated with MetS in all four study samples (P=7.23×10−9 in meta-analysis). The association was further supported by serum metabolite analysis, where rs964184 associated with various VLDL, TG, and HDL metabolites (P=0.024-1.88×10−5). Twenty-two previously identified susceptibility loci for individual MetS component traits were replicated in our GWA and factor analysis. Most of these associated with lipid phenotypes and none with two or more uncorrelated MetS components. A genetic risk score, calculated as the number of alleles in loci associated with individual MetS traits, was strongly associated with MetS status.
Conclusions
Our findings suggest that genes from lipid metabolism pathways have the key role in the genetic background of MetS. We found little evidence for pleiotropy linking dyslipidemia and obesity to the other MetS component traits such as hypertension and glucose intolerance.
doi:10.1161/CIRCGENETICS.111.961482
PMCID: PMC3378651  PMID: 22399527
metabolic syndrome; risk factors; genome-wide association study; meta-analysis; lipids
13.  A Genome-Wide Association Meta-Analysis of Circulating Sex Hormone–Binding Globulin Reveals Multiple Loci Implicated in Sex Steroid Hormone Regulation 
Coviello, Andrea D. | Haring, Robin | Wellons, Melissa | Vaidya, Dhananjay | Lehtimäki, Terho | Keildson, Sarah | Lunetta, Kathryn L. | He, Chunyan | Fornage, Myriam | Lagou, Vasiliki | Mangino, Massimo | Onland-Moret, N. Charlotte | Chen, Brian | Eriksson, Joel | Garcia, Melissa | Liu, Yong Mei | Koster, Annemarie | Lohman, Kurt | Lyytikäinen, Leo-Pekka | Petersen, Ann-Kristin | Prescott, Jennifer | Stolk, Lisette | Vandenput, Liesbeth | Wood, Andrew R. | Zhuang, Wei Vivian | Ruokonen, Aimo | Hartikainen, Anna-Liisa | Pouta, Anneli | Bandinelli, Stefania | Biffar, Reiner | Brabant, Georg | Cox, David G. | Chen, Yuhui | Cummings, Steven | Ferrucci, Luigi | Gunter, Marc J. | Hankinson, Susan E. | Martikainen, Hannu | Hofman, Albert | Homuth, Georg | Illig, Thomas | Jansson, John-Olov | Johnson, Andrew D. | Karasik, David | Karlsson, Magnus | Kettunen, Johannes | Kiel, Douglas P. | Kraft, Peter | Liu, Jingmin | Ljunggren, Östen | Lorentzon, Mattias | Maggio, Marcello | Markus, Marcello R. P. | Mellström, Dan | Miljkovic, Iva | Mirel, Daniel | Nelson, Sarah | Morin Papunen, Laure | Peeters, Petra H. M. | Prokopenko, Inga | Raffel, Leslie | Reincke, Martin | Reiner, Alex P. | Rexrode, Kathryn | Rivadeneira, Fernando | Schwartz, Stephen M. | Siscovick, David | Soranzo, Nicole | Stöckl, Doris | Tworoger, Shelley | Uitterlinden, André G. | van Gils, Carla H. | Vasan, Ramachandran S. | Wichmann, H.-Erich | Zhai, Guangju | Bhasin, Shalender | Bidlingmaier, Martin | Chanock, Stephen J. | De Vivo, Immaculata | Harris, Tamara B. | Hunter, David J. | Kähönen, Mika | Liu, Simin | Ouyang, Pamela | Spector, Tim D. | van der Schouw, Yvonne T. | Viikari, Jorma | Wallaschofski, Henri | McCarthy, Mark I. | Frayling, Timothy M. | Murray, Anna | Franks, Steve | Järvelin, Marjo-Riitta | de Jong, Frank H. | Raitakari, Olli | Teumer, Alexander | Ohlsson, Claes | Murabito, Joanne M. | Perry, John R. B.
PLoS Genetics  2012;8(7):e1002805.
Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8×10−106), PRMT6 (rs17496332, 1p13.3, p = 1.4×10−11), GCKR (rs780093, 2p23.3, p = 2.2×10−16), ZBTB10 (rs440837, 8q21.13, p = 3.4×10−09), JMJD1C (rs7910927, 10q21.3, p = 6.1×10−35), SLCO1B1 (rs4149056, 12p12.1, p = 1.9×10−08), NR2F2 (rs8023580, 15q26.2, p = 8.3×10−12), ZNF652 (rs2411984, 17q21.32, p = 3.5×10−14), TDGF3 (rs1573036, Xq22.3, p = 4.1×10−14), LHCGR (rs10454142, 2p16.3, p = 1.3×10−07), BAIAP2L1 (rs3779195, 7q21.3, p = 2.7×10−08), and UGT2B15 (rs293428, 4q13.2, p = 5.5×10−06). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p = 2.5×10−08, women p = 0.66, heterogeneity p = 0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained ∼15.6% and ∼8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance.
Author Summary
Sex hormone-binding globulin (SHBG) is the key protein responsible for binding and transporting the sex steroid hormones, testosterone and estradiol, in the circulatory system. SHBG regulates their bioavailability and therefore their effects in the body. SHBG has been linked to chronic diseases including type 2 diabetes and to hormone-sensitive cancers such as breast and prostate cancer. SHBG concentrations are approximately 50% heritable in family studies, suggesting SHBG concentrations are under significant genetic control; yet, little is known about the specific genes that influence SHBG. We conducted a large study of the association of SHBG concentrations with markers in the human genome in ∼22,000 white men and women to determine which loci influence SHBG concentrations. Genes near the identified genomic markers in addition to the SHBG protein coding gene included PRMT6, GCKR, ZBTB10, JMJD1C, SLCO1B1, NR2F2, ZNF652, TDGF3, LHCGR, BAIAP2L1, and UGT2B15. These genes represent a wide range of biologic pathways that may relate to SHBG function and sex steroid hormone biology, including liver function, lipid metabolism, carbohydrate metabolism and type 2 diabetes, and the development and progression of sex steroid hormone-responsive cancers.
doi:10.1371/journal.pgen.1002805
PMCID: PMC3400553  PMID: 22829776
14.  New gene functions in megakaryopoiesis and platelet formation 
Gieger, Christian | Radhakrishnan, Aparna | Cvejic, Ana | Tang, Weihong | Porcu, Eleonora | Pistis, Giorgio | Serbanovic-Canic, Jovana | Elling, Ulrich | Goodall, Alison H. | Labrune, Yann | Lopez, Lorna M. | Mägi, Reedik | Meacham, Stuart | Okada, Yukinori | Pirastu, Nicola | Sorice, Rossella | Teumer, Alexander | Voss, Katrin | Zhang, Weihua | Ramirez-Solis, Ramiro | Bis, Joshua C. | Ellinghaus, David | Gögele, Martin | Hottenga, Jouke-Jan | Langenberg, Claudia | Kovacs, Peter | O’Reilly, Paul F. | Shin, So-Youn | Esko, Tõnu | Hartiala, Jaana | Kanoni, Stavroula | Murgia, Federico | Parsa, Afshin | Stephens, Jonathan | van der Harst, Pim | van der Schoot, C. Ellen | Allayee, Hooman | Attwood, Antony | Balkau, Beverley | Bastardot, François | Basu, Saonli | Baumeister, Sebastian E. | Biino, Ginevra | Bomba, Lorenzo | Bonnefond, Amélie | Cambien, François | Chambers, John C. | Cucca, Francesco | D’Adamo, Pio | Davies, Gail | de Boer, Rudolf A. | de Geus, Eco J. C. | Döring, Angela | Elliott, Paul | Erdmann, Jeanette | Evans, David M. | Falchi, Mario | Feng, Wei | Folsom, Aaron R. | Frazer, Ian H. | Gibson, Quince D. | Glazer, Nicole L. | Hammond, Chris | Hartikainen, Anna-Liisa | Heckbert, Susan R. | Hengstenberg, Christian | Hersch, Micha | Illig, Thomas | Loos, Ruth J. F. | Jolley, Jennifer | Khaw, Kay Tee | Kühnel, Brigitte | Kyrtsonis, Marie-Christine | Lagou, Vasiliki | Lloyd-Jones, Heather | Lumley, Thomas | Mangino, Massimo | Maschio, Andrea | Leach, Irene Mateo | McKnight, Barbara | Memari, Yasin | Mitchell, Braxton D. | Montgomery, Grant W. | Nakamura, Yusuke | Nauck, Matthias | Navis, Gerjan | Nöthlings, Ute | Nolte, Ilja M. | Porteous, David J. | Pouta, Anneli | Pramstaller, Peter P. | Pullat, Janne | Ring, Susan M. | Rotter, Jerome I. | Ruggiero, Daniela | Ruokonen, Aimo | Sala, Cinzia | Samani, Nilesh J. | Sambrook, Jennifer | Schlessinger, David | Schreiber, Stefan | Schunkert, Heribert | Scott, James | Smith, Nicholas L. | Snieder, Harold | Starr, John M. | Stumvoll, Michael | Takahashi, Atsushi | Tang, W. H. Wilson | Taylor, Kent | Tenesa, Albert | Thein, Swee Lay | Tönjes, Anke | Uda, Manuela | Ulivi, Sheila | van Veldhuisen, Dirk J. | Visscher, Peter M. | Völker, Uwe | Wichmann, H.-Erich | Wiggins, Kerri L. | Willemsen, Gonneke | Yang, Tsun-Po | Zhao, Jing Hua | Zitting, Paavo | Bradley, John R. | Dedoussis, George V. | Gasparini, Paolo | Hazen, Stanley L. | Metspalu, Andres | Pirastu, Mario | Shuldiner, Alan R. | van Pelt, L. Joost | Zwaginga, Jaap-Jan | Boomsma, Dorret I. | Deary, Ian J. | Franke, Andre | Froguel, Philippe | Ganesh, Santhi K. | Jarvelin, Marjo-Riitta | Martin, Nicholas G. | Meisinger, Christa | Psaty, Bruce M. | Spector, Timothy D. | Wareham, Nicholas J. | Akkerman, Jan-Willem N. | Ciullo, Marina | Deloukas, Panos | Greinacher, Andreas | Jupe, Steve | Kamatani, Naoyuki | Khadake, Jyoti | Kooner, Jaspal S. | Penninger, Josef | Prokopenko, Inga | Stemple, Derek | Toniolo, Daniela | Wernisch, Lorenz | Sanna, Serena | Hicks, Andrew A. | Rendon, Augusto | Ferreira, Manuel A. | Ouwehand, Willem H. | Soranzo, Nicole
Nature  2011;480(7376):201-208.
Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function.
doi:10.1038/nature10659
PMCID: PMC3335296  PMID: 22139419
15.  A Genome-Wide Association Study Identifies rs2000999 as a Strong Genetic Determinant of Circulating Haptoglobin Levels 
PLoS ONE  2012;7(3):e32327.
Haptoglobin is an acute phase inflammatory marker. Its main function is to bind hemoglobin released from erythrocytes to aid its elimination, and thereby haptoglobin prevents the generation of reactive oxygen species in the blood. Haptoglobin levels have been repeatedly associated with a variety of inflammation-linked infectious and non-infectious diseases, including malaria, tuberculosis, human immunodeficiency virus, hepatitis C, diabetes, carotid atherosclerosis, and acute myocardial infarction. However, a comprehensive genetic assessment of the inter-individual variability of circulating haptoglobin levels has not been conducted so far.
We used a genome-wide association study initially conducted in 631 French children followed by a replication in three additional European sample sets and we identified a common single nucleotide polymorphism (SNP), rs2000999 located in the Haptoglobin gene (HP) as a strong genetic predictor of circulating Haptoglobin levels (Poverall = 8.1×10−59), explaining 45.4% of its genetic variability (11.8% of Hp global variance). The functional relevance of rs2000999 was further demonstrated by its specific association with HP mRNA levels (β = 0.23±0.08, P = 0.007). Finally, SNP rs2000999 was associated with decreased total and low-density lipoprotein cholesterol in 8,789 European children (Ptotal cholesterol = 0.002 and PLDL = 0.0008).
Given the central position of haptoglobin in many inflammation-related metabolic pathways, the relevance of rs2000999 genotyping when evaluating haptoglobin concentration should be further investigated in order to improve its diagnostic/therapeutic and/or prevention impact.
doi:10.1371/journal.pone.0032327
PMCID: PMC3293812  PMID: 22403646
16.  Genome-wide association study identifies variants in TMPRSS6 associated with hemoglobin levels 
Nature genetics  2009;41(11):1170-1172.
We carried out a genome-wide association study of hemoglobin levels in 16,001 individuals of European and Indian Asian ancestry. The most closely associated SNP (rs855791) results in nonsynonymous (V736A) change in the serine protease domain of TMPRSS6 and a blood hemoglobin concentration 0.13 (95% CI 0.09–0.17) g/dl lower per copy of allele A (P = 1.6 × 10−13). Our findings suggest that TMPRSS6, a regulator of hepcidin synthesis and iron handling, is crucial in hemoglobin level maintenance.
doi:10.1038/ng.462
PMCID: PMC3178047  PMID: 19820698
17.  Meta-analysis of genome-wide association studies in >80,000 subjects identifies multiple loci for C-reactive protein levels 
Dehghan, Abbas | Dupuis, Josée | Barbalic, Maja | Bis, Joshua C | Eiriksdottir, Gudny | Lu, Chen | Pellikka, Niina | Wallaschofski, Henri | Kettunen, Johannes | Henneman, Peter | Baumert, Jens | Strachan, David P | Fuchsberger, Christian | Vitart, Veronique | Wilson, James F | Paré, Guillaume | Naitza, Silvia | Rudock, Megan E | Surakka, Ida | de Geus, Eco JC | Alizadeh, Behrooz Z | Guralnik, Jack | Shuldiner, Alan | Tanaka, Toshiko | Zee, Robert YL | Schnabel, Renate B | Nambi, Vijay | Kavousi, Maryam | Ripatti, Samuli | Nauck, Matthias | Smith, Nicholas L | Smith, Albert V | Sundvall, Jouko | Scheet, Paul | Liu, Yongmei | Ruokonen, Aimo | Rose, Lynda M | Larson, Martin G | Hoogeveen, Ron C | Freimer, Nelson B | Teumer, Alexander | Tracy, Russell P | Launer, Lenore J | Buring, Julie E | Yamamoto, Jennifer F | Folsom, Aaron R | Sijbrands, Eric JG | Pankow, James | Elliott, Paul | Keaney, John F | Sun, Wei | Sarin, Antti-Pekka | Fontes, João D | Badola, Sunita | Astor, Brad C | Hofman, Albert | Pouta, Anneli | Werdan, Karl | Greiser, Karin H | Kuss, Oliver | Meyer zu Schwabedissen, Henriette E | Thiery, Joachim | Jamshidi, Yalda | Nolte, Ilja M | Soranzo, Nicole | Spector, Timothy D | Völzke, Henry | Parker, Alexander N | Aspelund, Thor | Bates, David | Young, Lauren | Tsui, Kim | Siscovick, David S | Guo, Xiuqing | Rotter, Jerome I | Uda, Manuela | Schlessinger, David | Rudan, Igor | Hicks, Andrew A | Penninx, Brenda W | Thorand, Barbara | Gieger, Christian | Coresh, Joe | Willemsen, Gonneke | Harris, Tamara B | Uitterlinden, Andre G | Järvelin, Marjo-Riitta | Rice, Kenneth | Radke, Dörte | Salomaa, Veikko | van Dijk, Ko Willems | Boerwinkle, Eric | Vasan, Ramachandran S | Ferrucci, Luigi | Gibson, Quince D | Bandinelli, Stefania | Snieder, Harold | Boomsma, Dorret I | Xiao, Xiangjun | Campbell, Harry | Hayward, Caroline | Pramstaller, Peter P | van Duijn, Cornelia M | Peltonen, Leena | Psaty, Bruce M | Gudnason, Vilmundur | Ridker, Paul M | Homuth, Georg | Koenig, Wolfgang | Ballantyne, Christie M | Witteman, Jacqueline CM | Benjamin, Emelia J | Perola, Markus | Chasman, Daniel I
Circulation  2011;123(7):731-738.
Background
C-reactive protein (CRP) is a heritable marker of chronic inflammation that is strongly associated with cardiovascular disease. We aimed to identify genetic variants that are associated with CRP levels.
Methods and Results
We performed a genome wide association (GWA) analysis of CRP in 66,185 participants from 15 population-based studies. We sought replication for the genome wide significant and suggestive loci in a replication panel comprising 16,540 individuals from ten independent studies. We found 18 genome-wide significant loci and we provided evidence of replication for eight of them. Our results confirm seven previously known loci and introduce 11 novel loci that are implicated in pathways related to the metabolic syndrome (APOC1, HNF1A, LEPR, GCKR, HNF4A, and PTPN2), immune system (CRP, IL6R, NLRP3, IL1F10, and IRF1), or that reside in regions previously not known to play a role in chronic inflammation (PPP1R3B, SALL1, PABPC4, ASCL1, RORA, and BCL7B). We found significant interaction of body mass index (BMI) with LEPR (p<2.9×10−6). A weighted genetic risk score that was developed to summarize the effect of risk alleles was strongly associated with CRP levels and explained approximately 5% of the trait variance; however, there was no evidence for these genetic variants explaining the association of CRP with coronary heart disease.
Conclusion
We identified 18 loci that were associated with CRP levels. Our study highlights immune response and metabolic regulatory pathways involved in the regulation of chronic inflammation.
doi:10.1161/CIRCULATIONAHA.110.948570
PMCID: PMC3147232  PMID: 21300955
genome-wide association; C-reactive protein; inflammation; epidemiology; coronary heart disease
18.  Association analyses of 249,796 individuals reveal eighteen new loci associated with body mass index 
Speliotes, Elizabeth K. | Willer, Cristen J. | Berndt, Sonja I. | Monda, Keri L. | Thorleifsson, Gudmar | Jackson, Anne U. | Allen, Hana Lango | Lindgren, Cecilia M. | Luan, Jian’an | Mägi, Reedik | Randall, Joshua C. | Vedantam, Sailaja | Winkler, Thomas W. | Qi, Lu | Workalemahu, Tsegaselassie | Heid, Iris M. | Steinthorsdottir, Valgerdur | Stringham, Heather M. | Weedon, Michael N. | Wheeler, Eleanor | Wood, Andrew R. | Ferreira, Teresa | Weyant, Robert J. | Segré, Ayellet V. | Estrada, Karol | Liang, Liming | Nemesh, James | Park, Ju-Hyun | Gustafsson, Stefan | Kilpeläinen, Tuomas O. | Yang, Jian | Bouatia-Naji, Nabila | Esko, Tõnu | Feitosa, Mary F. | Kutalik, Zoltán | Mangino, Massimo | Raychaudhuri, Soumya | Scherag, Andre | Smith, Albert Vernon | Welch, Ryan | Zhao, Jing Hua | Aben, Katja K. | Absher, Devin M. | Amin, Najaf | Dixon, Anna L. | Fisher, Eva | Glazer, Nicole L. | Goddard, Michael E. | Heard-Costa, Nancy L. | Hoesel, Volker | Hottenga, Jouke-Jan | Johansson, Åsa | Johnson, Toby | Ketkar, Shamika | Lamina, Claudia | Li, Shengxu | Moffatt, Miriam F. | Myers, Richard H. | Narisu, Narisu | Perry, John R.B. | Peters, Marjolein J. | Preuss, Michael | Ripatti, Samuli | Rivadeneira, Fernando | Sandholt, Camilla | Scott, Laura J. | Timpson, Nicholas J. | Tyrer, Jonathan P. | van Wingerden, Sophie | Watanabe, Richard M. | White, Charles C. | Wiklund, Fredrik | Barlassina, Christina | Chasman, Daniel I. | Cooper, Matthew N. | Jansson, John-Olov | Lawrence, Robert W. | Pellikka, Niina | Prokopenko, Inga | Shi, Jianxin | Thiering, Elisabeth | Alavere, Helene | Alibrandi, Maria T. S. | Almgren, Peter | Arnold, Alice M. | Aspelund, Thor | Atwood, Larry D. | Balkau, Beverley | Balmforth, Anthony J. | Bennett, Amanda J. | Ben-Shlomo, Yoav | Bergman, Richard N. | Bergmann, Sven | Biebermann, Heike | Blakemore, Alexandra I.F. | Boes, Tanja | Bonnycastle, Lori L. | Bornstein, Stefan R. | Brown, Morris J. | Buchanan, Thomas A. | Busonero, Fabio | Campbell, Harry | Cappuccio, Francesco P. | Cavalcanti-Proença, Christine | Chen, Yii-Der Ida | Chen, Chih-Mei | Chines, Peter S. | Clarke, Robert | Coin, Lachlan | Connell, John | Day, Ian N.M. | Heijer, Martin den | Duan, Jubao | Ebrahim, Shah | Elliott, Paul | Elosua, Roberto | Eiriksdottir, Gudny | Erdos, Michael R. | Eriksson, Johan G. | Facheris, Maurizio F. | Felix, Stephan B. | Fischer-Posovszky, Pamela | Folsom, Aaron R. | Friedrich, Nele | Freimer, Nelson B. | Fu, Mao | Gaget, Stefan | Gejman, Pablo V. | Geus, Eco J.C. | Gieger, Christian | Gjesing, Anette P. | Goel, Anuj | Goyette, Philippe | Grallert, Harald | Gräßler, Jürgen | Greenawalt, Danielle M. | Groves, Christopher J. | Gudnason, Vilmundur | Guiducci, Candace | Hartikainen, Anna-Liisa | Hassanali, Neelam | Hall, Alistair S. | Havulinna, Aki S. | Hayward, Caroline | Heath, Andrew C. | Hengstenberg, Christian | Hicks, Andrew A. | Hinney, Anke | Hofman, Albert | Homuth, Georg | Hui, Jennie | Igl, Wilmar | Iribarren, Carlos | Isomaa, Bo | Jacobs, Kevin B. | Jarick, Ivonne | Jewell, Elizabeth | John, Ulrich | Jørgensen, Torben | Jousilahti, Pekka | Jula, Antti | Kaakinen, Marika | Kajantie, Eero | Kaplan, Lee M. | Kathiresan, Sekar | Kettunen, Johannes | Kinnunen, Leena | Knowles, Joshua W. | Kolcic, Ivana | König, Inke R. | Koskinen, Seppo | Kovacs, Peter | Kuusisto, Johanna | Kraft, Peter | Kvaløy, Kirsti | Laitinen, Jaana | Lantieri, Olivier | Lanzani, Chiara | Launer, Lenore J. | Lecoeur, Cecile | Lehtimäki, Terho | Lettre, Guillaume | Liu, Jianjun | Lokki, Marja-Liisa | Lorentzon, Mattias | Luben, Robert N. | Ludwig, Barbara | Manunta, Paolo | Marek, Diana | Marre, Michel | Martin, Nicholas G. | McArdle, Wendy L. | McCarthy, Anne | McKnight, Barbara | Meitinger, Thomas | Melander, Olle | Meyre, David | Midthjell, Kristian | Montgomery, Grant W. | Morken, Mario A. | Morris, Andrew P. | Mulic, Rosanda | Ngwa, Julius S. | Nelis, Mari | Neville, Matt J. | Nyholt, Dale R. | O’Donnell, Christopher J. | O’Rahilly, Stephen | Ong, Ken K. | Oostra, Ben | Paré, Guillaume | Parker, Alex N. | Perola, Markus | Pichler, Irene | Pietiläinen, Kirsi H. | Platou, Carl G.P. | Polasek, Ozren | Pouta, Anneli | Rafelt, Suzanne | Raitakari, Olli | Rayner, Nigel W. | Ridderstråle, Martin | Rief, Winfried | Ruokonen, Aimo | Robertson, Neil R. | Rzehak, Peter | Salomaa, Veikko | Sanders, Alan R. | Sandhu, Manjinder S. | Sanna, Serena | Saramies, Jouko | Savolainen, Markku J. | Scherag, Susann | Schipf, Sabine | Schreiber, Stefan | Schunkert, Heribert | Silander, Kaisa | Sinisalo, Juha | Siscovick, David S. | Smit, Jan H. | Soranzo, Nicole | Sovio, Ulla | Stephens, Jonathan | Surakka, Ida | Swift, Amy J. | Tammesoo, Mari-Liis | Tardif, Jean-Claude | Teder-Laving, Maris | Teslovich, Tanya M. | Thompson, John R. | Thomson, Brian | Tönjes, Anke | Tuomi, Tiinamaija | van Meurs, Joyce B.J. | van Ommen, Gert-Jan | Vatin, Vincent | Viikari, Jorma | Visvikis-Siest, Sophie | Vitart, Veronique | Vogel, Carla I. G. | Voight, Benjamin F. | Waite, Lindsay L. | Wallaschofski, Henri | Walters, G. Bragi | Widen, Elisabeth | Wiegand, Susanna | Wild, Sarah H. | Willemsen, Gonneke | Witte, Daniel R. | Witteman, Jacqueline C. | Xu, Jianfeng | Zhang, Qunyuan | Zgaga, Lina | Ziegler, Andreas | Zitting, Paavo | Beilby, John P. | Farooqi, I. Sadaf | Hebebrand, Johannes | Huikuri, Heikki V. | James, Alan L. | Kähönen, Mika | Levinson, Douglas F. | Macciardi, Fabio | Nieminen, Markku S. | Ohlsson, Claes | Palmer, Lyle J. | Ridker, Paul M. | Stumvoll, Michael | Beckmann, Jacques S. | Boeing, Heiner | Boerwinkle, Eric | Boomsma, Dorret I. | Caulfield, Mark J. | Chanock, Stephen J. | Collins, Francis S. | Cupples, L. Adrienne | Smith, George Davey | Erdmann, Jeanette | Froguel, Philippe | Grönberg, Henrik | Gyllensten, Ulf | Hall, Per | Hansen, Torben | Harris, Tamara B. | Hattersley, Andrew T. | Hayes, Richard B. | Heinrich, Joachim | Hu, Frank B. | Hveem, Kristian | Illig, Thomas | Jarvelin, Marjo-Riitta | Kaprio, Jaakko | Karpe, Fredrik | Khaw, Kay-Tee | Kiemeney, Lambertus A. | Krude, Heiko | Laakso, Markku | Lawlor, Debbie A. | Metspalu, Andres | Munroe, Patricia B. | Ouwehand, Willem H. | Pedersen, Oluf | Penninx, Brenda W. | Peters, Annette | Pramstaller, Peter P. | Quertermous, Thomas | Reinehr, Thomas | Rissanen, Aila | Rudan, Igor | Samani, Nilesh J. | Schwarz, Peter E.H. | Shuldiner, Alan R. | Spector, Timothy D. | Tuomilehto, Jaakko | Uda, Manuela | Uitterlinden, André | Valle, Timo T. | Wabitsch, Martin | Waeber, Gérard | Wareham, Nicholas J. | Watkins, Hugh | Wilson, James F. | Wright, Alan F. | Zillikens, M. Carola | Chatterjee, Nilanjan | McCarroll, Steven A. | Purcell, Shaun | Schadt, Eric E. | Visscher, Peter M. | Assimes, Themistocles L. | Borecki, Ingrid B. | Deloukas, Panos | Fox, Caroline S. | Groop, Leif C. | Haritunians, Talin | Hunter, David J. | Kaplan, Robert C. | Mohlke, Karen L. | O’Connell, Jeffrey R. | Peltonen, Leena | Schlessinger, David | Strachan, David P. | van Duijn, Cornelia M. | Wichmann, H.-Erich | Frayling, Timothy M. | Thorsteinsdottir, Unnur | Abecasis, Gonçalo R. | Barroso, Inês | Boehnke, Michael | Stefansson, Kari | North, Kari E. | McCarthy, Mark I. | Hirschhorn, Joel N. | Ingelsson, Erik | Loos, Ruth J.F.
Nature genetics  2010;42(11):937-948.
Obesity is globally prevalent and highly heritable, but the underlying genetic factors remain largely elusive. To identify genetic loci for obesity-susceptibility, we examined associations between body mass index (BMI) and ~2.8 million SNPs in up to 123,865 individuals, with targeted follow-up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity-susceptibility loci and identified 18 new loci associated with BMI (P<5×10−8), one of which includes a copy number variant near GPRC5B. Some loci (MC4R, POMC, SH2B1, BDNF) map near key hypothalamic regulators of energy balance, and one is near GIPR, an incretin receptor. Furthermore, genes in other newly-associated loci may provide novel insights into human body weight regulation.
doi:10.1038/ng.686
PMCID: PMC3014648  PMID: 20935630
19.  Common Variation in the FTO Gene Alters Diabetes-Related Metabolic Traits to the Extent Expected Given Its Effect on BMI 
Diabetes  2008;57(5):1419-1426.
OBJECTIVE
Common variation in the FTO gene is associated with BMI and type 2 diabetes. Increased BMI is associated with diabetes risk factors, including raised insulin, glucose, and triglycerides. We aimed to test whether FTO genotype is associated with variation in these metabolic traits.
RESEARCH DESIGN AND METHODS
We tested the association between FTO genotype and 10 metabolic traits using data from 17,037 white European individuals. We compared the observed effect of FTO genotype on each trait to that expected given the FTO-BMI and BMI-trait associations.
RESULTS
Each copy of the FTO rs9939609 A allele was associated with higher fasting insulin (0.039 SD [95% CI 0.013–0.064]; P = 0.003), glucose (0.024 [0.001– 0.048]; P = 0.044), and triglycerides (0.028 [0.003– 0.052]; P = 0.025) and lower HDL cholesterol (0.032 [0.008 – 0.057]; P = 0.009). There was no evidence of these associations when adjusting for BMI. Associations with fasting alanine aminotransferase, γ-glutamyl-transferase, LDL cholesterol, A1C, and systolic and diastolic blood pressure were in the expected direction but did not reach P < 0.05. For all metabolic traits, effect sizes were consistent with those expected for the per allele change in BMI. FTO genotype was associated with a higher odds of metabolic syndrome (odds ratio 1.17 [95% CI 1.10 –1.25]; P = 3 × 10−6).
CONCLUSIONS
FTO genotype is associated with metabolic traits to an extent entirely consistent with its effect on BMI. Sample sizes of >12,000 individuals were needed to detect associations at P < 0.05. Our findings highlight the importance of using appropriately powered studies to assess the effects of a known diabetes or obesity variant on secondary traits correlated with these conditions.
doi:10.2337/db07-1466
PMCID: PMC3073395  PMID: 18346983
20.  Biological, Clinical, and Population Relevance of 95 Loci for Blood Lipids 
Teslovich, Tanya M. | Musunuru, Kiran | Smith, Albert V. | Edmondson, Andrew C. | Stylianou, Ioannis M. | Koseki, Masahiro | Pirruccello, James P. | Ripatti, Samuli | Chasman, Daniel I. | Willer, Cristen J. | Johansen, Christopher T. | Fouchier, Sigrid W. | Isaacs, Aaron | Peloso, Gina M. | Barbalic, Maja | Ricketts, Sally L. | Bis, Joshua C. | Aulchenko, Yurii S. | Thorleifsson, Gudmar | Feitosa, Mary F. | Chambers, John | Orho-Melander, Marju | Melander, Olle | Johnson, Toby | Li, Xiaohui | Guo, Xiuqing | Li, Mingyao | Cho, Yoon Shin | Go, Min Jin | Kim, Young Jin | Lee, Jong-Young | Park, Taesung | Kim, Kyunga | Sim, Xueling | Ong, Rick Twee-Hee | Croteau-Chonka, Damien C. | Lange, Leslie A. | Smith, Joshua D. | Song, Kijoung | Zhao, Jing Hua | Yuan, Xin | Luan, Jian'an | Lamina, Claudia | Ziegler, Andreas | Zhang, Weihua | Zee, Robert Y.L. | Wright, Alan F. | Witteman, Jacqueline C.M. | Wilson, James F. | Willemsen, Gonneke | Wichmann, H-Erich | Whitfield, John B. | Waterworth, Dawn M. | Wareham, Nicholas J. | Waeber, Gérard | Vollenweider, Peter | Voight, Benjamin F. | Vitart, Veronique | Uitterlinden, Andre G. | Uda, Manuela | Tuomilehto, Jaakko | Thompson, John R. | Tanaka, Toshiko | Surakka, Ida | Stringham, Heather M. | Spector, Tim D. | Soranzo, Nicole | Smit, Johannes H. | Sinisalo, Juha | Silander, Kaisa | Sijbrands, Eric J.G. | Scuteri, Angelo | Scott, James | Schlessinger, David | Sanna, Serena | Salomaa, Veikko | Saharinen, Juha | Sabatti, Chiara | Ruokonen, Aimo | Rudan, Igor | Rose, Lynda M. | Roberts, Robert | Rieder, Mark | Psaty, Bruce M. | Pramstaller, Peter P. | Pichler, Irene | Perola, Markus | Penninx, Brenda W.J.H. | Pedersen, Nancy L. | Pattaro, Cristian | Parker, Alex N. | Pare, Guillaume | Oostra, Ben A. | O'Donnell, Christopher J. | Nieminen, Markku S. | Nickerson, Deborah A. | Montgomery, Grant W. | Meitinger, Thomas | McPherson, Ruth | McCarthy, Mark I. | McArdle, Wendy | Masson, David | Martin, Nicholas G. | Marroni, Fabio | Mangino, Massimo | Magnusson, Patrik K.E. | Lucas, Gavin | Luben, Robert | Loos, Ruth J. F. | Lokki, Maisa | Lettre, Guillaume | Langenberg, Claudia | Launer, Lenore J. | Lakatta, Edward G. | Laaksonen, Reijo | Kyvik, Kirsten O. | Kronenberg, Florian | König, Inke R. | Khaw, Kay-Tee | Kaprio, Jaakko | Kaplan, Lee M. | Johansson, Åsa | Jarvelin, Marjo-Riitta | Janssens, A. Cecile J.W. | Ingelsson, Erik | Igl, Wilmar | Hovingh, G. Kees | Hottenga, Jouke-Jan | Hofman, Albert | Hicks, Andrew A. | Hengstenberg, Christian | Heid, Iris M. | Hayward, Caroline | Havulinna, Aki S. | Hastie, Nicholas D. | Harris, Tamara B. | Haritunians, Talin | Hall, Alistair S. | Gyllensten, Ulf | Guiducci, Candace | Groop, Leif C. | Gonzalez, Elena | Gieger, Christian | Freimer, Nelson B. | Ferrucci, Luigi | Erdmann, Jeanette | Elliott, Paul | Ejebe, Kenechi G. | Döring, Angela | Dominiczak, Anna F. | Demissie, Serkalem | Deloukas, Panagiotis | de Geus, Eco J.C. | de Faire, Ulf | Crawford, Gabriel | Collins, Francis S. | Chen, Yii-der I. | Caulfield, Mark J. | Campbell, Harry | Burtt, Noel P. | Bonnycastle, Lori L. | Boomsma, Dorret I. | Boekholdt, S. Matthijs | Bergman, Richard N. | Barroso, Inês | Bandinelli, Stefania | Ballantyne, Christie M. | Assimes, Themistocles L. | Quertermous, Thomas | Altshuler, David | Seielstad, Mark | Wong, Tien Y. | Tai, E-Shyong | Feranil, Alan B. | Kuzawa, Christopher W. | Adair, Linda S. | Taylor, Herman A. | Borecki, Ingrid B. | Gabriel, Stacey B. | Wilson, James G. | Stefansson, Kari | Thorsteinsdottir, Unnur | Gudnason, Vilmundur | Krauss, Ronald M. | Mohlke, Karen L. | Ordovas, Jose M. | Munroe, Patricia B. | Kooner, Jaspal S. | Tall, Alan R. | Hegele, Robert A. | Kastelein, John J.P. | Schadt, Eric E. | Rotter, Jerome I. | Boerwinkle, Eric | Strachan, David P. | Mooser, Vincent | Holm, Hilma | Reilly, Muredach P. | Samani, Nilesh J | Schunkert, Heribert | Cupples, L. Adrienne | Sandhu, Manjinder S. | Ridker, Paul M | Rader, Daniel J. | van Duijn, Cornelia M. | Peltonen, Leena | Abecasis, Gonçalo R. | Boehnke, Michael | Kathiresan, Sekar
Nature  2010;466(7307):707-713.
Serum concentrations of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with serum lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 × 10-8), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (e.g., CYP7A1, NPC1L1, and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and impact lipid traits in three non-European populations (East Asians, South Asians, and African Americans). Our results identify several novel loci associated with serum lipids that are also associated with CAD. Finally, we validated three of the novel genes—GALNT2, PPP1R3B, and TTC39B—with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.
doi:10.1038/nature09270
PMCID: PMC3039276  PMID: 20686565
21.  New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk 
Dupuis, Josée | Langenberg, Claudia | Prokopenko, Inga | Saxena, Richa | Soranzo, Nicole | Jackson, Anne U | Wheeler, Eleanor | Glazer, Nicole L | Bouatia-Naji, Nabila | Gloyn, Anna L | Lindgren, Cecilia M | Mägi, Reedik | Morris, Andrew P | Randall, Joshua | Johnson, Toby | Elliott, Paul | Rybin, Denis | Thorleifsson, Gudmar | Steinthorsdottir, Valgerdur | Henneman, Peter | Grallert, Harald | Dehghan, Abbas | Hottenga, Jouke Jan | Franklin, Christopher S | Navarro, Pau | Song, Kijoung | Goel, Anuj | Perry, John R B | Egan, Josephine M | Lajunen, Taina | Grarup, Niels | Sparsø, Thomas | Doney, Alex | Voight, Benjamin F | Stringham, Heather M | Li, Man | Kanoni, Stavroula | Shrader, Peter | Cavalcanti-Proença, Christine | Kumari, Meena | Qi, Lu | Timpson, Nicholas J | Gieger, Christian | Zabena, Carina | Rocheleau, Ghislain | Ingelsson, Erik | An, Ping | O’Connell, Jeffrey | Luan, Jian'an | Elliott, Amanda | McCarroll, Steven A | Payne, Felicity | Roccasecca, Rosa Maria | Pattou, François | Sethupathy, Praveen | Ardlie, Kristin | Ariyurek, Yavuz | Balkau, Beverley | Barter, Philip | Beilby, John P | Ben-Shlomo, Yoav | Benediktsson, Rafn | Bennett, Amanda J | Bergmann, Sven | Bochud, Murielle | Boerwinkle, Eric | Bonnefond, Amélie | Bonnycastle, Lori L | Borch-Johnsen, Knut | Böttcher, Yvonne | Brunner, Eric | Bumpstead, Suzannah J | Charpentier, Guillaume | Chen, Yii-Der Ida | Chines, Peter | Clarke, Robert | Coin, Lachlan J M | Cooper, Matthew N | Cornelis, Marilyn | Crawford, Gabe | Crisponi, Laura | Day, Ian N M | de Geus, Eco | Delplanque, Jerome | Dina, Christian | Erdos, Michael R | Fedson, Annette C | Fischer-Rosinsky, Antje | Forouhi, Nita G | Fox, Caroline S | Frants, Rune | Franzosi, Maria Grazia | Galan, Pilar | Goodarzi, Mark O | Graessler, Jürgen | Groves, Christopher J | Grundy, Scott | Gwilliam, Rhian | Gyllensten, Ulf | Hadjadj, Samy | Hallmans, Göran | Hammond, Naomi | Han, Xijing | Hartikainen, Anna-Liisa | Hassanali, Neelam | Hayward, Caroline | Heath, Simon C | Hercberg, Serge | Herder, Christian | Hicks, Andrew A | Hillman, David R | Hingorani, Aroon D | Hofman, Albert | Hui, Jennie | Hung, Joe | Isomaa, Bo | Johnson, Paul R V | Jørgensen, Torben | Jula, Antti | Kaakinen, Marika | Kaprio, Jaakko | Kesaniemi, Y Antero | Kivimaki, Mika | Knight, Beatrice | Koskinen, Seppo | Kovacs, Peter | Kyvik, Kirsten Ohm | Lathrop, G Mark | Lawlor, Debbie A | Le Bacquer, Olivier | Lecoeur, Cécile | Li, Yun | Lyssenko, Valeriya | Mahley, Robert | Mangino, Massimo | Manning, Alisa K | Martínez-Larrad, María Teresa | McAteer, Jarred B | McCulloch, Laura J | McPherson, Ruth | Meisinger, Christa | Melzer, David | Meyre, David | Mitchell, Braxton D | Morken, Mario A | Mukherjee, Sutapa | Naitza, Silvia | Narisu, Narisu | Neville, Matthew J | Oostra, Ben A | Orrù, Marco | Pakyz, Ruth | Palmer, Colin N A | Paolisso, Giuseppe | Pattaro, Cristian | Pearson, Daniel | Peden, John F | Pedersen, Nancy L. | Perola, Markus | Pfeiffer, Andreas F H | Pichler, Irene | Polasek, Ozren | Posthuma, Danielle | Potter, Simon C | Pouta, Anneli | Province, Michael A | Psaty, Bruce M | Rathmann, Wolfgang | Rayner, Nigel W | Rice, Kenneth | Ripatti, Samuli | Rivadeneira, Fernando | Roden, Michael | Rolandsson, Olov | Sandbaek, Annelli | Sandhu, Manjinder | Sanna, Serena | Sayer, Avan Aihie | Scheet, Paul | Scott, Laura J | Seedorf, Udo | Sharp, Stephen J | Shields, Beverley | Sigurðsson, Gunnar | Sijbrands, Erik J G | Silveira, Angela | Simpson, Laila | Singleton, Andrew | Smith, Nicholas L | Sovio, Ulla | Swift, Amy | Syddall, Holly | Syvänen, Ann-Christine | Tanaka, Toshiko | Thorand, Barbara | Tichet, Jean | Tönjes, Anke | Tuomi, Tiinamaija | Uitterlinden, André G | van Dijk, Ko Willems | van Hoek, Mandy | Varma, Dhiraj | Visvikis-Siest, Sophie | Vitart, Veronique | Vogelzangs, Nicole | Waeber, Gérard | Wagner, Peter J | Walley, Andrew | Walters, G Bragi | Ward, Kim L | Watkins, Hugh | Weedon, Michael N | Wild, Sarah H | Willemsen, 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S | Mohlke, Karen L | Tuomilehto, Jaakko | Valle, Timo T | Altshuler, David | Rotter, Jerome I | Siscovick, David S | Penninx, Brenda W J H | Boomsma, Dorret | Deloukas, Panos | Spector, Timothy D | Frayling, Timothy M | Ferrucci, Luigi | Kong, Augustine | Thorsteinsdottir, Unnur | Stefansson, Kari | van Duijn, Cornelia M | Aulchenko, Yurii S | Cao, Antonio | Scuteri, Angelo | Schlessinger, David | Uda, Manuela | Ruokonen, Aimo | Jarvelin, Marjo-Riitta | Waterworth, Dawn M | Vollenweider, Peter | Peltonen, Leena | Mooser, Vincent | Abecasis, Goncalo R | Wareham, Nicholas J | Sladek, Robert | Froguel, Philippe | Watanabe, Richard M | Meigs, James B | Groop, Leif | Boehnke, Michael | McCarthy, Mark I | Florez, Jose C | Barroso, Inês
Nature genetics  2010;42(2):105-116.
Circulating glucose levels are tightly regulated. To identify novel glycemic loci, we performed meta-analyses of 21 genome-wide associations studies informative for fasting glucose (FG), fasting insulin (FI) and indices of β-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 non-diabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with FG/HOMA-B and two associated with FI/HOMA-IR. These include nine new FG loci (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and FAM148B) and one influencing FI/HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB/TMEM195 with type 2 diabetes (T2D). Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify T2D risk loci, as well as loci that elevate FG modestly, but do not cause overt diabetes.
doi:10.1038/ng.520
PMCID: PMC3018764  PMID: 20081858
22.  Common Genetic Variation Near Melatonin Receptor MTNR1B Contributes to Raised Plasma Glucose and Increased Risk of Type 2 Diabetes Among Indian Asians and European Caucasians 
Diabetes  2009;58(11):2703-2708.
OBJECTIVE
Fasting plasma glucose and risk of type 2 diabetes are higher among Indian Asians than among European and North American Caucasians. Few studies have investigated genetic factors influencing glucose metabolism among Indian Asians.
RESEARCH DESIGN AND METHODS
We carried out genome-wide association studies for fasting glucose in 5,089 nondiabetic Indian Asians genotyped with the Illumina Hap610 BeadChip and 2,385 Indian Asians (698 with type 2 diabetes) genotyped with the Illumina 300 BeadChip. Results were compared with findings in 4,462 European Caucasians.
RESULTS
We identified three single nucleotide polymorphisms (SNPs) associated with glucose among Indian Asians at P < 5 × 10−8, all near melatonin receptor MTNR1B. The most closely associated was rs2166706 (combined P = 2.1 × 10−9), which is in moderate linkage disequilibrium with rs1387153 (r2 = 0.60) and rs10830963 (r2 = 0.45), both previously associated with glucose in European Caucasians. Risk allele frequency and effect sizes for rs2166706 were similar among Indian Asians and European Caucasians: frequency 46.2 versus 45.0%, respectively (P = 0.44); effect 0.05 (95% CI 0.01–0.08) versus 0.05 (0.03–0.07 mmol/l), respectively, higher glucose per allele copy (P = 0.84). SNP rs2166706 was associated with type 2 diabetes in Indian Asians (odds ratio 1.21 [95% CI 1.06–1.38] per copy of risk allele; P = 0.006). SNPs at the GCK, GCKR, and G6PC2 loci were also associated with glucose among Indian Asians. Risk allele frequencies of rs1260326 (GCKR) and rs560887 (G6PC2) were higher among Indian Asians compared with European Caucasians.
CONCLUSIONS
Common genetic variation near MTNR1B influences blood glucose and risk of type 2 diabetes in Indian Asians. Genetic variation at the MTNR1B, GCK, GCKR, and G6PC2 loci may contribute to abnormal glucose metabolism and related metabolic disturbances among Indian Asians.
doi:10.2337/db08-1805
PMCID: PMC2768158  PMID: 19651812
23.  Type 2 Diabetes Risk Alleles Are Associated With Reduced Size at Birth 
Diabetes  2009;58(6):1428-1433.
OBJECTIVE
Low birth weight is associated with an increased risk of type 2 diabetes. The mechanisms underlying this association are unknown and may represent intrauterine programming or two phenotypes of one genotype. The fetal insulin hypothesis proposes that common genetic variants that reduce insulin secretion or action may predispose to type 2 diabetes and also reduce birth weight, since insulin is a key fetal growth factor. We tested whether common genetic variants that predispose to type 2 diabetes also reduce birth weight.
RESEARCH DESIGN AND METHODS
We genotyped single-nucleotide polymorphisms (SNPs) at five recently identified type 2 diabetes loci (CDKAL1, CDKN2A/B, HHEX-IDE, IGF2BP2, and SLC30A8) in 7,986 mothers and 19,200 offspring from four studies of white Europeans. We tested the association between maternal or fetal genotype at each locus and birth weight of the offspring.
RESULTS
We found that type 2 diabetes risk alleles at the CDKAL1 and HHEX-IDE loci were associated with reduced birth weight when inherited by the fetus (21 g [95% CI 11–31], P = 2 × 10−5, and 14 g [4–23], P = 0.004, lower birth weight per risk allele, respectively). The 4% of offspring carrying four risk alleles at these two loci were 80 g (95% CI 39–120) lighter at birth than the 8% carrying none (Ptrend = 5 × 10−7). There were no associations between birth weight and fetal genotypes at the three other loci or maternal genotypes at any locus.
CONCLUSIONS
Our results are in keeping with the fetal insulin hypothesis and provide robust evidence that common disease-associated variants can alter size at birth directly through the fetal genotype.
doi:10.2337/db08-1739
PMCID: PMC2682672  PMID: 19228808
24.  Genetic Loci Influencing C-reactive Protein Levels and Risk of Coronary Heart Disease 
Context:
Plasma levels of C-reactive protein (CRP) are independently associated with risk of coronary heart disease, but whether CRP is causally associated with coronary heart disease or merely a marker of underlying atherosclerosis is uncertain.
Objective:
To investigate association of genetic loci with CRP levels and risk of coronary heart disease.
Design, setting and participants:
We first carried out a genome-wide association (n=17,967) and replication study (n=14,747) to identify genetic loci associated with plasma CRP concentrations. Data collection took place between 1989 and 2008 and genotyping between 2003 and 2008. We carried out a Mendelian randomisation study of the most closely associated SNP in the CRP locus and published data on other CRP variants involving a total of 28,112 cases and 100,823 controls, to investigate the association of CRP variants with coronary heart disease. We compared our finding with that predicted from meta-analysis of observational studies of CRP levels and risk of coronary heart disease. For the other loci associated with CRP levels, we selected the most closely associated SNP for testing against coronary heart disease among 14,365 cases and 32,069 controls.
Main outcome measure:
Risk of coronary heart disease.
Results:
Polymorphisms in five genetic loci were strongly associated with CRP levels (% difference per minor allele): SNP rs6700896 in LEPR (−14.7% [95% Confidence Interval {CI}], −17.5 – −11.9, P=1.6×10−21), rs4537545 in IL6R (−10.8% [95% CI, −13.8 – −7.7], P=5.1×10−11), rs7553007 in CRP locus (−20.7% [95% CI, −23.5 – −17.9], P=3.3×10−38), rs1183910 in HNF1A (−13.6% [95% CI, −16.4 – −10.6], P=1.2×10−17) and rs4420638 in APOE-CI-CII (−21.8% [95% CI, −25.4 – −18.1], P=2.1×10−25). Association of SNP rs7553007 in the CRP locus with coronary heart disease gave odds ratio (OR) 0.98 (95% CI, 0.94 – 1.01) per 20% lower CRP. Our Mendelian randomisation study of variants in the CRP locus showed no association with coronary heart disease: OR 1.00 (95% CI, 0.97 – 1.02) per 20% lower CRP, compared with OR 0.94 (95% CI, 0.94 – 0.95) predicted from meta-analysis of the observational studies of CRP levels and coronary heart disease (Z-score −3.45, P<.001). SNPs rs6700896 in LEPR (OR 1.06 [95% CI, 1.02 – 1.09] per minor allele), rs4537545 in IL6R (OR 0.94 [95% CI, 0.91 – 0.97]) and rs4420638 in the APOE-CI-CII cluster (OR 1.16 [95% CI, 1.12 – 1.21]) were all associated with risk of coronary heart disease.
Conclusions:
The lack of concordance between the effect on coronary heart disease risk of CRP genotypes and CRP levels argues against a causal association of CRP with coronary heart disease.
doi:10.1001/jama.2009.954
PMCID: PMC2803020  PMID: 19567438
25.  Type 2 Diabetes Risk Alleles are Associated with Reduced Size at Birth 
Diabetes  2009;58(6):1428-1433.
Objective
Low birth weight is associated with an increased risk of type 2 diabetes. The mechanisms underlying this association are unknown and may represent intrauterine programming or two phenotypes of one genotype. The fetal insulin hypothesis proposes that common genetic variants that reduce insulin secretion or action may predispose to type 2 diabetes and also reduce birth weight, since insulin is a key fetal growth factor. We tested whether common genetic variants that predispose to type 2 diabetes also reduce birth weight.
Research design and methods
We genotyped single nucleotide polymorphisms (SNPs) at five recently identified type 2 diabetes loci (CDKAL1, CDKN2A/B, HHEX-IDE, IGF2BP2 and SLC30A8) in 7986 mothers and 19200 offspring from four studies of white Europeans. We tested the association between maternal or fetal genotype at each locus and birth weight of the offspring.
Results
We found that type 2 diabetes risk alleles at the CDKAL1 and HHEX-IDE loci were associated with reduced birth weight when inherited by the fetus: 21g [95%CI:11-31g], P=2×10-5 and 14g [4-23g], P=0.004 lower birth weight per risk allele, respectively. The 4% of offspring carrying four risk alleles at these two loci were 80g [39-120g] lighter at birth than the 8% carrying none (Ptrend =5×10-7). There were no associations between birth weight and fetal genotypes at the three other loci, or maternal genotypes at any locus.
Conclusions
Our results are in keeping with the fetal insulin hypothesis and provide robust evidence that common disease-associated variants can alter size at birth directly through the fetal genotype.
doi:10.2337/db08-1739
PMCID: PMC2682672  PMID: 19228808

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