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1.  Variant Discovery and Fine Mapping of Genetic Loci Associated with Blood Pressure Traits in Hispanics and African Americans 
PLoS ONE  2016;11(10):e0164132.
Despite the substantial burden of hypertension in US minority populations, few genetic studies of blood pressure have been conducted in Hispanics and African Americans, and it is unclear whether many of the established loci identified in European-descent populations contribute to blood pressure variation in non-European descent populations. Using the Metabochip array, we sought to characterize the genetic architecture of previously identified blood pressure loci, and identify novel cardiometabolic variants related to systolic and diastolic blood pressure in a multi-ethnic US population including Hispanics (n = 19,706) and African Americans (n = 18,744). Several known blood pressure loci replicated in African Americans and Hispanics. Fourteen variants in three loci (KCNK3, FGF5, ATXN2-SH2B3) were significantly associated with blood pressure in Hispanics. The most significant diastolic blood pressure variant identified in our analysis, rs2586886/KCNK3 (P = 5.2 x 10−9), also replicated in independent Hispanic and European-descent samples. African American and trans-ethnic meta-analysis data identified novel variants in the FGF5, ULK4 and HOXA-EVX1 loci, which have not been previously associated with blood pressure traits. Our identification and independent replication of variants in KCNK3, a gene implicated in primary hyperaldosteronism, as well as a variant in HOTTIP (HOXA-EVX1) suggest that further work to clarify the roles of these genes may be warranted. Overall, our findings suggest that loci identified in European descent populations also contribute to blood pressure variation in diverse populations including Hispanics and African Americans—populations that are understudied for hypertension genetic risk factors.
doi:10.1371/journal.pone.0164132
PMCID: PMC5063457  PMID: 27736895
2.  Correction: The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study 
Winkler, Thomas W. | Justice, Anne E. | Graff, Mariaelisa | Barata, Llilda | Feitosa, Mary F. | Chu, Su | Czajkowski, Jacek | Esko, Tõnu | Fall, Tove | Kilpeläinen, Tuomas O. | Lu, Yingchang | Mägi, Reedik | Mihailov, Evelin | Pers, Tune H. | Rüeger, Sina | Teumer, Alexander | Ehret, Georg B. | Ferreira, Teresa | Heard-Costa, Nancy L. | Karjalainen, Juha | Lagou, Vasiliki | Mahajan, Anubha | Neinast, Michael D. | Prokopenko, Inga | Simino, Jeannette | Teslovich, Tanya M. | Jansen, Rick | Westra, Harm-Jan | White, Charles C. | Absher, Devin | Ahluwalia, Tarunveer S. | Ahmad, Shafqat | Albrecht, Eva | Alves, Alexessander Couto | Bragg-Gresham, Jennifer L. | de Craen, Anton J. M. | Bis, Joshua C. | Bonnefond, Amélie | Boucher, Gabrielle | Cadby, Gemma | Cheng, Yu-Ching | Chiang, Charleston W. K. | Delgado, Graciela | Demirkan, Ayse | Dueker, Nicole | Eklund, Niina | Eiriksdottir, Gudny | Eriksson, Joel | Feenstra, Bjarke | Fischer, Krista | Frau, Francesca | Galesloot, Tessel E. | Geller, Frank | Goel, Anuj | Gorski, Mathias | Grammer, Tanja B. | Gustafsson, Stefan | Haitjema, Saskia | Hottenga, Jouke-Jan | Huffman, Jennifer E. | Jackson, Anne U. | Jacobs, Kevin B. | Johansson, Åsa | Kaakinen, Marika | Kleber, Marcus E. | Lahti, Jari | Mateo Leach, Irene | Lehne, Benjamin | Liu, Youfang | Lo, Ken Sin | Lorentzon, Mattias | Luan, Jian'an | Madden, Pamela A. F. | Mangino, Massimo | McKnight, Barbara | Medina-Gomez, Carolina | Monda, Keri L. | Montasser, May E. | Müller, Gabriele | Müller-Nurasyid, Martina | Nolte, Ilja M. | Panoutsopoulou, Kalliope | Pascoe, Laura | Paternoster, Lavinia | Rayner, Nigel W. | Renström, Frida | Rizzi, Federica | Rose, Lynda M. | Ryan, Kathy A. | Salo, Perttu | Sanna, Serena | Scharnagl, Hubert | Shi, Jianxin | Smith, Albert Vernon | Southam, Lorraine | Stančáková, Alena | Steinthorsdottir, Valgerdur | Strawbridge, Rona J. | Sung, Yun Ju | Tachmazidou, Ioanna | Tanaka, Toshiko | Thorleifsson, Gudmar | Trompet, Stella | Pervjakova, Natalia | Tyrer, Jonathan P. | Vandenput, Liesbeth | van der Laan, Sander W | van der Velde, Nathalie | van Setten, Jessica | van Vliet-Ostaptchouk, Jana V. | Verweij, Niek | Vlachopoulou, Efthymia | Waite, Lindsay L. | Wang, Sophie R. | Wang, Zhaoming | Wild, Sarah H. | Willenborg, Christina | Wilson, James F. | Wong, Andrew | Yang, Jian | Yengo, Loïc | Yerges-Armstrong, Laura M. | Yu, Lei | Zhang, Weihua | Zhao, Jing Hua | Andersson, Ehm A. | Bakker, Stephan J. L. | Baldassarre, Damiano | Banasik, Karina | Barcella, Matteo | Barlassina, Cristina | Bellis, Claire | Benaglio, Paola | Blangero, John | Blüher, Matthias | Bonnet, Fabrice | Bonnycastle, Lori L. | Boyd, Heather A. | Bruinenberg, Marcel | Buchman, Aron S | Campbell, Harry | Chen, Yii-Der Ida | Chines, Peter S. | Claudi-Boehm, Simone | Cole, John | Collins, Francis S. | de Geus, Eco J. C. | de Groot, Lisette C. P. G. M. | Dimitriou, Maria | Duan, Jubao | Enroth, Stefan | Eury, Elodie | Farmaki, Aliki-Eleni | Forouhi, Nita G. | Friedrich, Nele | Gejman, Pablo V. | Gigante, Bruna | Glorioso, Nicola | Go, Alan S. | Gottesman, Omri | Gräßler, Jürgen | Grallert, Harald | Grarup, Niels | Gu, Yu-Mei | Broer, Linda | Ham, Annelies C. | Hansen, Torben | Harris, Tamara B. | Hartman, Catharina A. | Hassinen, Maija | Hastie, Nicholas | Hattersley, Andrew T. | Heath, Andrew C. | Henders, Anjali K. | Hernandez, Dena | Hillege, Hans | Holmen, Oddgeir | Hovingh, Kees G | Hui, Jennie | Husemoen, Lise L. | Hutri-Kähönen, Nina | Hysi, Pirro G. | Illig, Thomas | De Jager, Philip L. | Jalilzadeh, Shapour | Jørgensen, Torben | Jukema, J. Wouter | Juonala, Markus | Kanoni, Stavroula | Karaleftheri, Maria | Khaw, Kay Tee | Kinnunen, Leena | Kittner, Steven J. | Koenig, Wolfgang | Kolcic, Ivana | Kovacs, Peter | Krarup, Nikolaj T. | Kratzer, Wolfgang | Krüger, Janine | Kuh, Diana | Kumari, Meena | Kyriakou, Theodosios | Langenberg, Claudia | Lannfelt, Lars | Lanzani, Chiara | Lotay, Vaneet | Launer, Lenore J. | Leander, Karin | Lindström, Jaana | Linneberg, Allan | Liu, Yan-Ping | Lobbens, Stéphane | Luben, Robert | Lyssenko, Valeriya | Männistö, Satu | Magnusson, Patrik K. | McArdle, Wendy L. | Menni, Cristina | Merger, Sigrun | Milani, Lili | Montgomery, Grant W. | Morris, Andrew P. | Narisu, Narisu | Nelis, Mari | Ong, Ken K. | Palotie, Aarno | Pérusse, Louis | Pichler, Irene | Pilia, Maria G. | Pouta, Anneli | Rheinberger, Myriam | Ribel-Madsen, Rasmus | Richards, Marcus | Rice, Kenneth M. | Rice, Treva K. | Rivolta, Carlo | Salomaa, Veikko | Sanders, Alan R. | Sarzynski, Mark A. | Scholtens, Salome | Scott, Robert A. | Scott, William R. | Sebert, Sylvain | Sengupta, Sebanti | Sennblad, Bengt | Seufferlein, Thomas | Silveira, Angela | Slagboom, P. Eline | Smit, Jan H. | Sparsø, Thomas H. | Stirrups, Kathleen | Stolk, Ronald P. | Stringham, Heather M. | Swertz, Morris A | Swift, Amy J. | Syvänen, Ann-Christine | Tan, Sian-Tsung | Thorand, Barbara | Tönjes, Anke | Tremblay, Angelo | Tsafantakis, Emmanouil | van der Most, Peter J. | Völker, Uwe | Vohl, Marie-Claude | Vonk, Judith M. | Waldenberger, Melanie | Walker, Ryan W. | Wennauer, Roman | Widén, Elisabeth | Willemsen, Gonneke | Wilsgaard, Tom | Wright, Alan F. | Zillikens, M. Carola | van Dijk, Suzanne C. | van Schoor, Natasja M. | Asselbergs, Folkert W. | de Bakker, Paul I. W. | Beckmann, Jacques S. | Beilby, John | Bennett, David A. | Bergman, Richard N. | Bergmann, Sven | Böger, Carsten A. | Boehm, Bernhard O. | Boerwinkle, Eric | Boomsma, Dorret I. | Bornstein, Stefan R. | Bottinger, Erwin P. | Bouchard, Claude | Chambers, John C. | Chanock, Stephen J. | Chasman, Daniel I. | Cucca, Francesco | Cusi, Daniele | Dedoussis, George | Erdmann, Jeanette | Eriksson, Johan G. | Evans, Denis A. | de Faire, Ulf | Farrall, Martin | Ferrucci, Luigi | Ford, Ian | Franke, Lude | Franks, Paul W. | Froguel, Philippe | Gansevoort, Ron T. | Gieger, Christian | Grönberg, Henrik | Gudnason, Vilmundur | Gyllensten, Ulf | Hall, Per | Hamsten, Anders | van der Harst, Pim | Hayward, Caroline | Heliövaara, Markku | Hengstenberg, Christian | Hicks, Andrew A | Hingorani, Aroon | Hofman, Albert | Hu, Frank | Huikuri, Heikki V. | Hveem, Kristian | James, Alan L. | Jordan, Joanne M. | Jula, Antti | Kähönen, Mika | Kajantie, Eero | Kathiresan, Sekar | Kiemeney, Lambertus A. L. M. | Kivimaki, Mika | Knekt, Paul B. | Koistinen, Heikki A. | Kooner, Jaspal S. | Koskinen, Seppo | Kuusisto, Johanna | Maerz, Winfried | Martin, Nicholas G | Laakso, Markku | Lakka, Timo A. | Lehtimäki, Terho | Lettre, Guillaume | Levinson, Douglas F. | Lind, Lars | Lokki, Marja-Liisa | Mäntyselkä, Pekka | Melbye, Mads | Metspalu, Andres | Mitchell, Braxton D. | Moll, Frans L. | Murray, Jeffrey C. | Musk, Arthur W. | Nieminen, Markku S. | Njølstad, Inger | Ohlsson, Claes | Oldehinkel, Albertine J. | Oostra, Ben A. | Palmer, Lyle J | Pankow, James S. | Pasterkamp, Gerard | Pedersen, Nancy L. | Pedersen, Oluf | Penninx, Brenda W. | Perola, Markus | Peters, Annette | Polašek, Ozren | Pramstaller, Peter P. | Psaty, Bruce M. | Qi, Lu | Quertermous, Thomas | Raitakari, Olli T. | Rankinen, Tuomo | Rauramaa, Rainer | Ridker, Paul M. | Rioux, John D. | Rivadeneira, Fernando | Rotter, Jerome I. | Rudan, Igor | den Ruijter, Hester M. | Saltevo, Juha | Sattar, Naveed | Schunkert, Heribert | Schwarz, Peter E. H. | Shuldiner, Alan R. | Sinisalo, Juha | Snieder, Harold | Sørensen, Thorkild I. A. | Spector, Tim D. | Staessen, Jan A. | Stefania, Bandinelli | Thorsteinsdottir, Unnur | Stumvoll, Michael | Tardif, Jean-Claude | Tremoli, Elena | Tuomilehto, Jaakko | Uitterlinden, André G. | Uusitupa, Matti | Verbeek, André L. M. | Vermeulen, Sita H. | Viikari, Jorma S. | Vitart, Veronique | Völzke, Henry | Vollenweider, Peter | Waeber, Gérard | Walker, Mark | Wallaschofski, Henri | Wareham, Nicholas J. | Watkins, Hugh | Zeggini, Eleftheria | Chakravarti, Aravinda | Clegg, Deborah J. | Cupples, L. Adrienne | Gordon-Larsen, Penny | Jaquish, Cashell E. | Rao, D. C. | Abecasis, Goncalo R. | Assimes, Themistocles L. | Barroso, Inês | Berndt, Sonja I. | Boehnke, Michael | Deloukas, Panos | Fox, Caroline S. | Groop, Leif C. | Hunter, David J. | Ingelsson, Erik | Kaplan, Robert C. | McCarthy, Mark I. | Mohlke, Karen L. | O'Connell, Jeffrey R. | Schlessinger, David | Strachan, David P. | Stefansson, Kari | van Duijn, Cornelia M. | Hirschhorn, Joel N. | Lindgren, Cecilia M. | Heid, Iris M. | North, Kari E. | Borecki, Ingrid B. | Kutalik, Zoltán | Loos, Ruth J. F.
PLoS Genetics  2016;12(6):e1006166.
doi:10.1371/journal.pgen.1006166
PMCID: PMC4927064  PMID: 27355579
3.  Rare coding TTN variants are associated with electrocardiographic QT interval in the general population 
Scientific Reports  2016;6:28356.
We have shown previously that noncoding variants mapping around a specific set of 170 genes encoding cardiomyocyte intercalated disc (ID) proteins are more enriched for associations with QT interval than observed for genome-wide comparisons. At a false discovery rate (FDR) of 5%, we had identified 28 such ID protein-encoding genes. Here, we assessed whether coding variants at these 28 genes affect QT interval in the general population as well. We used exome sequencing in 4,469 European American (EA) and 1,880 African American (AA) ancestry individuals from the population-based ARIC (Atherosclerosis Risk In Communities) Study cohort to focus on rare (allele frequency <1%) potentially deleterious (nonsynonymous, stop-gain, splice) variants (n = 2,398 for EA; n = 1,693 for AA) and tested their effects on standardized QT interval residuals. We identified 27 nonsynonymous variants associated with QT interval (FDR 5%), 22 of which were in TTN. Taken together with the mapping of a QT interval GWAS locus near TTN, our observation of rare deleterious coding variants in TTN associated with QT interval show that TTN plays a role in regulation of cardiac electrical conductance and coupling, and is a risk factor for cardiac arrhythmias and sudden cardiac death.
doi:10.1038/srep28356
PMCID: PMC4913250  PMID: 27321809
4.  Global Implementation of Genomic Medicine: We Are Not Alone 
Science translational medicine  2015;7(290):290ps13.
Advances in high-throughput genomic technologies coupled with a growing number of genomic results potentially useful in clinical care have led to ground-breaking genomic medicine implementation programs in various nations. Many of these innovative programs capitalize on unique local capabilities arising from the structure of their health care systems or their cultural or political milieu, as well as from unusual burdens of disease or risk alleles. Many such programs are being conducted in relative isolation and might benefit from sharing of approaches and lessons learned in other nations. The National Human Genome Research Institute recently brought together 25 of these groups from around the world to describe and compare projects, examine the current state of implementation and desired near-term capabilities, and identify opportunities for collaboration to promote the responsible implementation of genomic medicine.
The wide variety of nascent programs in diverse settings demonstrates that implementation of genomic medicine is expanding globally in varied and highly innovative ways. Opportunities for collaboration abound in the areas of evidence generation, health information technology, education, workforce development, pharmacogenomics, and policy and regulatory issues. Several international organizations that are already facilitating effective research collaborations should engage to ensure implementation proceeds collaboratively without potentially wasteful duplication. Efforts to coalesce these groups around concrete but compelling signature projects, such as global eradication of genetically-mediated drug reactions or developing a truly global genomic variant data resource across a wide number of ethnicities, would accelerate appropriate implementation of genomics to improve clinical care world-wide.
doi:10.1126/scitranslmed.aab0194
PMCID: PMC4898888  PMID: 26041702
medical genomics; implementation; global collaborations; practice standards; pharmacogenomics; personalized medicine; precision medicine
5.  Population variation in total genetic risk of Hirschsprung disease from common RET, SEMA3 and NRG1 susceptibility polymorphisms 
Human Molecular Genetics  2015;24(10):2997-3003.
The risk of Hirschsprung disease (HSCR) is ∼15/100 000 live births per newborn but has been reported to show significant inter-individual variation from the effects of seven common susceptibility alleles at the RET, SEMA3 and NRG1 loci. We show, by analyses of these variants in 997 samples from 376 HSCR families of European ancestry, that significant genetic risk can only be detected at RET (rs2435357 and rs2506030) and at SEMA3 (rs11766001), but not at NRG1. RET rs2435357 also showed significant frequency differences by gender, segment length of aganglionosis and familiality. Further, in combination, disease risk varied >30-fold between individuals with none and up to 6 susceptibility alleles. Thus, these polymorphisms can be used to stratify the newborn population into distinct phenotypic classes with defined risks to understand HSCR etiology.
doi:10.1093/hmg/ddv051
PMCID: PMC4406299  PMID: 25666438
6.  Generation of a cre recombinase-conditional Nos1ap over-expression transgenic mouse 
Biotechnology letters  2014;36(6):1179-1185.
Polymorphic non-coding variants at the NOS1AP locus have been associated with the common cardiac, metabolic and neurological traits and diseases. Although, in vitro gene targeting-based cellular and biochemical studies have shed some light on NOS1AP function in cardiac and neuronal tissue, to enhance our understanding of NOS1AP function in mammalian physiology and disease, we report the generation of cre recombinase-conditional Nos1ap over-expression transgenic mice (Nos1apTg). Conditional transgenic mice were generated by the pronuclear injection method and three independent, single-site, multiple copies integration event-based founder lines were selected. For heart-restricted over-expression, Nos1apTg mice were crossed with Mlc2v-cre and Nos1ap transcript over-expression was observed in left ventricles from Nos1apTg; Mlc2v-cre F1 mice. We believe that with the potential of conditional over-expression, Nos1apTg mice will be a useful resource in studying NOS1AP function in various tissues under physiological and disease states.
doi:10.1007/s10529-014-1473-x
PMCID: PMC4850732  PMID: 24563304
Cardiac arrhythmia; Conditional over-expression; GENOME-wide association studies; NOS1AP; QT interval; Sudden cardiac death; Transgenic mouse
7.  Intestinal Neuronal Dysplasia-Like Submucosal Ganglion Cell Hyperplasia at the Proximal Margins of Hirschsprung Disease Resections 
Intestinal neuronal dysplasia type B (IND) denotes an increased proportion of hyperplastic submucosal ganglia, as resolved histochemically in 15 µm-thick frozen sections. IND has been reported proximal to the aganglionic segment in patients with Hirschsprung disease (HSCR) and is putatively associated with a higher rate of post-surgical dysmotility. We have developed and validated histological criteria to diagnose IND-like submucosal ganglion cell hyperplasia (IND-SH) in paraffin sections, and used the approach to study the incidence and clinical/genetic associations of IND-SH at the proximal margins of HSCR pull-through resection specimens. Full-circumference paraffin sections from the proximal margins of 64 HSCR colonic pull-through specimens and 24 autopsy controls were immunostained for the neuron-specific Hu antigen and nucleated ganglion cells in each submucosal ganglion were counted. In controls, an age-related decline in the relative abundance of “giant” ganglia (≥7 nucleated Hu+ ganglion cells) was observed. A conservative diagnostic threshold for IND-SH (control mean + 3 times the standard deviation) was derived from 15 controls less than 25 weeks of age. No control exceeded this threshold, whereas in the same age range, IND-SH was observed at the proximal margins in 15% (7/46) of HSCR resections, up to 15 cm proximal to the aganglionic segment. No significant correlation was observed between IND-SH and length of or distance from the aganglionic segment, gender, trisomy 21, RET or SEMA3C/D polymorphisms, or clinical outcome, but analysis of more patients with better long-term follow-up will be required to clarify the significance of this histological phenotype.
doi:10.2350/15-07-1675-OA.1
PMCID: PMC4809533  PMID: 26699691
Hirschsprung; neuronal dysplasia; hyperganglionosis; transition zone; observer bias
8.  Directional dominance on stature and cognition in diverse human populations 
Joshi, Peter K. | Esko, Tonu | Mattsson, Hannele | Eklund, Niina | Gandin, Ilaria | Nutile, Teresa | Jackson, Anne U. | Schurmann, Claudia | Smith, Albert V. | Zhang, Weihua | Okada, Yukinori | Stančáková, Alena | Faul, Jessica D. | Zhao, Wei | Bartz, Traci M. | Concas, Maria Pina | Franceschini, Nora | Enroth, Stefan | Vitart, Veronique | Trompet, Stella | Guo, Xiuqing | Chasman, Daniel I. | O’Connel, Jeffery R. | Corre, Tanguy | Nongmaithem, Suraj S. | Chen, Yuning | Mangino, Massimo | Ruggiero, Daniela | Traglia, Michela | Farmaki, Aliki-Eleni | Kacprowski, Tim | Bjonnes, Andrew | van der Spek, Ashley | Wu, Ying | Giri, Anil K. | Yanek, Lisa R. | Wang, Lihua | Hofer, Edith | Rietveld, Cornelius A. | McLeod, Olga | Cornelis, Marilyn C. | Pattaro, Cristian | Verweij, Niek | Baumbach, Clemens | Abdellaoui, Abdel | Warren, Helen R. | Vuckovic, Dragana | Mei, Hao | Bouchard, Claude | Perry, John R.B. | Cappellani, Stefania | Mirza, Saira S. | Benton, Miles C. | Broeckel, Ulrich | Medland, Sarah E. | Lind, Penelope A. | Malerba, Giovanni | Drong, Alexander | Yengo, Loic | Bielak, Lawrence F. | Zhi, Degui | van der Most, Peter J. | Shriner, Daniel | Mägi, Reedik | Hemani, Gibran | Karaderi, Tugce | Wang, Zhaoming | Liu, Tian | Demuth, Ilja | Zhao, Jing Hua | Meng, Weihua | Lataniotis, Lazaros | van der Laan, Sander W. | Bradfield, Jonathan P. | Wood, Andrew R. | Bonnefond, Amelie | Ahluwalia, Tarunveer S. | Hall, Leanne M. | Salvi, Erika | Yazar, Seyhan | Carstensen, Lisbeth | de Haan, Hugoline G. | Abney, Mark | Afzal, Uzma | Allison, Matthew A. | Amin, Najaf | Asselbergs, Folkert W. | Bakker, Stephan J.L. | Barr, R. Graham | Baumeister, Sebastian E. | Benjamin, Daniel J. | Bergmann, Sven | Boerwinkle, Eric | Bottinger, Erwin P. | Campbell, Archie | Chakravarti, Aravinda | Chan, Yingleong | Chanock, Stephen J. | Chen, Constance | Chen, Y.-D. Ida | Collins, Francis S. | Connell, John | Correa, Adolfo | Cupples, L. Adrienne | Smith, George Davey | Davies, Gail | Dörr, Marcus | Ehret, Georg | Ellis, Stephen B. | Feenstra, Bjarke | Feitosa, Mary F. | Ford, Ian | Fox, Caroline S. | Frayling, Timothy M. | Friedrich, Nele | Geller, Frank | Scotland, Generation | Gillham-Nasenya, Irina | Gottesman, Omri | Graff, Misa | Grodstein, Francine | Gu, Charles | Haley, Chris | Hammond, Christopher J. | Harris, Sarah E. | Harris, Tamara B. | Hastie, Nicholas D. | Heard-Costa, Nancy L. | Heikkilä, Kauko | Hocking, Lynne J. | Homuth, Georg | Hottenga, Jouke-Jan | Huang, Jinyan | Huffman, Jennifer E. | Hysi, Pirro G. | Ikram, M. Arfan | Ingelsson, Erik | Joensuu, Anni | Johansson, Åsa | Jousilahti, Pekka | Jukema, J. Wouter | Kähönen, Mika | Kamatani, Yoichiro | Kanoni, Stavroula | Kerr, Shona M. | Khan, Nazir M. | Koellinger, Philipp | Koistinen, Heikki A. | Kooner, Manraj K. | Kubo, Michiaki | Kuusisto, Johanna | Lahti, Jari | Launer, Lenore J. | Lea, Rodney A. | Lehne, Benjamin | Lehtimäki, Terho | Liewald, David C.M. | Lind, Lars | Loh, Marie | Lokki, Marja-Liisa | London, Stephanie J. | Loomis, Stephanie J. | Loukola, Anu | Lu, Yingchang | Lumley, Thomas | Lundqvist, Annamari | Männistö, Satu | Marques-Vidal, Pedro | Masciullo, Corrado | Matchan, Angela | Mathias, Rasika A. | Matsuda, Koichi | Meigs, James B. | Meisinger, Christa | Meitinger, Thomas | Menni, Cristina | Mentch, Frank D. | Mihailov, Evelin | Milani, Lili | Montasser, May E. | Montgomery, Grant W. | Morrison, Alanna | Myers, Richard H. | Nadukuru, Rajiv | Navarro, Pau | Nelis, Mari | Nieminen, Markku S. | Nolte, Ilja M. | O’Connor, George T. | Ogunniyi, Adesola | Padmanabhan, Sandosh | Palmas, Walter R. | Pankow, James S. | Patarcic, Inga | Pavani, Francesca | Peyser, Patricia A. | Pietilainen, Kirsi | Poulter, Neil | Prokopenko, Inga | Ralhan, Sarju | Redmond, Paul | Rich, Stephen S. | Rissanen, Harri | Robino, Antonietta | Rose, Lynda M. | Rose, Richard | Sala, Cinzia | Salako, Babatunde | Salomaa, Veikko | Sarin, Antti-Pekka | Saxena, Richa | Schmidt, Helena | Scott, Laura J. | Scott, William R. | Sennblad, Bengt | Seshadri, Sudha | Sever, Peter | Shrestha, Smeeta | Smith, Blair H. | Smith, Jennifer A. | Soranzo, Nicole | Sotoodehnia, Nona | Southam, Lorraine | Stanton, Alice V. | Stathopoulou, Maria G. | Strauch, Konstantin | Strawbridge, Rona J. | Suderman, Matthew J. | Tandon, Nikhil | Tang, Sian-Tsun | Taylor, Kent D. | Tayo, Bamidele O. | Töglhofer, Anna Maria | Tomaszewski, Maciej | Tšernikova, Natalia | Tuomilehto, Jaakko | Uitterlinden, Andre G. | Vaidya, Dhananjay | van Hylckama Vlieg, Astrid | van Setten, Jessica | Vasankari, Tuula | Vedantam, Sailaja | Vlachopoulou, Efthymia | Vozzi, Diego | Vuoksimaa, Eero | Waldenberger, Melanie | Ware, Erin B. | Wentworth-Shields, William | Whitfield, John B. | Wild, Sarah | Willemsen, Gonneke | Yajnik, Chittaranjan S. | Yao, Jie | Zaza, Gianluigi | Zhu, Xiaofeng | Project, The BioBank Japan | Salem, Rany M. | Melbye, Mads | Bisgaard, Hans | Samani, Nilesh J. | Cusi, Daniele | Mackey, David A. | Cooper, Richard S. | Froguel, Philippe | Pasterkamp, Gerard | Grant, Struan F.A. | Hakonarson, Hakon | Ferrucci, Luigi | Scott, Robert A. | Morris, Andrew D. | Palmer, Colin N.A. | Dedoussis, George | Deloukas, Panos | Bertram, Lars | Lindenberger, Ulman | Berndt, Sonja I. | Lindgren, Cecilia M. | Timpson, Nicholas J. | Tönjes, Anke | Munroe, Patricia B. | Sørensen, Thorkild I.A. | Rotimi, Charles N. | Arnett, Donna K. | Oldehinkel, Albertine J. | Kardia, Sharon L.R. | Balkau, Beverley | Gambaro, Giovanni | Morris, Andrew P. | Eriksson, Johan G. | Wright, Margie J. | Martin, Nicholas G. | Hunt, Steven C. | Starr, John M. | Deary, Ian J. | Griffiths, Lyn R. | Tiemeier, Henning | Pirastu, Nicola | Kaprio, Jaakko | Wareham, Nicholas J. | Pérusse, Louis | Wilson, James G. | Girotto, Giorgia | Caulfield, Mark J. | Raitakari, Olli | Boomsma, Dorret I. | Gieger, Christian | van der Harst, Pim | Hicks, Andrew A. | Kraft, Peter | Sinisalo, Juha | Knekt, Paul | Johannesson, Magnus | Magnusson, Patrik K.E. | Hamsten, Anders | Schmidt, Reinhold | Borecki, Ingrid B. | Vartiainen, Erkki | Becker, Diane M. | Bharadwaj, Dwaipayan | Mohlke, Karen L. | Boehnke, Michael | van Duijn, Cornelia M. | Sanghera, Dharambir K. | Teumer, Alexander | Zeggini, Eleftheria | Metspalu, Andres | Gasparini, Paolo | Ulivi, Sheila | Ober, Carole | Toniolo, Daniela | Rudan, Igor | Porteous, David J. | Ciullo, Marina | Spector, Tim D. | Hayward, Caroline | Dupuis, Josée | Loos, Ruth J.F. | Wright, Alan F. | Chandak, Giriraj R. | Vollenweider, Peter | Shuldiner, Alan | Ridker, Paul M. | Rotter, Jerome I. | Sattar, Naveed | Gyllensten, Ulf | North, Kari E. | Pirastu, Mario | Psaty, Bruce M. | Weir, David R. | Laakso, Markku | Gudnason, Vilmundur | Takahashi, Atsushi | Chambers, John C. | Kooner, Jaspal S. | Strachan, David P. | Campbell, Harry | Hirschhorn, Joel N. | Perola, Markus | Polašek, Ozren | Wilson, James F.
Nature  2015;523(7561):459-462.
Homozygosity has long been associated with rare, often devastating, Mendelian disorders1 and Darwin was one of the first to recognise that inbreeding reduces evolutionary fitness2. However, the effect of the more distant parental relatedness common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity, ROH), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power3,4. Here we use ROH to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts and find statistically significant associations between summed runs of homozygosity (SROH) and four complex traits: height, forced expiratory lung volume in 1 second (FEV1), general cognitive ability (g) and educational attainment (nominal p<1 × 10−300, 2.1 × 10−6, 2.5 × 10−10, 1.8 × 10−10). In each case increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing convincing evidence for the first time that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples5,6, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein (LDL) cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection7, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
doi:10.1038/nature14618
PMCID: PMC4516141  PMID: 26131930
9.  Transcriptional regulation of PRPF31 gene expression by MSR1 repeat elements causes incomplete penetrance in retinitis pigmentosa 
Scientific Reports  2016;6:19450.
PRPF31-associated retinitis pigmentosa presents a fascinating enigma: some mutation carriers are blind, while others are asymptomatic. We identify the major molecular cause of this incomplete penetrance through three cardinal features: (1) there is population variation in the number (3 or 4) of a minisatellite repeat element (MSR1) adjacent to the PRPF31 core promoter; (2) in vitro, 3-copies of the MSR1 element can repress gene transcription by 50 to 115-fold; (3) the higher-expressing 4-copy allele is not observed among symptomatic PRPF31 mutation carriers and correlates with the rate of asymptomatic carriers in different populations. Thus, a linked transcriptional modifier decreases PRPF31 gene expression that leads to haploinsufficiency. This result, taken with other identified risk alleles, allows precise genetic counseling for the first time. We also demonstrate that across the human genome, the presence of MSR1 repeats in the promoters or first introns of genes is associated with greater population variability in gene expression indicating that copy number variation of MSR1s is a generic controller of gene expression and promises to provide new insights into our understanding of gene expression regulation.
doi:10.1038/srep19450
PMCID: PMC4725990  PMID: 26781568
10.  Role of Rare Variants in Systolic Blood Pressure: Analysis of Exome Chip Data in HyperGEN African Americans 
Human heredity  2015;79(1):20-27.
Cardiovascular disease is among the most significant health problems in the United States today, with its major risk factor, hypertension, disproportionately affecting African Americans (AAs). Although genome-wide association studies (GWAS) have identified dozens of common variants associated with blood pressure (BP) and hypertension in European Americans; these variants collectively explain less than 2.5% of BP variance, and most of the genetic variants remain yet to be identified. Here we report the results from rare variant analysis of systolic blood pressure (SBP) using 94,595 rare and low frequency variants (MAF < 5%) from the Illumina exome array genotyped in 2,045 HyperGEN AA. In addition to single-variant analysis, four gene-level association tests were used for analysis: burden and famSKAT tests using minor allele frequency (MAF) cutoffs of 1% and 5%. Gene-based methods often provided lower p-values than the single-variant approach. Some consistency was observed across these four gene-based analysis options. While neither gene-based analysis nor single variant analysis produced genome-wide significant results, the top signals, which had supporting evidence from multiple gene-based methods, were of borderline significance. Though additional molecular validations are required, six of the 16 most promising genes are biologically plausible with physiological connections to blood pressure regulation.
doi:10.1159/000375373
PMCID: PMC4374048  PMID: 25765051
Rare variants; Exome chip; Gene-based analysis; burden tests; SKAT; SBP; family studies
11.  Effects of RET and NRG1 polymorphisms in Indonesian patients with Hirschsprung disease 
Journal of pediatric surgery  2014;49(11):1614-1618.
Background
Hirschsprung disease (HSCR) is a neurocristopathy characterized by absence of intramural ganglion cells along variable lengths of the gastrointestinal tract in neonates. Three polymorphisms, rs2435357, within a conserved transcriptional enhancer of RET, and, rs7835688 and rs16879552, within intron 1 of NRG1, have been shown to be associated with isolated forms of HSCR. We wished to replicate these findings, and study the interactions between these variants, in Indonesian HSCR patients.
Methods
Sixty isolated HSCR patients and 124 controls were ascertained for this study. The three genetic markers were examined using TaqMan Genotyping Assays in genomic DNA for association studies.
Results
RET rs2435357 showed the strongest association with HSCR both by case–control analysis (p = 2.5 × 10−8) and transmission disequilibrium test (p = 4.2 × 10−6). NRG1 rs7835688 was modestly associated with HSCR only by case–control analysis (p = 4.3 × 10−3), whereas rs16879552 demonstrated no association (p > 0.097). Two locus analyses of variants showed significant interactions with increased and decreased disease risks of HSCR at NRG1 but conditional on rs2435357 genotype.
Conclusions
RET and NRG1 variants are common susceptibility factors for HSCR in Indonesia. These common variants demonstrate that development of HSCR requires joint effects of RET and NRG1 early in gut development.
doi:10.1016/j.jpedsurg.2014.04.011
PMCID: PMC4258000  PMID: 25475805
Hirschsprung disease; Common polymorphisms; Genetic interaction; Indonesian cases
12.  Loss of delta catenin function in severe autism 
Nature  2015;520(7545):51-56.
SUMMARY
Autism is a multifactorial neurodevelopmental disorder affecting more males than females; consequently, under a multifactorial genetic hypothesis, females are affected only when they cross a higher biological threshold. We hypothesize that deleterious variants at conserved residues are enriched in severely affected patients arising from FEMFs (female-enriched multiplex families) with severe disease, enhancing the detection of key autism genes in modest numbers of cases. We show the utility of this strategy by identifying missense and dosage sequence variants in the gene encoding the adhesive junction-associated delta catenin protein (CTNND2) in FEMFs and demonstrating their loss-of-function effect by functional analyses in zebrafish embryos and cultured hippocampal neurons from wildtype and Ctnnd2 null mouse embryos. Finally, through gene expression and network analyses, we highlight a critical role for CTNND2 in neuronal development and an intimate connection to chromatin biology. Our data contribute to the understanding of the genetic architecture of autism and suggest that genetic analyses of phenotypic extremes, such as FEMFs, are of innate value in multifactorial disorders.
doi:10.1038/nature14186
PMCID: PMC4383723  PMID: 25807484
13.  The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study 
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Wouter | Juonala, Markus | Kanoni, Stavroula | Karaleftheri, Maria | Khaw, Kay Tee | Kinnunen, Leena | Kittner, Steven J. | Koenig, Wolfgang | Kolcic, Ivana | Kovacs, Peter | Krarup, Nikolaj T. | Kratzer, Wolfgang | Krüger, Janine | Kuh, Diana | Kumari, Meena | Kyriakou, Theodosios | Langenberg, Claudia | Lannfelt, Lars | Lanzani, Chiara | Lotay, Vaneet | Launer, Lenore J. | Leander, Karin | Lindström, Jaana | Linneberg, Allan | Liu, Yan-Ping | Lobbens, Stéphane | Luben, Robert | Lyssenko, Valeriya | Männistö, Satu | Magnusson, Patrik K. | McArdle, Wendy L. | Menni, Cristina | Merger, Sigrun | Milani, Lili | Montgomery, Grant W. | Morris, Andrew P. | Narisu, Narisu | Nelis, Mari | Ong, Ken K. | Palotie, Aarno | Pérusse, Louis | Pichler, Irene | Pilia, Maria G. | Pouta, Anneli | Rheinberger, Myriam | Ribel-Madsen, Rasmus | Richards, Marcus | Rice, Kenneth M. | Rice, Treva K. | Rivolta, Carlo | Salomaa, Veikko | Sanders, Alan R. | Sarzynski, Mark A. | Scholtens, Salome | Scott, Robert A. | Scott, William R. | Sebert, Sylvain | Sengupta, Sebanti | Sennblad, Bengt | Seufferlein, Thomas | Silveira, Angela | Slagboom, P. Eline | Smit, Jan H. | Sparsø, Thomas H. | Stirrups, Kathleen | Stolk, Ronald P. | Stringham, Heather M. | Swertz, Morris A | Swift, Amy J. | Syvänen, Ann-Christine | Tan, Sian-Tsung | Thorand, Barbara | Tönjes, Anke | Tremblay, Angelo | Tsafantakis, Emmanouil | van der Most, Peter J. | Völker, Uwe | Vohl, Marie-Claude | Vonk, Judith M. | Waldenberger, Melanie | Walker, Ryan W. | Wennauer, Roman | Widén, Elisabeth | Willemsen, Gonneke | Wilsgaard, Tom | Wright, Alan F. | Zillikens, M. Carola | van Dijk, Suzanne C. | van Schoor, Natasja M. | Asselbergs, Folkert W. | de Bakker, Paul I. W. | Beckmann, Jacques S. | Beilby, John | Bennett, David A. | Bergman, Richard N. | Bergmann, Sven | Böger, Carsten A. | Boehm, Bernhard O. | Boerwinkle, Eric | Boomsma, Dorret I. | Bornstein, Stefan R. | Bottinger, Erwin P. | Bouchard, Claude | Chambers, John C. | Chanock, Stephen J. | Chasman, Daniel I. | Cucca, Francesco | Cusi, Daniele | Dedoussis, George | Erdmann, Jeanette | Eriksson, Johan G. | Evans, Denis A. | de Faire, Ulf | Farrall, Martin | Ferrucci, Luigi | Ford, Ian | Franke, Lude | Franks, Paul W. | Froguel, Philippe | Gansevoort, Ron T. | Gieger, Christian | Grönberg, Henrik | Gudnason, Vilmundur | Gyllensten, Ulf | Hall, Per | Hamsten, Anders | van der Harst, Pim | Hayward, Caroline | Heliövaara, Markku | Hengstenberg, Christian | Hicks, Andrew A | Hingorani, Aroon | Hofman, Albert | Hu, Frank | Huikuri, Heikki V. | Hveem, Kristian | James, Alan L. | Jordan, Joanne M. | Jula, Antti | Kähönen, Mika | Kajantie, Eero | Kathiresan, Sekar | Kiemeney, Lambertus A. L. M. | Kivimaki, Mika | Knekt, Paul B. | Koistinen, Heikki A. | Kooner, Jaspal S. | Koskinen, Seppo | Kuusisto, Johanna | Maerz, Winfried | Martin, Nicholas G | Laakso, Markku | Lakka, Timo A. | Lehtimäki, Terho | Lettre, Guillaume | Levinson, Douglas F. | Lind, Lars | Lokki, Marja-Liisa | Mäntyselkä, Pekka | Melbye, Mads | Metspalu, Andres | Mitchell, Braxton D. | Moll, Frans L. | Murray, Jeffrey C. | Musk, Arthur W. | Nieminen, Markku S. | Njølstad, Inger | Ohlsson, Claes | Oldehinkel, Albertine J. | Oostra, Ben A. | Palmer, Lyle J | Pankow, James S. | Pasterkamp, Gerard | Pedersen, Nancy L. | Pedersen, Oluf | Penninx, Brenda W. | Perola, Markus | Peters, Annette | Polašek, Ozren | Pramstaller, Peter P. | Psaty, Bruce M. | Qi, Lu | Quertermous, Thomas | Raitakari, Olli T. | Rankinen, Tuomo | Rauramaa, Rainer | Ridker, Paul M. | Rioux, John D. | Rivadeneira, Fernando | Rotter, Jerome I. | Rudan, Igor | den Ruijter, Hester M. | Saltevo, Juha | Sattar, Naveed | Schunkert, Heribert | Schwarz, Peter E. H. | Shuldiner, Alan R. | Sinisalo, Juha | Snieder, Harold | Sørensen, Thorkild I. A. | Spector, Tim D. | Staessen, Jan A. | Stefania, Bandinelli | Thorsteinsdottir, Unnur | Stumvoll, Michael | Tardif, Jean-Claude | Tremoli, Elena | Tuomilehto, Jaakko | Uitterlinden, André G. | Uusitupa, Matti | Verbeek, André L. M. | Vermeulen, Sita H. | Viikari, Jorma S. | Vitart, Veronique | Völzke, Henry | Vollenweider, Peter | Waeber, Gérard | Walker, Mark | Wallaschofski, Henri | Wareham, Nicholas J. | Watkins, Hugh | Zeggini, Eleftheria | Chakravarti, Aravinda | Clegg, Deborah J. | Cupples, L. Adrienne | Gordon-Larsen, Penny | Jaquish, Cashell E. | Rao, D. C. | Abecasis, Goncalo R. | Assimes, Themistocles L. | Barroso, Inês | Berndt, Sonja I. | Boehnke, Michael | Deloukas, Panos | Fox, Caroline S. | Groop, Leif C. | Hunter, David J. | Ingelsson, Erik | Kaplan, Robert C. | McCarthy, Mark I. | Mohlke, Karen L. | O'Connell, Jeffrey R. | Schlessinger, David | Strachan, David P. | Stefansson, Kari | van Duijn, Cornelia M. | Hirschhorn, Joel N. | Lindgren, Cecilia M. | Heid, Iris M. | North, Kari E. | Borecki, Ingrid B. | Kutalik, Zoltán | Loos, Ruth J. F.
PLoS Genetics  2015;11(10):e1005378.
Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.
Author Summary
Adult body size and body shape differ substantially between men and women and change over time. More than 100 genetic variants that influence body mass index (measure of body size) or waist-to-hip ratio (measure of body shape) have been identified. While there is evidence that some genetic loci affect body shape differently in men than in women, little is known about whether genetic effects differ in older compared to younger adults, and whether such changes differ between men and women. Therefore, we conducted a systematic genome-wide search, including 114 studies (>320,000 individuals), to specifically identify genetic loci with age- and or sex-dependent effects on body size and shape. We identified 15 loci of which the effect on BMI was different in older compared to younger adults, whereas we found no evidence for loci with different effects in men compared to women. The opposite was seen for body shape as we identified 44 loci of which the effect on waist-to-hip ratio differed between men and women, but no difference between younger and older adults were observed. Our observations may provide new insights into the biology that underlies weight change with age or the sexual dimorphism of body shape.
doi:10.1371/journal.pgen.1005378
PMCID: PMC4591371  PMID: 26426971
14.  New genetic loci link adipose and insulin biology to body fat distribution 
Shungin, Dmitry | Winkler, Thomas W | Croteau-Chonka, Damien C | Ferreira, Teresa | Locke, Adam E | Mägi, Reedik | Strawbridge, Rona J | Pers, Tune H | Fischer, Krista | Justice, Anne E | Workalemahu, Tsegaselassie | Wu, Joseph M.W. | Buchkovich, Martin L | Heard-Costa, Nancy L | Roman, Tamara S | Drong, Alexander W | Song, Ci | Gustafsson, Stefan | Day, Felix R | Esko, Tonu | Fall, Tove | Kutalik, Zoltán | Luan, Jian’an | Randall, Joshua C | Scherag, André | Vedantam, Sailaja | Wood, Andrew R | Chen, Jin | Fehrmann, Rudolf | Karjalainen, Juha | Kahali, Bratati | Liu, Ching-Ti | Schmidt, Ellen M | Absher, Devin | Amin, Najaf | Anderson, Denise | Beekman, Marian | Bragg-Gresham, Jennifer L | Buyske, Steven | Demirkan, Ayse | Ehret, Georg B | Feitosa, Mary F | Goel, Anuj | Jackson, Anne U | Johnson, Toby | Kleber, Marcus E | Kristiansson, Kati | Mangino, Massimo | Leach, Irene Mateo | Medina-Gomez, Carolina | Palmer, Cameron D | Pasko, Dorota | Pechlivanis, Sonali | Peters, Marjolein J | Prokopenko, Inga | Stančáková, Alena | Sung, Yun Ju | Tanaka, Toshiko | Teumer, Alexander | Van Vliet-Ostaptchouk, Jana V | Yengo, Loïc | Zhang, Weihua | Albrecht, Eva | Ärnlöv, Johan | Arscott, Gillian M | Bandinelli, Stefania | Barrett, Amy | Bellis, Claire | Bennett, Amanda J | Berne, Christian | Blüher, Matthias | Böhringer, Stefan | Bonnet, Fabrice | Böttcher, Yvonne | Bruinenberg, Marcel | Carba, Delia B | Caspersen, Ida H | Clarke, Robert | Daw, E Warwick | Deelen, Joris | Deelman, Ewa | Delgado, Graciela | Doney, Alex SF | Eklund, Niina | Erdos, Michael R | Estrada, Karol | Eury, Elodie | Friedrich, Nele | Garcia, Melissa E | Giedraitis, Vilmantas | Gigante, Bruna | Go, Alan S | Golay, Alain | Grallert, Harald | Grammer, Tanja B | Gräßler, Jürgen | Grewal, Jagvir | Groves, Christopher J | Haller, Toomas | Hallmans, Goran | Hartman, Catharina A | Hassinen, Maija | Hayward, Caroline | Heikkilä, Kauko | Herzig, Karl-Heinz | Helmer, Quinta | Hillege, Hans L | Holmen, Oddgeir | Hunt, Steven C | Isaacs, Aaron | Ittermann, Till | James, Alan L | Johansson, Ingegerd | Juliusdottir, Thorhildur | Kalafati, Ioanna-Panagiota | Kinnunen, Leena | Koenig, Wolfgang | Kooner, Ishminder K | Kratzer, Wolfgang | Lamina, Claudia | Leander, Karin | Lee, Nanette R | Lichtner, Peter | Lind, Lars | Lindström, Jaana | Lobbens, Stéphane | Lorentzon, Mattias | Mach, François | Magnusson, Patrik KE | Mahajan, Anubha | McArdle, Wendy L | Menni, Cristina | Merger, Sigrun | Mihailov, Evelin | Milani, Lili | Mills, Rebecca | Moayyeri, Alireza | Monda, Keri L | Mooijaart, Simon P | Mühleisen, Thomas W | Mulas, Antonella | Müller, Gabriele | Müller-Nurasyid, Martina | Nagaraja, Ramaiah | Nalls, Michael A | Narisu, Narisu | Glorioso, Nicola | Nolte, Ilja M | Olden, Matthias | Rayner, Nigel W | Renstrom, Frida | Ried, Janina S | Robertson, Neil R | Rose, Lynda M | Sanna, Serena | Scharnagl, Hubert | Scholtens, Salome | Sennblad, Bengt | Seufferlein, Thomas | Sitlani, Colleen M | Smith, Albert Vernon | Stirrups, Kathleen | Stringham, Heather M | Sundström, Johan | Swertz, Morris A | Swift, Amy J | Syvänen, Ann-Christine | Tayo, Bamidele O | Thorand, Barbara | Thorleifsson, Gudmar | Tomaschitz, Andreas | Troffa, Chiara | van Oort, Floor VA | Verweij, Niek | Vonk, Judith M | Waite, Lindsay L | Wennauer, Roman | Wilsgaard, Tom | Wojczynski, Mary K | Wong, Andrew | Zhang, Qunyuan | Zhao, Jing Hua | Brennan, Eoin P. | Choi, Murim | Eriksson, Per | Folkersen, Lasse | Franco-Cereceda, Anders | Gharavi, Ali G | Hedman, Åsa K | Hivert, Marie-France | Huang, Jinyan | Kanoni, Stavroula | Karpe, Fredrik | Keildson, Sarah | Kiryluk, Krzysztof | Liang, Liming | Lifton, Richard P | Ma, Baoshan | McKnight, Amy J | McPherson, Ruth | Metspalu, Andres | Min, Josine L | Moffatt, Miriam F | Montgomery, Grant W | Murabito, Joanne M | Nicholson, George | Nyholt, Dale R | Olsson, Christian | Perry, John RB | Reinmaa, Eva | Salem, Rany M | Sandholm, Niina | Schadt, Eric E | Scott, Robert A | Stolk, Lisette | Vallejo, Edgar E. | Westra, Harm-Jan | Zondervan, Krina T | Amouyel, Philippe | Arveiler, Dominique | Bakker, Stephan JL | Beilby, John | Bergman, Richard N | Blangero, John | Brown, Morris J | Burnier, Michel | Campbell, Harry | Chakravarti, Aravinda | Chines, Peter S | Claudi-Boehm, Simone | Collins, Francis S | Crawford, Dana C | Danesh, John | de Faire, Ulf | de Geus, Eco JC | Dörr, Marcus | Erbel, Raimund | Eriksson, Johan G | Farrall, Martin | Ferrannini, Ele | Ferrières, Jean | Forouhi, Nita G | Forrester, Terrence | Franco, Oscar H | Gansevoort, Ron T | Gieger, Christian | Gudnason, Vilmundur | Haiman, Christopher A | Harris, Tamara B | Hattersley, Andrew T | Heliövaara, Markku | Hicks, Andrew A | Hingorani, Aroon D | Hoffmann, Wolfgang | Hofman, Albert | Homuth, Georg | Humphries, Steve E | Hyppönen, Elina | Illig, Thomas | Jarvelin, Marjo-Riitta | Johansen, Berit | Jousilahti, Pekka | Jula, Antti M | Kaprio, Jaakko | Kee, Frank | Keinanen-Kiukaanniemi, Sirkka M | Kooner, Jaspal S | Kooperberg, Charles | Kovacs, Peter | Kraja, Aldi T | Kumari, Meena | Kuulasmaa, Kari | Kuusisto, Johanna | Lakka, Timo A | Langenberg, Claudia | Le Marchand, Loic | Lehtimäki, Terho | Lyssenko, Valeriya | Männistö, Satu | Marette, André | Matise, Tara C | McKenzie, Colin A | McKnight, Barbara | Musk, Arthur W | Möhlenkamp, Stefan | Morris, Andrew D | Nelis, Mari | Ohlsson, Claes | Oldehinkel, Albertine J | Ong, Ken K | Palmer, Lyle J | Penninx, Brenda W | Peters, Annette | Pramstaller, Peter P | Raitakari, Olli T | Rankinen, Tuomo | Rao, DC | Rice, Treva K | Ridker, Paul M | Ritchie, Marylyn D. | Rudan, Igor | Salomaa, Veikko | Samani, Nilesh J | Saramies, Jouko | Sarzynski, Mark A | Schwarz, Peter EH | Shuldiner, Alan R | Staessen, Jan A | Steinthorsdottir, Valgerdur | Stolk, Ronald P | Strauch, Konstantin | Tönjes, Anke | Tremblay, Angelo | Tremoli, Elena | Vohl, Marie-Claude | Völker, Uwe | Vollenweider, Peter | Wilson, James F | Witteman, Jacqueline C | Adair, Linda S | Bochud, Murielle | Boehm, Bernhard O | Bornstein, Stefan R | Bouchard, Claude | Cauchi, Stéphane | Caulfield, Mark J | Chambers, John C | Chasman, Daniel I | Cooper, Richard S | Dedoussis, George | Ferrucci, Luigi | Froguel, Philippe | Grabe, Hans-Jörgen | Hamsten, Anders | Hui, Jennie | Hveem, Kristian | Jöckel, Karl-Heinz | Kivimaki, Mika | Kuh, Diana | Laakso, Markku | Liu, Yongmei | März, Winfried | Munroe, Patricia B | Njølstad, Inger | Oostra, Ben A | Palmer, Colin NA | Pedersen, Nancy L | Perola, Markus | Pérusse, Louis | Peters, Ulrike | Power, Chris | Quertermous, Thomas | Rauramaa, Rainer | Rivadeneira, Fernando | Saaristo, Timo E | Saleheen, Danish | Sinisalo, Juha | Slagboom, P Eline | Snieder, Harold | Spector, Tim D | Stefansson, Kari | Stumvoll, Michael | Tuomilehto, Jaakko | Uitterlinden, André G | Uusitupa, Matti | van der Harst, Pim | Veronesi, Giovanni | Walker, Mark | Wareham, Nicholas J | Watkins, Hugh | Wichmann, H-Erich | Abecasis, Goncalo R | Assimes, Themistocles L | Berndt, Sonja I | Boehnke, Michael | Borecki, Ingrid B | Deloukas, Panos | Franke, Lude | Frayling, Timothy M | Groop, Leif C | Hunter, David J. | Kaplan, Robert C | O’Connell, Jeffrey R | Qi, Lu | Schlessinger, David | Strachan, David P | Thorsteinsdottir, Unnur | van Duijn, Cornelia M | Willer, Cristen J | Visscher, Peter M | Yang, Jian | Hirschhorn, Joel N | Zillikens, M Carola | McCarthy, Mark I | Speliotes, Elizabeth K | North, Kari E | Fox, Caroline S | Barroso, Inês | Franks, Paul W | Ingelsson, Erik | Heid, Iris M | Loos, Ruth JF | Cupples, L Adrienne | Morris, Andrew P | Lindgren, Cecilia M | Mohlke, Karen L
Nature  2015;518(7538):187-196.
Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, we conducted genome-wide association meta-analyses of waist and hip circumference-related traits in up to 224,459 individuals. We identified 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (WHRadjBMI) and an additional 19 loci newly associated with related waist and hip circumference measures (P<5×10−8). Twenty of the 49 WHRadjBMI loci showed significant sexual dimorphism, 19 of which displayed a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation, and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
doi:10.1038/nature14132
PMCID: PMC4338562  PMID: 25673412
15.  Direct Estimates of the Genomic Contributions to Blood Pressure Heritability within a Population-Based Cohort (ARIC) 
PLoS ONE  2015;10(7):e0133031.
Blood pressure (BP) is a heritable trait with multiple environmental and genetic contributions, with current heritability estimates from twin and family studies being ~ 40%. Here, we use genome-wide polymorphism data from the Atherosclerosis Risk in Communities (ARIC) study to estimate BP heritability from genomic relatedness among cohort members. We utilized data on 6,365,596 and 9,578,528 genotyped and imputed common single nucleotide polymorphisms (SNPs), in 8,901 European ancestry (EA) and 2,860 African Ancestry (AA) ARIC participants, respectively, and a mixed linear model for analyses, to make four observations. First, for BP measurements, the heritability is ~20%/~50% and ~27%/~39% for systolic (SBP)/diastolic (DBP) blood pressure in European and African ancestry individuals, respectively, consistent with prior studies. Second, common variants with allele frequency >10% recapitulate most of the BP heritability in these data. Third, the vast majority of BP heritability varies by chromosome, depending on its length, and is largely concentrated in noncoding genomic regions annotated as DNaseI hypersensitive sites (DHSs). Fourth, the majority of this heritability arises from loci not harboring currently known cardiovascular and renal genes. Recent meta-analyses of large-scale genome-wide association studies (GWASs) and admixture mapping have identified ~50 loci associated with BP and hypertension (HTN), and yet they account for only a small fraction (~2%) of the heritability.
doi:10.1371/journal.pone.0133031
PMCID: PMC4498745  PMID: 26162070
16.  Linkage Analysis Incorporating Gene-Age Interactions Identifies Seven Novel Lipid Loci: The Family Blood Pressure Program 
Atherosclerosis  2014;235(1):84-93.
OBJECTIVE
To detect novel loci with age-dependent effects on fasting (≥8 hours) levels of total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglycerides using3,600 African Americans, 1,283 Asians, 3,218 European Americans, and 2,026 Mexican Americans from the Family Blood Pressure Program (FBPP).
METHODS
Within each subgroup (defined by network, race, and sex), we employedstepwise linear regression (retention p≤0.05) to adjust lipid levels for age, age-squared, age-cubed,body-mass-index, current smoking status, current drinking status, field center, estrogen therapy (females only), as well asantidiabetic, antihypertensive, and antilipidemic medication use. For each trait, we pooled the standardized male and female residuals within each network and race and fit a generalized variance components model that incorporated gene-age interactions. We conducted FBPP-wide and race-specific meta-analyses by combining the p-values of each linkage marker across subgroups usinga modifiedFisher's method.
RESULTS
We identified seven novel loci with age-dependent effects; four total cholesterol loci from the meta-analysis of Mexican Americans (on chromosomes 2q24.1, 4q21.21, 8q22.2, and 12p11.23) and three high-density lipoprotein loci from the meta-analysis of all FBPP subgroups (on chromosomes 1p12, 14q11.2, and 21q21.1). These loci lacked significant genome-wide linkage or association evidence in the literature and hadlogarithm of odds (LOD) score ≥ 3 in the meta-analysis with LOD≥1 in at least two network and race subgroups (exclusively of non-European descent).
CONCLUSION
Incorporating gene-age interactions into the analysis of lipids using multi-ethnic cohorts can enhance gene discovery. These interaction loci can guide the selection of familiesfor sequencingstudies of lipid-associated variants.
doi:10.1016/j.atherosclerosis.2014.04.008
PMCID: PMC4322916  PMID: 24819747
Lipids; aging; genetics; meta-analysis; gene-age interactions; linkage; triglyceride; cholesterol
17.  Defining the role of common variation in the genomic and biological architecture of adult human height 
Wood, Andrew R | Esko, Tonu | Yang, Jian | Vedantam, Sailaja | Pers, Tune H | Gustafsson, Stefan | Chu, Audrey Y | Estrada, Karol | Luan, Jian’an | Kutalik, Zoltán | Amin, Najaf | Buchkovich, Martin L | Croteau-Chonka, Damien C | Day, Felix R | Duan, Yanan | Fall, Tove | Fehrmann, Rudolf | Ferreira, Teresa | Jackson, Anne U | Karjalainen, Juha | Lo, Ken Sin | Locke, Adam E | Mägi, Reedik | Mihailov, Evelin | Porcu, Eleonora | Randall, Joshua C | Scherag, André | Vinkhuyzen, Anna AE | Westra, Harm-Jan | Winkler, Thomas W | Workalemahu, Tsegaselassie | Zhao, Jing Hua | Absher, Devin | Albrecht, Eva | Anderson, Denise | Baron, Jeffrey | Beekman, Marian | Demirkan, Ayse | Ehret, Georg B | Feenstra, Bjarke | Feitosa, Mary F | Fischer, Krista | Fraser, Ross M | Goel, Anuj | Gong, Jian | Justice, Anne E | Kanoni, Stavroula | Kleber, Marcus E | Kristiansson, Kati | Lim, Unhee | Lotay, Vaneet | Lui, Julian C | Mangino, Massimo | Leach, Irene Mateo | Medina-Gomez, Carolina | Nalls, Michael A | Nyholt, Dale R | Palmer, Cameron D | Pasko, Dorota | Pechlivanis, Sonali | Prokopenko, Inga | Ried, Janina S | Ripke, Stephan | Shungin, Dmitry | Stancáková, Alena | Strawbridge, Rona J | Sung, Yun Ju | Tanaka, Toshiko | Teumer, Alexander | Trompet, Stella | van der Laan, Sander W | van Setten, Jessica | Van Vliet-Ostaptchouk, Jana V | Wang, Zhaoming | Yengo, Loïc | Zhang, Weihua | Afzal, Uzma | Ärnlöv, Johan | Arscott, Gillian M | Bandinelli, Stefania | Barrett, Amy | Bellis, Claire | Bennett, Amanda J | Berne, Christian | Blüher, Matthias | Bolton, Jennifer L | Böttcher, Yvonne | Boyd, Heather A | Bruinenberg, Marcel | Buckley, Brendan M | Buyske, Steven | Caspersen, Ida H | Chines, Peter S | Clarke, Robert | Claudi-Boehm, Simone | Cooper, Matthew | Daw, E Warwick | De Jong, Pim A | Deelen, Joris | Delgado, Graciela | Denny, Josh C | Dhonukshe-Rutten, Rosalie | Dimitriou, Maria | Doney, Alex SF | Dörr, Marcus | Eklund, Niina | Eury, Elodie | Folkersen, Lasse | Garcia, Melissa E | Geller, Frank | Giedraitis, Vilmantas | Go, Alan S | Grallert, Harald | Grammer, Tanja B | Gräßler, Jürgen | Grönberg, Henrik | de Groot, Lisette C.P.G.M. | Groves, Christopher J | Haessler, Jeffrey | Hall, Per | Haller, Toomas | Hallmans, Goran | Hannemann, Anke | Hartman, Catharina A | Hassinen, Maija | Hayward, Caroline | Heard-Costa, Nancy L | Helmer, Quinta | Hemani, Gibran | Henders, Anjali K | Hillege, Hans L | Hlatky, Mark A | Hoffmann, Wolfgang | Hoffmann, Per | Holmen, Oddgeir | Houwing-Duistermaat, Jeanine J | Illig, Thomas | Isaacs, Aaron | James, Alan L | Jeff, Janina | Johansen, Berit | Johansson, Åsa | Jolley, Jennifer | Juliusdottir, Thorhildur | Junttila, Juhani | Kho, Abel N | Kinnunen, Leena | Klopp, Norman | Kocher, Thomas | Kratzer, Wolfgang | Lichtner, Peter | Lind, Lars | Lindström, Jaana | Lobbens, Stéphane | Lorentzon, Mattias | Lu, Yingchang | Lyssenko, Valeriya | Magnusson, Patrik KE | Mahajan, Anubha | Maillard, Marc | McArdle, Wendy L | McKenzie, Colin A | McLachlan, Stela | McLaren, Paul J | Menni, Cristina | Merger, Sigrun | Milani, Lili | Moayyeri, Alireza | Monda, Keri L | Morken, Mario A | Müller, Gabriele | Müller-Nurasyid, Martina | Musk, Arthur W | Narisu, Narisu | Nauck, Matthias | Nolte, Ilja M | Nöthen, Markus M | Oozageer, Laticia | Pilz, Stefan | Rayner, Nigel W | Renstrom, Frida | Robertson, Neil R | Rose, Lynda M | Roussel, Ronan | Sanna, Serena | Scharnagl, Hubert | Scholtens, Salome | Schumacher, Fredrick R | Schunkert, Heribert | Scott, Robert A | Sehmi, Joban | Seufferlein, Thomas | Shi, Jianxin | Silventoinen, Karri | Smit, Johannes H | Smith, Albert Vernon | Smolonska, Joanna | Stanton, Alice V | Stirrups, Kathleen | Stott, David J | Stringham, Heather M | Sundström, Johan | Swertz, Morris A | Syvänen, Ann-Christine | Tayo, Bamidele O | Thorleifsson, Gudmar | Tyrer, Jonathan P | van Dijk, Suzanne | van Schoor, Natasja M | van der Velde, Nathalie | van Heemst, Diana | van Oort, Floor VA | Vermeulen, Sita H | Verweij, Niek | Vonk, Judith M | Waite, Lindsay L | Waldenberger, Melanie | Wennauer, Roman | Wilkens, Lynne R | Willenborg, Christina | Wilsgaard, Tom | Wojczynski, Mary K | Wong, Andrew | Wright, Alan F | Zhang, Qunyuan | Arveiler, Dominique | Bakker, Stephan JL | Beilby, John | Bergman, Richard N | Bergmann, Sven | Biffar, Reiner | Blangero, John | Boomsma, Dorret I | Bornstein, Stefan R | Bovet, Pascal | Brambilla, Paolo | Brown, Morris J | Campbell, Harry | Caulfield, Mark J | Chakravarti, Aravinda | Collins, Rory | Collins, Francis S | Crawford, Dana C | Cupples, L Adrienne | Danesh, John | de Faire, Ulf | den Ruijter, Hester M | Erbel, Raimund | Erdmann, Jeanette | Eriksson, Johan G | Farrall, Martin | Ferrannini, Ele | Ferrières, Jean | Ford, Ian | Forouhi, Nita G | Forrester, Terrence | Gansevoort, Ron T | Gejman, Pablo V | Gieger, Christian | Golay, Alain | Gottesman, Omri | Gudnason, Vilmundur | Gyllensten, Ulf | Haas, David W | Hall, Alistair S | Harris, Tamara B | Hattersley, Andrew T | Heath, Andrew C | Hengstenberg, Christian | Hicks, Andrew A | Hindorff, Lucia A | Hingorani, Aroon D | Hofman, Albert | Hovingh, G Kees | Humphries, Steve E | Hunt, Steven C | Hypponen, Elina | Jacobs, Kevin B | Jarvelin, Marjo-Riitta | Jousilahti, Pekka | Jula, Antti M | Kaprio, Jaakko | Kastelein, John JP | Kayser, Manfred | Kee, Frank | Keinanen-Kiukaanniemi, Sirkka M | Kiemeney, Lambertus A | Kooner, Jaspal S | Kooperberg, Charles | Koskinen, Seppo | Kovacs, Peter | Kraja, Aldi T | Kumari, Meena | Kuusisto, Johanna | Lakka, Timo A | Langenberg, Claudia | Le Marchand, Loic | Lehtimäki, Terho | Lupoli, Sara | Madden, Pamela AF | Männistö, Satu | Manunta, Paolo | Marette, André | Matise, Tara C | McKnight, Barbara | Meitinger, Thomas | Moll, Frans L | Montgomery, Grant W | Morris, Andrew D | Morris, Andrew P | Murray, Jeffrey C | Nelis, Mari | Ohlsson, Claes | Oldehinkel, Albertine J | Ong, Ken K | Ouwehand, Willem H | Pasterkamp, Gerard | Peters, Annette | Pramstaller, Peter P | Price, Jackie F | Qi, Lu | Raitakari, Olli T | Rankinen, Tuomo | Rao, DC | Rice, Treva K | Ritchie, Marylyn | Rudan, Igor | Salomaa, Veikko | Samani, Nilesh J | Saramies, Jouko | Sarzynski, Mark A | Schwarz, Peter EH | Sebert, Sylvain | Sever, Peter | Shuldiner, Alan R | Sinisalo, Juha | Steinthorsdottir, Valgerdur | Stolk, Ronald P | Tardif, Jean-Claude | Tönjes, Anke | Tremblay, Angelo | Tremoli, Elena | Virtamo, Jarmo | Vohl, Marie-Claude | Amouyel, Philippe | Asselbergs, Folkert W | Assimes, Themistocles L | Bochud, Murielle | Boehm, Bernhard O | Boerwinkle, Eric | Bottinger, Erwin P | Bouchard, Claude | Cauchi, Stéphane | Chambers, John C | Chanock, Stephen J | Cooper, Richard S | de Bakker, Paul IW | Dedoussis, George | Ferrucci, Luigi | Franks, Paul W | Froguel, Philippe | Groop, Leif C | Haiman, Christopher A | Hamsten, Anders | Hayes, M Geoffrey | Hui, Jennie | Hunter, David J. | Hveem, Kristian | Jukema, J Wouter | Kaplan, Robert C | Kivimaki, Mika | Kuh, Diana | Laakso, Markku | Liu, Yongmei | Martin, Nicholas G | März, Winfried | Melbye, Mads | Moebus, Susanne | Munroe, Patricia B | Njølstad, Inger | Oostra, Ben A | Palmer, Colin NA | Pedersen, Nancy L | Perola, Markus | Pérusse, Louis | Peters, Ulrike | Powell, Joseph E | Power, Chris | Quertermous, Thomas | Rauramaa, Rainer | Reinmaa, Eva | Ridker, Paul M | Rivadeneira, Fernando | Rotter, Jerome I | Saaristo, Timo E | Saleheen, Danish | Schlessinger, David | Slagboom, P Eline | Snieder, Harold | Spector, Tim D | Strauch, Konstantin | Stumvoll, Michael | Tuomilehto, Jaakko | Uusitupa, Matti | van der Harst, Pim | Völzke, Henry | Walker, Mark | Wareham, Nicholas J | Watkins, Hugh | Wichmann, H-Erich | Wilson, James F | Zanen, Pieter | Deloukas, Panos | Heid, Iris M | Lindgren, Cecilia M | Mohlke, Karen L | Speliotes, Elizabeth K | Thorsteinsdottir, Unnur | Barroso, Inês | Fox, Caroline S | North, Kari E | Strachan, David P | Beckmann, Jacques S. | Berndt, Sonja I | Boehnke, Michael | Borecki, Ingrid B | McCarthy, Mark I | Metspalu, Andres | Stefansson, Kari | Uitterlinden, André G | van Duijn, Cornelia M | Franke, Lude | Willer, Cristen J | Price, Alkes L. | Lettre, Guillaume | Loos, Ruth JF | Weedon, Michael N | Ingelsson, Erik | O’Connell, Jeffrey R | Abecasis, Goncalo R | Chasman, Daniel I | Goddard, Michael E | Visscher, Peter M | Hirschhorn, Joel N | Frayling, Timothy M
Nature genetics  2014;46(11):1173-1186.
Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explain one-fifth of heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ~2,000, ~3,700 and ~9,500 SNPs explained ~21%, ~24% and ~29% of phenotypic variance. Furthermore, all common variants together captured the majority (60%) of heritability. The 697 variants clustered in 423 loci enriched for genes, pathways, and tissue-types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/beta-catenin, and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
doi:10.1038/ng.3097
PMCID: PMC4250049  PMID: 25282103
18.  Defining the role of common variation in the genomic and biological architecture of adult human height 
Wood, Andrew R | Esko, Tonu | Yang, Jian | Vedantam, Sailaja | Pers, Tune H | Gustafsson, Stefan | Chu, Audrey Y | Estrada, Karol | Luan, Jian’an | Kutalik, Zoltán | Amin, Najaf | Buchkovich, Martin L | Croteau-Chonka, Damien C | Day, Felix R | Duan, Yanan | Fall, Tove | Fehrmann, Rudolf | Ferreira, Teresa | Jackson, Anne U | Karjalainen, Juha | Lo, Ken Sin | Locke, Adam E | Mägi, Reedik | Mihailov, Evelin | Porcu, Eleonora | Randall, Joshua C | Scherag, André | Vinkhuyzen, Anna AE | Westra, Harm-Jan | Winkler, Thomas W | Workalemahu, Tsegaselassie | Zhao, Jing Hua | Absher, Devin | Albrecht, Eva | Anderson, Denise | Baron, Jeffrey | Beekman, Marian | Demirkan, Ayse | Ehret, Georg B | Feenstra, Bjarke | Feitosa, Mary F | Fischer, Krista | Fraser, Ross M | Goel, Anuj | Gong, Jian | Justice, Anne E | Kanoni, Stavroula | Kleber, Marcus E | Kristiansson, Kati | Lim, Unhee | Lotay, Vaneet | Lui, Julian C | Mangino, Massimo | Leach, Irene Mateo | Medina-Gomez, Carolina | Nalls, Michael A | Nyholt, Dale R | Palmer, Cameron D | Pasko, Dorota | Pechlivanis, Sonali | Prokopenko, Inga | Ried, Janina S | Ripke, Stephan | Shungin, Dmitry | Stancáková, Alena | Strawbridge, Rona J | Sung, Yun Ju | Tanaka, Toshiko | Teumer, Alexander | Trompet, Stella | van der Laan, Sander W | van Setten, Jessica | Van Vliet-Ostaptchouk, Jana V | Wang, Zhaoming | Yengo, Loïc | Zhang, Weihua | Afzal, Uzma | Ärnlöv, Johan | Arscott, Gillian M | Bandinelli, Stefania | Barrett, Amy | Bellis, Claire | Bennett, Amanda J | Berne, Christian | Blüher, Matthias | Bolton, Jennifer L | Böttcher, Yvonne | Boyd, Heather A | Bruinenberg, Marcel | Buckley, Brendan M | Buyske, Steven | Caspersen, Ida H | Chines, Peter S | Clarke, Robert | Claudi-Boehm, Simone | Cooper, Matthew | Daw, E Warwick | De Jong, Pim A | Deelen, Joris | Delgado, Graciela | Denny, Josh C | Dhonukshe-Rutten, Rosalie | Dimitriou, Maria | Doney, Alex SF | Dörr, Marcus | Eklund, Niina | Eury, Elodie | Folkersen, Lasse | Garcia, Melissa E | Geller, Frank | Giedraitis, Vilmantas | Go, Alan S | Grallert, Harald | Grammer, Tanja B | Gräßler, Jürgen | Grönberg, Henrik | de Groot, Lisette C.P.G.M. | Groves, Christopher J | Haessler, Jeffrey | Hall, Per | Haller, Toomas | Hallmans, Goran | Hannemann, Anke | Hartman, Catharina A | Hassinen, Maija | Hayward, Caroline | Heard-Costa, Nancy L | Helmer, Quinta | Hemani, Gibran | Henders, Anjali K | Hillege, Hans L | Hlatky, Mark A | Hoffmann, Wolfgang | Hoffmann, Per | Holmen, Oddgeir | Houwing-Duistermaat, Jeanine J | Illig, Thomas | Isaacs, Aaron | James, Alan L | Jeff, Janina | Johansen, Berit | Johansson, Åsa | Jolley, Jennifer | Juliusdottir, Thorhildur | Junttila, Juhani | Kho, Abel N | Kinnunen, Leena | Klopp, Norman | Kocher, Thomas | Kratzer, Wolfgang | Lichtner, Peter | Lind, Lars | Lindström, Jaana | Lobbens, Stéphane | Lorentzon, Mattias | Lu, Yingchang | Lyssenko, Valeriya | Magnusson, Patrik KE | Mahajan, Anubha | Maillard, Marc | McArdle, Wendy L | McKenzie, Colin A | McLachlan, Stela | McLaren, Paul J | Menni, Cristina | Merger, Sigrun | Milani, Lili | Moayyeri, Alireza | Monda, Keri L | Morken, Mario A | Müller, Gabriele | Müller-Nurasyid, Martina | Musk, Arthur W | Narisu, Narisu | Nauck, Matthias | Nolte, Ilja M | Nöthen, Markus M | Oozageer, Laticia | Pilz, Stefan | Rayner, Nigel W | Renstrom, Frida | Robertson, Neil R | Rose, Lynda M | Roussel, Ronan | Sanna, Serena | Scharnagl, Hubert | Scholtens, Salome | Schumacher, Fredrick R | Schunkert, Heribert | Scott, Robert A | Sehmi, Joban | Seufferlein, Thomas | Shi, Jianxin | Silventoinen, Karri | Smit, Johannes H | Smith, Albert Vernon | Smolonska, Joanna | Stanton, Alice V | Stirrups, Kathleen | Stott, David J | Stringham, Heather M | Sundström, Johan | Swertz, Morris A | Syvänen, Ann-Christine | Tayo, Bamidele O | Thorleifsson, Gudmar | Tyrer, Jonathan P | van Dijk, Suzanne | van Schoor, Natasja M | van der Velde, Nathalie | van Heemst, Diana | van Oort, Floor VA | Vermeulen, Sita H | Verweij, Niek | Vonk, Judith M | Waite, Lindsay L | Waldenberger, Melanie | Wennauer, Roman | Wilkens, Lynne R | Willenborg, Christina | Wilsgaard, Tom | Wojczynski, Mary K | Wong, Andrew | Wright, Alan F | Zhang, Qunyuan | Arveiler, Dominique | Bakker, Stephan JL | Beilby, John | Bergman, Richard N | Bergmann, Sven | Biffar, Reiner | Blangero, John | Boomsma, Dorret I | Bornstein, Stefan R | Bovet, Pascal | Brambilla, Paolo | Brown, Morris J | Campbell, Harry | Caulfield, Mark J | Chakravarti, Aravinda | Collins, Rory | Collins, Francis S | Crawford, Dana C | Cupples, L Adrienne | Danesh, John | de Faire, Ulf | den Ruijter, Hester M | Erbel, Raimund | Erdmann, Jeanette | Eriksson, Johan G | Farrall, Martin | Ferrannini, Ele | Ferrières, Jean | Ford, Ian | Forouhi, Nita G | Forrester, Terrence | Gansevoort, Ron T | Gejman, Pablo V | Gieger, Christian | Golay, Alain | Gottesman, Omri | Gudnason, Vilmundur | Gyllensten, Ulf | Haas, David W | Hall, Alistair S | Harris, Tamara B | Hattersley, Andrew T | Heath, Andrew C | Hengstenberg, Christian | Hicks, Andrew A | Hindorff, Lucia A | Hingorani, Aroon D | Hofman, Albert | Hovingh, G Kees | Humphries, Steve E | Hunt, Steven C | Hypponen, Elina | Jacobs, Kevin B | Jarvelin, Marjo-Riitta | Jousilahti, Pekka | Jula, Antti M | Kaprio, Jaakko | Kastelein, John JP | Kayser, Manfred | Kee, Frank | Keinanen-Kiukaanniemi, Sirkka M | Kiemeney, Lambertus A | Kooner, Jaspal S | Kooperberg, Charles | Koskinen, Seppo | Kovacs, Peter | Kraja, Aldi T | Kumari, Meena | Kuusisto, Johanna | Lakka, Timo A | Langenberg, Claudia | Le Marchand, Loic | Lehtimäki, Terho | Lupoli, Sara | Madden, Pamela AF | Männistö, Satu | Manunta, Paolo | Marette, André | Matise, Tara C | McKnight, Barbara | Meitinger, Thomas | Moll, Frans L | Montgomery, Grant W | Morris, Andrew D | Morris, Andrew P | Murray, Jeffrey C | Nelis, Mari | Ohlsson, Claes | Oldehinkel, Albertine J | Ong, Ken K | Ouwehand, Willem H | Pasterkamp, Gerard | Peters, Annette | Pramstaller, Peter P | Price, Jackie F | Qi, Lu | Raitakari, Olli T | Rankinen, Tuomo | Rao, DC | Rice, Treva K | Ritchie, Marylyn | Rudan, Igor | Salomaa, Veikko | Samani, Nilesh J | Saramies, Jouko | Sarzynski, Mark A | Schwarz, Peter EH | Sebert, Sylvain | Sever, Peter | Shuldiner, Alan R | Sinisalo, Juha | Steinthorsdottir, Valgerdur | Stolk, Ronald P | Tardif, Jean-Claude | Tönjes, Anke | Tremblay, Angelo | Tremoli, Elena | Virtamo, Jarmo | Vohl, Marie-Claude | Amouyel, Philippe | Asselbergs, Folkert W | Assimes, Themistocles L | Bochud, Murielle | Boehm, Bernhard O | Boerwinkle, Eric | Bottinger, Erwin P | Bouchard, Claude | Cauchi, Stéphane | Chambers, John C | Chanock, Stephen J | Cooper, Richard S | de Bakker, Paul IW | Dedoussis, George | Ferrucci, Luigi | Franks, Paul W | Froguel, Philippe | Groop, Leif C | Haiman, Christopher A | Hamsten, Anders | Hayes, M Geoffrey | Hui, Jennie | Hunter, David J. | Hveem, Kristian | Jukema, J Wouter | Kaplan, Robert C | Kivimaki, Mika | Kuh, Diana | Laakso, Markku | Liu, Yongmei | Martin, Nicholas G | März, Winfried | Melbye, Mads | Moebus, Susanne | Munroe, Patricia B | Njølstad, Inger | Oostra, Ben A | Palmer, Colin NA | Pedersen, Nancy L | Perola, Markus | Pérusse, Louis | Peters, Ulrike | Powell, Joseph E | Power, Chris | Quertermous, Thomas | Rauramaa, Rainer | Reinmaa, Eva | Ridker, Paul M | Rivadeneira, Fernando | Rotter, Jerome I | Saaristo, Timo E | Saleheen, Danish | Schlessinger, David | Slagboom, P Eline | Snieder, Harold | Spector, Tim D | Strauch, Konstantin | Stumvoll, Michael | Tuomilehto, Jaakko | Uusitupa, Matti | van der Harst, Pim | Völzke, Henry | Walker, Mark | Wareham, Nicholas J | Watkins, Hugh | Wichmann, H-Erich | Wilson, James F | Zanen, Pieter | Deloukas, Panos | Heid, Iris M | Lindgren, Cecilia M | Mohlke, Karen L | Speliotes, Elizabeth K | Thorsteinsdottir, Unnur | Barroso, Inês | Fox, Caroline S | North, Kari E | Strachan, David P | Beckmann, Jacques S. | Berndt, Sonja I | Boehnke, Michael | Borecki, Ingrid B | McCarthy, Mark I | Metspalu, Andres | Stefansson, Kari | Uitterlinden, André G | van Duijn, Cornelia M | Franke, Lude | Willer, Cristen J | Price, Alkes L. | Lettre, Guillaume | Loos, Ruth JF | Weedon, Michael N | Ingelsson, Erik | O’Connell, Jeffrey R | Abecasis, Goncalo R | Chasman, Daniel I | Goddard, Michael E | Visscher, Peter M | Hirschhorn, Joel N | Frayling, Timothy M
Nature genetics  2014;46(11):1173-1186.
Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explain one-fifth of heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ~2,000, ~3,700 and ~9,500 SNPs explained ~21%, ~24% and ~29% of phenotypic variance. Furthermore, all common variants together captured the majority (60%) of heritability. The 697 variants clustered in 423 loci enriched for genes, pathways, and tissue-types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/beta-catenin, and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
doi:10.1038/ng.3097
PMCID: PMC4250049  PMID: 25282103
19.  Genetic studies of body mass index yield new insights for obesity biology 
Locke, Adam E. | Kahali, Bratati | Berndt, Sonja I. | Justice, Anne E. | Pers, Tune H. | Day, Felix R. | Powell, Corey | Vedantam, Sailaja | Buchkovich, Martin L. | Yang, Jian | Croteau-Chonka, Damien C. | Esko, Tonu | Fall, Tove | Ferreira, Teresa | Gustafsson, Stefan | Kutalik, Zoltán | Luan, Jian’an | Mägi, Reedik | Randall, Joshua C. | Winkler, Thomas W. | Wood, Andrew R. | Workalemahu, Tsegaselassie | Faul, Jessica D. | Smith, Jennifer A. | Zhao, Jing Hua | Zhao, Wei | Chen, Jin | Fehrmann, Rudolf | Hedman, Åsa K. | Karjalainen, Juha | Schmidt, Ellen M. | Absher, Devin | Amin, Najaf | Anderson, Denise | Beekman, Marian | Bolton, Jennifer L. | Bragg-Gresham, Jennifer L. | Buyske, Steven | Demirkan, Ayse | Deng, Guohong | Ehret, Georg B. | Feenstra, Bjarke | Feitosa, Mary F. | Fischer, Krista | Goel, Anuj | Gong, Jian | Jackson, Anne U. | Kanoni, Stavroula | Kleber, Marcus E. | Kristiansson, Kati | Lim, Unhee | Lotay, Vaneet | Mangino, Massimo | Leach, Irene Mateo | Medina-Gomez, Carolina | Medland, Sarah E. | Nalls, Michael A. | Palmer, Cameron D. | Pasko, Dorota | Pechlivanis, Sonali | Peters, Marjolein J. | Prokopenko, Inga | Shungin, Dmitry | Stančáková, Alena | Strawbridge, Rona J. | Sung, Yun Ju | Tanaka, Toshiko | Teumer, Alexander | Trompet, Stella | van der Laan, Sander W. | van Setten, Jessica | Van Vliet-Ostaptchouk, Jana V. | Wang, Zhaoming | Yengo, Loïc | Zhang, Weihua | Isaacs, Aaron | Albrecht, Eva | Ärnlöv, Johan | Arscott, Gillian M. | Attwood, Antony P. | Bandinelli, Stefania | Barrett, Amy | Bas, Isabelita N. | Bellis, Claire | Bennett, Amanda J. | Berne, Christian | Blagieva, Roza | Blüher, Matthias | Böhringer, Stefan | Bonnycastle, Lori L. | Böttcher, Yvonne | Boyd, Heather A. | Bruinenberg, Marcel | Caspersen, Ida H. | Chen, Yii-Der Ida | Clarke, Robert | Daw, E. Warwick | de Craen, Anton J. M. | Delgado, Graciela | Dimitriou, Maria | Doney, Alex S. 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E. | Mahajan, Anubha | McArdle, Wendy L. | McLachlan, Stela | Menni, Cristina | Merger, Sigrun | Mihailov, Evelin | Milani, Lili | Moayyeri, Alireza | Monda, Keri L. | Morken, Mario A. | Mulas, Antonella | Müller, Gabriele | Müller-Nurasyid, Martina | Musk, Arthur W. | Nagaraja, Ramaiah | Nöthen, Markus M. | Nolte, Ilja M. | Pilz, Stefan | Rayner, Nigel W. | Renstrom, Frida | Rettig, Rainer | Ried, Janina S. | Ripke, Stephan | Robertson, Neil R. | Rose, Lynda M. | Sanna, Serena | Scharnagl, Hubert | Scholtens, Salome | Schumacher, Fredrick R. | Scott, William R. | Seufferlein, Thomas | Shi, Jianxin | Smith, Albert Vernon | Smolonska, Joanna | Stanton, Alice V. | Steinthorsdottir, Valgerdur | Stirrups, Kathleen | Stringham, Heather M. | Sundström, Johan | Swertz, Morris A. | Swift, Amy J. | Syvänen, Ann-Christine | Tan, Sian-Tsung | Tayo, Bamidele O. | Thorand, Barbara | Thorleifsson, Gudmar | Tyrer, Jonathan P. | Uh, Hae-Won | Vandenput, Liesbeth | Verhulst, Frank C. | Vermeulen, Sita H. | Verweij, Niek | Vonk, Judith M. | Waite, Lindsay L. | Warren, Helen R. | Waterworth, Dawn | Weedon, Michael N. | Wilkens, Lynne R. | Willenborg, Christina | Wilsgaard, Tom | Wojczynski, Mary K. | Wong, Andrew | Wright, Alan F. | Zhang, Qunyuan | Brennan, Eoin P. | Choi, Murim | Dastani, Zari | Drong, Alexander W. | Eriksson, Per | Franco-Cereceda, Anders | Gådin, Jesper R. | Gharavi, Ali G. | Goddard, Michael E. | Handsaker, Robert E. | Huang, Jinyan | Karpe, Fredrik | Kathiresan, Sekar | Keildson, Sarah | Kiryluk, Krzysztof | Kubo, Michiaki | Lee, Jong-Young | Liang, Liming | Lifton, Richard P. | Ma, Baoshan | McCarroll, Steven A. | McKnight, Amy J. | Min, Josine L. | Moffatt, Miriam F. | Montgomery, Grant W. | Murabito, Joanne M. | Nicholson, George | Nyholt, Dale R. | Okada, Yukinori | Perry, John R. B. | Dorajoo, Rajkumar | Reinmaa, Eva | Salem, Rany M. | Sandholm, Niina | Scott, Robert A. | Stolk, Lisette | Takahashi, Atsushi | Tanaka, Toshihiro | van ’t Hooft, Ferdinand M. | Vinkhuyzen, Anna A. E. | Westra, Harm-Jan | Zheng, Wei | Zondervan, Krina T. | Heath, Andrew C. | Arveiler, Dominique | Bakker, Stephan J. L. | Beilby, John | Bergman, Richard N. | Blangero, John | Bovet, Pascal | Campbell, Harry | Caulfield, Mark J. | Cesana, Giancarlo | Chakravarti, Aravinda | Chasman, Daniel I. | Chines, Peter S. | Collins, Francis S. | Crawford, Dana C. | Cupples, L. Adrienne | Cusi, Daniele | Danesh, John | de Faire, Ulf | den Ruijter, Hester M. | Dominiczak, Anna F. | Erbel, Raimund | Erdmann, Jeanette | Eriksson, Johan G. | Farrall, Martin | Felix, Stephan B. | Ferrannini, Ele | Ferrières, Jean | Ford, Ian | Forouhi, Nita G. | Forrester, Terrence | Franco, Oscar H. | Gansevoort, Ron T. | Gejman, Pablo V. | Gieger, Christian | Gottesman, Omri | Gudnason, Vilmundur | Gyllensten, Ulf | Hall, Alistair S. | Harris, Tamara B. | Hattersley, Andrew T. | Hicks, Andrew A. | Hindorff, Lucia A. | Hingorani, Aroon D. | Hofman, Albert | Homuth, Georg | Hovingh, G. Kees | Humphries, Steve E. | Hunt, Steven C. | Hyppönen, Elina | Illig, Thomas | Jacobs, Kevin B. | Jarvelin, Marjo-Riitta | Jöckel, Karl-Heinz | Johansen, Berit | Jousilahti, Pekka | Jukema, J. Wouter | Jula, Antti M. | Kaprio, Jaakko | Kastelein, John J. P. | Keinanen-Kiukaanniemi, Sirkka M. | Kiemeney, Lambertus A. | Knekt, Paul | Kooner, Jaspal S. | Kooperberg, Charles | Kovacs, Peter | Kraja, Aldi T. | Kumari, Meena | Kuusisto, Johanna | Lakka, Timo A. | Langenberg, Claudia | Marchand, Loic Le | Lehtimäki, Terho | Lyssenko, Valeriya | Männistö, Satu | Marette, André | Matise, Tara C. | McKenzie, Colin A. | McKnight, Barbara | Moll, Frans L. | Morris, Andrew D. | Morris, Andrew P. | Murray, Jeffrey C. | Nelis, Mari | Ohlsson, Claes | Oldehinkel, Albertine J. | Ong, Ken K. | Madden, Pamela A. F. | Pasterkamp, Gerard | Peden, John F. | Peters, Annette | Postma, Dirkje S. | Pramstaller, Peter P. | Price, Jackie F. | Qi, Lu | Raitakari, Olli T. | Rankinen, Tuomo | Rao, D. C. | Rice, Treva K. | Ridker, Paul M. | Rioux, John D. | Ritchie, Marylyn D. | Rudan, Igor | Salomaa, Veikko | Samani, Nilesh J. | Saramies, Jouko | Sarzynski, Mark A. | Schunkert, Heribert | Schwarz, Peter E. H. | Sever, Peter | Shuldiner, Alan R. | Sinisalo, Juha | Stolk, Ronald P. | Strauch, Konstantin | Tönjes, Anke | Trégouët, David-Alexandre | Tremblay, Angelo | Tremoli, Elena | Virtamo, Jarmo | Vohl, Marie-Claude | Völker, Uwe | Waeber, Gérard | Willemsen, Gonneke | Witteman, Jacqueline C. | Zillikens, M. Carola | Adair, Linda S. | Amouyel, Philippe | Asselbergs, Folkert W. | Assimes, Themistocles L. | Bochud, Murielle | Boehm, Bernhard O. | Boerwinkle, Eric | Bornstein, Stefan R. | Bottinger, Erwin P. | Bouchard, Claude | Cauchi, Stéphane | Chambers, John C. | Chanock, Stephen J. | Cooper, Richard S. | de Bakker, Paul I. W. | Dedoussis, George | Ferrucci, Luigi | Franks, Paul W. | Froguel, Philippe | Groop, Leif C. | Haiman, Christopher A. | Hamsten, Anders | Hui, Jennie | Hunter, David J. | Hveem, Kristian | Kaplan, Robert C. | Kivimaki, Mika | Kuh, Diana | Laakso, Markku | Liu, Yongmei | Martin, Nicholas G. | März, Winfried | Melbye, Mads | Metspalu, Andres | Moebus, Susanne | Munroe, Patricia B. | Njølstad, Inger | Oostra, Ben A. | Palmer, Colin N. A. | Pedersen, Nancy L. | Perola, Markus | Pérusse, Louis | Peters, Ulrike | Power, Chris | Quertermous, Thomas | Rauramaa, Rainer | Rivadeneira, Fernando | Saaristo, Timo E. | Saleheen, Danish | Sattar, Naveed | Schadt, Eric E. | Schlessinger, David | Slagboom, P. Eline | Snieder, Harold | Spector, Tim D. | Thorsteinsdottir, Unnur | Stumvoll, Michael | Tuomilehto, Jaakko | Uitterlinden, André G. | Uusitupa, Matti | van der Harst, Pim | Walker, Mark | Wallaschofski, Henri | Wareham, Nicholas J. | Watkins, Hugh | Weir, David R. | Wichmann, H-Erich | Wilson, James F. | Zanen, Pieter | Borecki, Ingrid B. | Deloukas, Panos | Fox, Caroline S. | Heid, Iris M. | O’Connell, Jeffrey R. | Strachan, David P. | Stefansson, Kari | van Duijn, Cornelia M. | Abecasis, Gonçalo R. | Franke, Lude | Frayling, Timothy M. | McCarthy, Mark I. | Visscher, Peter M. | Scherag, André | Willer, Cristen J. | Boehnke, Michael | Mohlke, Karen L. | Lindgren, Cecilia M. | Beckmann, Jacques S. | Barroso, Inês | North, Kari E. | Ingelsson, Erik | Hirschhorn, Joel N. | Loos, Ruth J. F. | Speliotes, Elizabeth K.
Nature  2015;518(7538):197-206.
Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10−8), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ~2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
doi:10.1038/nature14177
PMCID: PMC4382211  PMID: 25673413
20.  Common Variation in Fatty Acid Metabolic Genes and Risk of Incident Sudden Cardiac Arrest 
Background
There is limited information on genetic factors associated with sudden cardiac arrest (SCA).
Objective
To assess the association of common variation in genes in fatty acid pathways with SCA risk.
Methods
We selected 85 candidate genes and 1155 single nucleotide polymorphisms (SNPs) tagging common variation in each gene. We investigated the SNP associations with SCA in a population-based case-control study. Cases (n=2160) were from a repository of SCA in the greater Seattle area. Controls (n=2615), frequency-matched on age and sex, were from the same area. We used linear logistic regression to examine SNP associations with SCA. We performed p-min permutation tests to account for multiple comparisons within each gene. The SNP associations with corrected p-value < 0.05 were then examined in a meta-analysis of these SNP associations in nine replication studies totaling 2129 SCA cases and 23833 non-cases.
Results
Eight SNPs in or near 8 genes were associated with SCA risk in the discovery study, one of which was nominally significant in the replication phase (rs7737692, minor allele frequency 36%, near the LPCAT1 gene). For each copy of the minor allele, rs7737692 was associated with 13% lower SCA risk (−21% to −5%) in the discovery phase and 9% lower risk (95% CI −16% to - 1%) in the replication phase.
Conclusions
While none of the associations reached significance with Bonferroni correction, a common genetic variant near LPCAT1, a gene involved in the remodeling of phospholipids, was nominally associated with incident SCA risk. Further study is needed to validate this observation.
doi:10.1016/j.hrthm.2014.01.008
PMCID: PMC3966996  PMID: 24418166
death; sudden; genetic epidemiology
21.  Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization 
Arking, Dan E. | Pulit, Sara L. | Crotti, Lia | van der Harst, Pim | Munroe, Patricia B. | Koopmann, Tamara T. | Sotoodehnia, Nona | Rossin, Elizabeth J. | Morley, Michael | Wang, Xinchen | Johnson, Andrew D. | Lundby, Alicia | Gudbjartsson, Daníel F. | Noseworthy, Peter A. | Eijgelsheim, Mark | Bradford, Yuki | Tarasov, Kirill V. | Dörr, Marcus | Müller-Nurasyid, Martina | Lahtinen, Annukka M. | Nolte, Ilja M. | Smith, Albert Vernon | Bis, Joshua C. | Isaacs, Aaron | Newhouse, Stephen J. | Evans, Daniel S. | Post, Wendy S. | Waggott, Daryl | Lyytikäinen, Leo-Pekka | Hicks, Andrew A. | Eisele, Lewin | Ellinghaus, David | Hayward, Caroline | Navarro, Pau | Ulivi, Sheila | Tanaka, Toshiko | Tester, David J. | Chatel, Stéphanie | Gustafsson, Stefan | Kumari, Meena | Morris, Richard W. | Naluai, Åsa T. | Padmanabhan, Sandosh | Kluttig, Alexander | Strohmer, Bernhard | Panayiotou, Andrie G. | Torres, Maria | Knoflach, Michael | Hubacek, Jaroslav A. | Slowikowski, Kamil | Raychaudhuri, Soumya | Kumar, Runjun D. | Harris, Tamara B. | Launer, Lenore J. | Shuldiner, Alan R. | Alonso, Alvaro | Bader, Joel S. | Ehret, Georg | Huang, Hailiang | Kao, W.H. Linda | Strait, James B. | Macfarlane, Peter W. | Brown, Morris | Caulfield, Mark J. | Samani, Nilesh J. | Kronenberg, Florian | Willeit, Johann | Smith, J. Gustav | Greiser, Karin H. | zu Schwabedissen, Henriette Meyer | Werdan, Karl | Carella, Massimo | Zelante, Leopoldo | Heckbert, Susan R. | Psaty, Bruce M. | Rotter, Jerome I. | Kolcic, Ivana | Polašek, Ozren | Wright, Alan F. | Griffin, Maura | Daly, Mark J. | Arnar, David O. | Hólm, Hilma | Thorsteinsdottir, Unnur | Denny, Joshua C. | Roden, Dan M. | Zuvich, Rebecca L. | Emilsson, Valur | Plump, Andrew S. | Larson, Martin G. | O'Donnell, Christopher J. | Yin, Xiaoyan | Bobbo, Marco | D'Adamo, Adamo P. | Iorio, Annamaria | Sinagra, Gianfranco | Carracedo, Angel | Cummings, Steven R. | Nalls, Michael A. | Jula, Antti | Kontula, Kimmo K. | Marjamaa, Annukka | Oikarinen, Lasse | Perola, Markus | Porthan, Kimmo | Erbel, Raimund | Hoffmann, Per | Jöckel, Karl-Heinz | Kälsch, Hagen | Nöthen, Markus M. | consortium, HRGEN | den Hoed, Marcel | Loos, Ruth J.F. | Thelle, Dag S. | Gieger, Christian | Meitinger, Thomas | Perz, Siegfried | Peters, Annette | Prucha, Hanna | Sinner, Moritz F. | Waldenberger, Melanie | de Boer, Rudolf A. | Franke, Lude | van der Vleuten, Pieter A. | Beckmann, Britt Maria | Martens, Eimo | Bardai, Abdennasser | Hofman, Nynke | Wilde, Arthur A.M. | Behr, Elijah R. | Dalageorgou, Chrysoula | Giudicessi, John R. | Medeiros-Domingo, Argelia | Barc, Julien | Kyndt, Florence | Probst, Vincent | Ghidoni, Alice | Insolia, Roberto | Hamilton, Robert M. | Scherer, Stephen W. | Brandimarto, Jeffrey | Margulies, Kenneth | Moravec, Christine E. | Fabiola Del, Greco M. | Fuchsberger, Christian | O'Connell, Jeffrey R. | Lee, Wai K. | Watt, Graham C.M. | Campbell, Harry | Wild, Sarah H. | El Mokhtari, Nour E. | Frey, Norbert | Asselbergs, Folkert W. | Leach, Irene Mateo | Navis, Gerjan | van den Berg, Maarten P. | van Veldhuisen, Dirk J. | Kellis, Manolis | Krijthe, Bouwe P. | Franco, Oscar H. | Hofman, Albert | Kors, Jan A. | Uitterlinden, André G. | Witteman, Jacqueline C.M. | Kedenko, Lyudmyla | Lamina, Claudia | Oostra, Ben A. | Abecasis, Gonçalo R. | Lakatta, Edward G. | Mulas, Antonella | Orrú, Marco | Schlessinger, David | Uda, Manuela | Markus, Marcello R.P. | Völker, Uwe | Snieder, Harold | Spector, Timothy D. | Ärnlöv, Johan | Lind, Lars | Sundström, Johan | Syvänen, Ann-Christine | Kivimaki, Mika | Kähönen, Mika | Mononen, Nina | Raitakari, Olli T. | Viikari, Jorma S. | Adamkova, Vera | Kiechl, Stefan | Brion, Maria | Nicolaides, Andrew N. | Paulweber, Bernhard | Haerting, Johannes | Dominiczak, Anna F. | Nyberg, Fredrik | Whincup, Peter H. | Hingorani, Aroon | Schott, Jean-Jacques | Bezzina, Connie R. | Ingelsson, Erik | Ferrucci, Luigi | Gasparini, Paolo | Wilson, James F. | Rudan, Igor | Franke, Andre | Mühleisen, Thomas W. | Pramstaller, Peter P. | Lehtimäki, Terho J. | Paterson, Andrew D. | Parsa, Afshin | Liu, Yongmei | van Duijn, Cornelia | Siscovick, David S. | Gudnason, Vilmundur | Jamshidi, Yalda | Salomaa, Veikko | Felix, Stephan B. | Sanna, Serena | Ritchie, Marylyn D. | Stricker, Bruno H. | Stefansson, Kari | Boyer, Laurie A. | Cappola, Thomas P. | Olsen, Jesper V. | Lage, Kasper | Schwartz, Peter J. | Kääb, Stefan | Chakravarti, Aravinda | Ackerman, Michael J. | Pfeufer, Arne | de Bakker, Paul I.W. | Newton-Cheh, Christopher
Nature genetics  2014;46(8):826-836.
The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal Mendelian Long QT Syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals we identified 35 common variant QT interval loci, that collectively explain ∼8-10% of QT variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 novel QT loci in 298 unrelated LQTS probands identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode for proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies novel candidate genes for ventricular arrhythmias, LQTS,and SCD.
doi:10.1038/ng.3014
PMCID: PMC4124521  PMID: 24952745
genome-wide association study; QT interval; Long QT Syndrome; sudden cardiac death; myocardial repolarization; arrhythmias
22.  HPASubC: A suite of tools for user subclassification of human protein atlas tissue images 
Background:
The human protein atlas (HPA) is a powerful proteomic tool for visualizing the distribution of protein expression across most human tissues and many common malignancies. The HPA includes immunohistochemically-stained images from tissue microarrays (TMAs) that cover 48 tissue types and 20 common malignancies. The TMA data are used to provide expression information at the tissue, cellular, and occasionally, subcellular level. The HPA also provides subcellular data from confocal immunofluorescence data on three cell lines. Despite the availability of localization data, many unique patterns of cellular and subcellular expression are not documented.
Materials and Methods:
To get at this more granular data, we have developed a suite of Python scripts, HPASubC, to aid in subcellular, and cell-type specific classification of HPA images. This method allows the user to download and optimize specific HPA TMA images for review. Then, using a playstation-style video game controller, a trained observer can rapidly step through 10's of 1000's of images to identify patterns of interest.
Results:
We have successfully used this method to identify 703 endothelial cell (EC) and/or smooth muscle cell (SMCs) specific proteins discovered within 49,200 heart TMA images. This list will assist us in subdividing cardiac gene or protein array data into expression by one of the predominant cell types of the myocardium: Myocytes, SMCs or ECs.
Conclusions:
The opportunity to further characterize unique staining patterns across a range of human tissues and malignancies will accelerate our understanding of disease processes and point to novel markers for tissue evaluation in surgical pathology.
doi:10.4103/2153-3539.159213
PMCID: PMC4485190  PMID: 26167380
Biomarker; heart; human protein atlas; subcellular localization; tissue microarray
23.  DISTILLING PATHOPHYSIOLOGY FROM COMPLEX DISEASE GENETICS 
Cell  2013;155(1):21-26.
Technologies for genome-wide sequence interrogation have dramatically improved our ability to identify loci associated with complex human disease. However, a chasm remains between correlations and causality that stems, in part, from a limiting theoretical framework derived from Mendelian genetics, and an incomplete understanding of disease physiology. Here we propose a set of criteria, akin to Koch’s postulates for infectious disease, for assigning causality between genetic variants and human disease phenotypes.
doi:10.1016/j.cell.2013.09.001
PMCID: PMC4244836  PMID: 24074858
24.  Sequence Analysis of Six Blood Pressure Candidate Regions in 4,178 Individuals: The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study 
PLoS ONE  2014;9(10):e109155.
Background
Genome-wide association studies (GWAS) identified multiple loci for blood pressure (BP) and hypertension. Six genes – ATP2B1, CACNB2, CYP17A1, JAG1, PLEKHA7, and SH2B3 – were evaluated for sequence variation with large effects on systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), and mean arterial pressure (MAP).
Methods and Results
Targeted genomic sequence was determined in 4,178 European ancestry participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Common variants (≥50 minor allele copies) were evaluated individually and rare variants (minor allele frequency, MAF≤1%) were aggregated by locus. 464 common variants were identified across the 6 genes. An upstream CYP17A1 variant, rs11191416 (MAF = 0.09), was the most significant association for SBP (P = 0.0005); however the association was attenuated (P = 0.0469) after conditioning on the GWAS index single nucleotide polymorphism (SNP). A PLEKHA7 intronic variant was the strongest DBP association (rs12806040, MAF = 0.007, P = 0.0006) and was not in LD (r2 = 0.01) with the GWAS SNP. A CACNB2 intronic SNP, rs1571787, was the most significant association with PP (MAF = 0.27, P = 0.0003), but was not independent from the GWAS SNP (r2 = 0.34). Three variants (rs6163 and rs743572 in the CYP17A1 region and rs112467382 in PLEKHA7) were associated with BP traits (P<0.001). Rare variation, aggregately assessed in the 6 regions, was not significantly associated with BP measures.
Conclusion
Six targeted gene regions, previously identified by GWAS, did not harbor novel variation with large effects on BP in this sample.
doi:10.1371/journal.pone.0109155
PMCID: PMC4183565  PMID: 25275628
25.  Loci influencing blood pressure identified using a cardiovascular gene-centric array 
Ganesh, Santhi K. | Tragante, Vinicius | Guo, Wei | Guo, Yiran | Lanktree, Matthew B. | Smith, Erin N. | Johnson, Toby | Castillo, Berta Almoguera | Barnard, John | Baumert, Jens | Chang, Yen-Pei Christy | Elbers, Clara C. | Farrall, Martin | Fischer, Mary E. | Franceschini, Nora | Gaunt, Tom R. | Gho, Johannes M.I.H. | Gieger, Christian | Gong, Yan | Isaacs, Aaron | Kleber, Marcus E. | Leach, Irene Mateo | McDonough, Caitrin W. | Meijs, Matthijs F.L. | Mellander, Olle | Molony, Cliona M. | Nolte, Ilja M. | Padmanabhan, Sandosh | Price, Tom S. | Rajagopalan, Ramakrishnan | Shaffer, Jonathan | Shah, Sonia | Shen, Haiqing | Soranzo, Nicole | van der Most, Peter J. | Van Iperen, Erik P.A. | Van Setten, Jessica | Vonk, Judith M. | Zhang, Li | Beitelshees, Amber L. | Berenson, Gerald S. | Bhatt, Deepak L. | Boer, Jolanda M.A. | Boerwinkle, Eric | Burkley, Ben | Burt, Amber | Chakravarti, Aravinda | Chen, Wei | Cooper-DeHoff, Rhonda M. | Curtis, Sean P. | Dreisbach, Albert | Duggan, David | Ehret, Georg B. | Fabsitz, Richard R. | Fornage, Myriam | Fox, Ervin | Furlong, Clement E. | Gansevoort, Ron T. | Hofker, Marten H. | Hovingh, G. Kees | Kirkland, Susan A. | Kottke-Marchant, Kandice | Kutlar, Abdullah | LaCroix, Andrea Z. | Langaee, Taimour Y. | Li, Yun R. | Lin, Honghuang | Liu, Kiang | Maiwald, Steffi | Malik, Rainer | Murugesan, Gurunathan | Newton-Cheh, Christopher | O'Connell, Jeffery R. | Onland-Moret, N. Charlotte | Ouwehand, Willem H. | Palmas, Walter | Penninx, Brenda W. | Pepine, Carl J. | Pettinger, Mary | Polak, Joseph F. | Ramachandran, Vasan S. | Ranchalis, Jane | Redline, Susan | Ridker, Paul M. | Rose, Lynda M. | Scharnag, Hubert | Schork, Nicholas J. | Shimbo, Daichi | Shuldiner, Alan R. | Srinivasan, Sathanur R. | Stolk, Ronald P. | Taylor, Herman A. | Thorand, Barbara | Trip, Mieke D. | van Duijn, Cornelia M. | Verschuren, W. Monique | Wijmenga, Cisca | Winkelmann, Bernhard R. | Wyatt, Sharon | Young, J. Hunter | Boehm, Bernhard O. | Caulfield, Mark J. | Chasman, Daniel I. | Davidson, Karina W. | Doevendans, Pieter A. | FitzGerald, Garret A. | Gums, John G. | Hakonarson, Hakon | Hillege, Hans L. | Illig, Thomas | Jarvik, Gail P. | Johnson, Julie A. | Kastelein, John J.P. | Koenig, Wolfgang | März, Winfried | Mitchell, Braxton D. | Murray, Sarah S. | Oldehinkel, Albertine J. | Rader, Daniel J. | Reilly, Muredach P. | Reiner, Alex P. | Schadt, Eric E. | Silverstein, Roy L. | Snieder, Harold | Stanton, Alice V. | Uitterlinden, André G. | van der Harst, Pim | van der Schouw, Yvonne T. | Samani, Nilesh J. | Johnson, Andrew D. | Munroe, Patricia B. | de Bakker, Paul I.W. | Zhu, Xiaofeng | Levy, Daniel | Keating, Brendan J. | Asselbergs, Folkert W.
Human Molecular Genetics  2013;22(16):3394-3395.
doi:10.1093/hmg/ddt177
PMCID: PMC3888295

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