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1.  Susceptibility Loci for Clinical CAD and Subclinical Coronary Atherosclerosis Throughout the Life-Course 
Background
Recent genome wide association studies (GWAS) have identified 49 single nucleotide polymorphisms (SNPs) associated with clinical CAD. The mechanism by which these loci influence risk remains largely unclear.
Methods and Results
We examined the association between a genetic risk score (GRS) composed of high-risk alleles at the 49 SNPs and the degree of subclinical coronary atherosclerosis in 7,798 participants from six studies stratified into four age groups at the time of assessment (15-34, 35-54, 55-74, >75 years). Atherosclerosis was quantified by staining and direct visual inspection of the right coronary artery in the youngest group, and by scanning for coronary artery calcification in the remaining groups. We defined cases as subjects within the top quartile of degree of atherosclerosis in three groups and as subjects with a CAC>0 in the fourth (35-54 years) where less than one quarter had any CAC. In our meta-analysis of all strata, we found one SD increase in the GRS increased the risk of advanced subclinical coronary atherosclerosis by 36% (p=8.3×10-25). This increase in risk was significant in all four age groups including the youngest group where atherosclerosis consisted primarily of raised lesions without macroscopic evidence of plaque rupture or thrombosis. Results were similar when we restricted the GRS to 32 SNPs not associated with traditional risk factors (TRFs) and/or when we adjusted for TRFs.
Conclusions
A GRS for clinical CAD is associated with advanced subclinical coronary atherosclerosis throughout the life-course. This association is apparent even at the earliest, uncomplicated stages of atherosclerosis.
doi:10.1161/CIRCGENETICS.114.001071
PMCID: PMC4824193  PMID: 26417035
genetic epidemiology; genetics, human; coronary artery calcification; coronary atherosclerosis; coronary artery disease
2.  Nat1 deficiency is associated with mitochondrial dysfunction and exercise intolerance in mice 
Cell reports  2016;17(2):527-540.
Summary
We recently identified human N-acetyltransferase 2 (NAT2) as an insulin resistance (IR) gene. Here we examine the cellular mechanism linking NAT2 to IR and find that Nat1 (mouse ortholog of NAT2) is co-regulated with key regulators of mitochondria. RNA-interference mediated silencing of Nat1 led to mitochondrial dysfunction characterized by increased intracellular reactive oxygen species and mitochondrial fragmentation as well as decreased mitochondrial membrane potential, biogenesis, mass, cellular respiration and ATP generation. These effects were consistent in 3T3-L1 adipocytes, C2C12 myoblasts and in tissues from Nat1 deficient mice including white adipose tissue, heart and skeletal muscle. Nat1 deficient mice had changes in plasma metabolites and lipids consistent with a decreased ability to utilize fats for energy and a decrease in basal metabolic rate and exercise capacity without altered thermogenesis. Collectively, our results suggest that Nat1 deficiency results in mitochondrial dysfunction, which may constitute a mechanistic link between this gene and IR.
Graphical Abstract
doi:10.1016/j.celrep.2016.09.005
PMCID: PMC5097870  PMID: 27705799
NAT2; Nat1; Insulin resistance; Mitochondrial dysfunction; Adipose tissue
4.  Integrative functional genomics identifies regulatory mechanisms at coronary artery disease loci 
Nature Communications  2016;7:12092.
Coronary artery disease (CAD) is the leading cause of mortality and morbidity, driven by both genetic and environmental risk factors. Meta-analyses of genome-wide association studies have identified >150 loci associated with CAD and myocardial infarction susceptibility in humans. A majority of these variants reside in non-coding regions and are co-inherited with hundreds of candidate regulatory variants, presenting a challenge to elucidate their functions. Herein, we use integrative genomic, epigenomic and transcriptomic profiling of perturbed human coronary artery smooth muscle cells and tissues to begin to identify causal regulatory variation and mechanisms responsible for CAD associations. Using these genome-wide maps, we prioritize 64 candidate variants and perform allele-specific binding and expression analyses at seven top candidate loci: 9p21.3, SMAD3, PDGFD, IL6R, BMP1, CCDC97/TGFB1 and LMOD1. We validate our findings in expression quantitative trait loci cohorts, which together reveal new links between CAD associations and regulatory function in the appropriate disease context.
Coronary heart disease is the leading cause of death worldwide with multiple environmental and genetic risk factors. Here the authors integrate genomic, epigenomic and transcriptomic mapping to elucidate causal variation and mechanisms of known genetic associations.
doi:10.1038/ncomms12092
PMCID: PMC4941121  PMID: 27386823
5.  Systems Genetics Analysis of GWAS reveals Novel Associations between Key Biological Processes and Coronary Artery Disease 
Objective
Genome-wide association (GWA) studies have identified multiple genetic variants affecting the risk of coronary artery disease (CAD). However, individually these explain only a small fraction of the heritability of CAD and for most, the causal biological mechanisms remain unclear. We sought to obtain further insights into potential causal processes of CAD by integrating large-scale GWA data with expertly curated databases of core human pathways and functional networks.
Approaches and Results
Employing pathways (gene sets) from Reactome, we carried out a two-stage gene set enrichment analysis strategy. From a meta-analyzed discovery cohort of 7 CADGWAS data sets (9,889 cases/11,089 controls), nominally significant gene-sets were tested for replication in a meta-analysis of 9 additional studies (15,502 cases/55,730 controls) from the CARDIoGRAM Consortium. A total of 32 of 639 Reactome pathways tested showed convincing association with CAD (replication p<0.05). These pathways resided in 9 of 21 core biological processes represented in Reactome, and included pathways relevant to extracellular matrix integrity, innate immunity, axon guidance, and signaling by PDRF, NOTCH, and the TGF-β/SMAD receptor complex. Many of these pathways had strengths of association comparable to those observed in lipid transport pathways. Network analysis of unique genes within the replicated pathways further revealed several interconnected functional and topologically interacting modules representing novel associations (e.g. semaphorin regulated axonal guidance pathway) besides confirming known processes (lipid metabolism). The connectivity in the observed networks was statistically significant compared to random networks (p<0.001). Network centrality analysis (‘degree’ and ‘betweenness’) further identified genes (e.g. NCAM1, FYN, FURIN etc.) likely to play critical roles in the maintenance and functioning of several of the replicated pathways.
Conclusions
These findings provide novel insights into how genetic variation, interpreted in the context of biological processes and functional interactions among genes, may help define the genetic architecture of CAD.
doi:10.1161/ATVBAHA.115.305513
PMCID: PMC4841833  PMID: 25977570
GWAS; coronary artery disease; pathway analysis; network analysis
6.  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
7.  Prepregnancy Diabetes and Offspring Risk of Congenital Heart Disease 
Circulation  2016;133(23):2243-2253.
Background—
Maternal diabetes mellitus is associated with an increased risk of offspring congenital heart defects (CHD); however, the causal mechanism is poorly understood. We further investigated this association in a Danish nationwide cohort.
Methods and Results—
In a national cohort study, we identified 2 025 727 persons born from 1978 to 2011; among them were 7296 (0.36%) persons exposed to maternal pregestational diabetes mellitus. Pregestational diabetes mellitus was identified by using the National Patient Register and individual-level information on all prescriptions filled in Danish pharmacies. Persons with CHD (n=16 325) were assigned to embryologically related cardiac phenotypes. The CHD prevalence in the offspring of mothers with pregestational diabetes mellitus was 318 per 10 000 live births (n=232) in comparison with a baseline risk of 80 per 10 000; the adjusted relative risk for CHD was 4.00 (95% confidence interval, 3.51–4.53). The association was not modified by year of birth, maternal age at diabetes onset, or diabetes duration, and CHD risks associated with type 1 (insulin-dependent) and type 2 (insulin-independent) diabetes mellitus did not differ significantly. Persons born to women with previous acute diabetes complications had a higher CHD risk than those exposed to maternal diabetes mellitus without complications (relative risk, 7.62; 95% confidence interval, 5.23–10.6, and relative risk, 3.49; 95% confidence interval, 2.91–4.13, respectively; P=0.0004). All specific CHD phenotypes were associated with maternal pregestational diabetes mellitus (relative risk range, 2.74–13.8).
Conclusions—
The profoundly increased CHD risk conferred by maternal pregestational diabetes mellitus neither changed over time nor differed by diabetes subtype. The association with acute pregestational diabetes complications was particularly strong, suggesting a role for glucose in the causal pathway.
doi:10.1161/CIRCULATIONAHA.115.017465
PMCID: PMC4890838  PMID: 27166384
congenital abnormalities; diabetes mellitus; heart defects, congenital; insulin; pregnancy
8.  An “Almost Exhaustive” Search-Based Sequential Permutation Method for Detecting Epistasis in Disease Association Studies 
Genetic epidemiology  2010;34(5):434-443.
Due to the complex nature of common diseases, their etiology is likely to involve “uncommon but strong” (UBS) interactive effects—i.e. allelic combinations that are each present in only a small fraction of the patients but associated with high disease risk. However, the identification of such effects using standard methods for testing association can be difficult. In this work, we introduce a method for testing interactions that is particularly powerful in detecting UBS effects. The method consists of two modules—one is a pattern counting algorithm designed for efficiently evaluating the risk significance of each marker combination, and the other is a sequential permutation scheme for multiple testing correction. We demonstrate the work of our method using a candidate gene data set for cardiovascular and coronary diseases with an injected UBS three-locus interaction. In addition, we investigate the power and false rejection properties of our method using data sets simulated from a joint dominance three-locus model that gives rise to UBS interactive effects. The results show that our method can be much more powerful than standard approaches such as trend test and multifactor dimensionality reduction for detecting UBS interactions.
doi:10.1002/gepi.20496
PMCID: PMC4830696  PMID: 20583286
genetic interaction; nonparametric test; case-control study; frequent-pattern mining
9.  A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease 
Nikpay, Majid | Goel, Anuj | Won, Hong-Hee | Hall, Leanne M | Willenborg, Christina | Kanoni, Stavroula | Saleheen, Danish | Kyriakou, Theodosios | Nelson, Christopher P | Hopewell, Jemma C | Webb, Thomas R | Zeng, Lingyao | Dehghan, Abbas | Alver, Maris | Armasu, Sebastian M | Auro, Kirsi | Bjonnes, Andrew | Chasman, Daniel I | Chen, Shufeng | Ford, Ian | Franceschini, Nora | Gieger, Christian | Grace, Christopher | Gustafsson, Stefan | Huang, Jie | Hwang, Shih-Jen | Kim, Yun Kyoung | Kleber, Marcus E | Lau, King Wai | Lu, Xiangfeng | Lu, Yingchang | Lyytikäinen, Leo-Pekka | Mihailov, Evelin | Morrison, Alanna C | Pervjakova, Natalia | Qu, Liming | Rose, Lynda M | Salfati, Elias | Saxena, Richa | Scholz, Markus | Smith, Albert V | Tikkanen, Emmi | Uitterlinden, Andre | Yang, Xueli | Zhang, Weihua | Zhao, Wei | de Andrade, Mariza | de Vries, Paul S | van Zuydam, Natalie R | Anand, Sonia S | Bertram, Lars | Beutner, Frank | Dedoussis, George | Frossard, Philippe | Gauguier, Dominique | Goodall, Alison H | Gottesman, Omri | Haber, Marc | Han, Bok-Ghee | Huang, Jianfeng | Jalilzadeh, Shapour | Kessler, Thorsten | König, Inke R | Lannfelt, Lars | Lieb, Wolfgang | Lind, Lars | Lindgren, Cecilia M | Lokki, Marja-Liisa | Magnusson, Patrik K | Mallick, Nadeem H | Mehra, Narinder | Meitinger, Thomas | Memon, Fazal-ur-Rehman | Morris, Andrew P | Nieminen, Markku S | Pedersen, Nancy L | Peters, Annette | Rallidis, Loukianos S | Rasheed, Asif | Samuel, Maria | Shah, Svati H | Sinisalo, Juha | Stirrups, Kathleen E | Trompet, Stella | Wang, Laiyuan | Zaman, Khan S | Ardissino, Diego | Boerwinkle, Eric | Borecki, Ingrid B | Bottinger, Erwin P | Buring, Julie E | Chambers, John C | Collins, Rory | Cupples, L Adrienne | Danesh, John | Demuth, Ilja | Elosua, Roberto | Epstein, Stephen E | Esko, Tõnu | Feitosa, Mary F | Franco, Oscar H | Franzosi, Maria Grazia | Granger, Christopher B | Gu, Dongfeng | Gudnason, Vilmundur | Hall, Alistair S | Hamsten, Anders | Harris, Tamara B | Hazen, Stanley L | Hengstenberg, Christian | Hofman, Albert | Ingelsson, Erik | Iribarren, Carlos | Jukema, J Wouter | Karhunen, Pekka J | Kim, Bong-Jo | Kooner, Jaspal S | Kullo, Iftikhar J | Lehtimäki, Terho | Loos, Ruth J F | Melander, Olle | Metspalu, Andres | März, Winfried | Palmer, Colin N | Perola, Markus | Quertermous, Thomas | Rader, Daniel J | Ridker, Paul M | Ripatti, Samuli | Roberts, Robert | Salomaa, Veikko | Sanghera, Dharambir K | Schwartz, Stephen M | Seedorf, Udo | Stewart, Alexandre F | Stott, David J | Thiery, Joachim | Zalloua, Pierre A | O’Donnell, Christopher J | Reilly, Muredach P | Assimes, Themistocles L | Thompson, John R | Erdmann, Jeanette | Clarke, Robert | Watkins, Hugh | Kathiresan, Sekar | McPherson, Ruth | Deloukas, Panos | Schunkert, Heribert | Samani, Nilesh J | Farrall, Martin
Nature genetics  2015;47(10):1121-1130.
Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association studies (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of 185 thousand CAD cases and controls, interrogating 6.7 million common (MAF>0.05) as well as 2.7 million low frequency (0.005
doi:10.1038/ng.3396
PMCID: PMC4589895  PMID: 26343387
PLoS ONE  2016;11(3):e0138014.
By means of a combination of genome-wide and follow-up studies, recent large-scale association studies of populations of European descent have now identified over 46 loci associated with coronary artery disease (CAD). As part of the TAICHI Consortium, we have collected and genotyped 8556 subjects from Taiwan, comprising 5423 controls and 3133 cases with coronary artery disease, for 9087 CAD SNPs using the CardioMetaboChip. We applied penalized logistic regression to ascertain the top SNPs that contribute together to CAD susceptibility in Taiwan. We observed that the 9p21 locus contributes to CAD at the level of genome-wide significance (rs1537372, with the presence of C, the major allele, the effect estimate is -0.216, standard error 0.033, p value 5.8x10-10). In contrast to a previous report, we propose that the 9p21 locus is a single genetic contribution to CAD in Taiwan because: 1) the penalized logistic regression and the follow-up conditional analysis suggested that rs1537372 accounts for all of the CAD association in 9p21, and 2) the high linkage disequilibrium observed for all associated SNPs in 9p21. We also observed evidence for the following loci at a false discovery rate >5%: SH2B3, ADAMTS7, PHACTR1, GGCX, HTRA1, COL4A1, and LARP6-LRRC49. We also took advantage of the fact that penalized methods are an efficient approach to search for gene-by-gene interactions, and observed that two-way interactions between the PHACTR1 and ADAMTS7 loci and between the SH2B3 and COL4A1 loci contribute to CAD risk. Both the similarities and differences between the significance of these loci when compared with significance of loci in studies of populations of European descent underscore the fact that further genetic association of studies in additional populations will provide clues to identify the genetic architecture of CAD across all populations worldwide.
doi:10.1371/journal.pone.0138014
PMCID: PMC4794124  PMID: 26982883
Scientific Reports  2015;5:14380.
Proprotein convertase subtilisin/kexin type 2 (PCSK2) is a prohormone processing enzyme involved in insulin and glucagon biosynthesis. We previously found the genetic polymorphism of PCSK2 on chromosome 20 was responsible for the linkage peak of several glucose homeostasis parameters. The aim of this study is to investigate the association between genetic variants of PCSK2 and glucose homeostasis parameters and incident diabetes. Total 1142 Chinese participants were recruited from the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) family study, and 759 participants were followed up for 5 years. Ten SNPs of the PCSK2 gene were genotyped. Variants of rs6044695 and rs2284912 were associated with fasting plasma glucose, and variants of rs2269023 were associated with fasting plasma glucose and 1-hour plasma glucose during OGTT. Haplotypes of rs4814605/rs1078199 were associated with fasting plasma insulin levels and HOMA-IR. Haplotypes of rs890609/rs2269023 were also associated with fasting plasma glucose, fasting insulin and HOMA-IR. In the longitudinal study, we found individuals carrying TA/AA genotypes of rs6044695 or TC/CC genotypes of rs2284912 had lower incidence of diabetes during the 5-year follow-up. Our results indicated that PCSK2 gene polymorphisms are associated with pleiotropic effects on various traits of glucose homeostasis and incident diabetes.
doi:10.1038/srep14380
PMCID: PMC4660384  PMID: 26607656
PLoS Genetics  2015;11(10):e1005496.
Abstract
High throughput sequencing has facilitated a precipitous drop in the cost of genomic sequencing, prompting predictions of a revolution in medicine via genetic personalization of diagnostic and therapeutic strategies. There are significant barriers to realizing this goal that are related to the difficult task of interpreting personal genetic variation. A comprehensive, widely accessible application for interpretation of whole genome sequence data is needed. Here, we present a series of methods for identification of genetic variants and genotypes with clinical associations, phasing genetic data and using Mendelian inheritance for quality control, and providing predictive genetic information about risk for rare disease phenotypes and response to pharmacological therapy in single individuals and father-mother-child trios. We demonstrate application of these methods for disease and drug response prognostication in whole genome sequence data from twelve unrelated adults, and for disease gene discovery in one father-mother-child trio with apparently simplex congenital ventricular arrhythmia. In doing so we identify clinically actionable inherited disease risk and drug response genotypes in pre-symptomatic individuals. We also nominate a new candidate gene in congenital arrhythmia, ATP2B4, and provide experimental evidence of a regulatory role for variants discovered using this framework.
Author Summary
Technological advances have dramatically reduced the cost of sequencing the human genome. Tools for analyzing such data across families including annotation of clinically important variants and aggregation of variants for personalizing drug prescriptions have been developed but few are publically available. Here we describe such tools then demonstrate their application in several distinct data sets. In particular, we use the tools to define the genetic basis of a new congenital arrhythmia syndrome.
doi:10.1371/journal.pgen.1005496
PMCID: PMC4598191  PMID: 26448358
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 | Leach, Irene Mateo | 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  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
PLoS ONE  2015;10(8):e0135681.
Objectives
Growth arrest-specific 6 (Gas6), a vitamin K-dependent protein, has been implicated in systemic inflammation, obesity, and insulin resistance (IR). Data from recent studies suggest that polymorphisms in the Gas6 gene are associated with cardiovascular disorders and type 2 diabetes (T2D). However, the association of Gas6 gene variants with obesity, IR, and T2D development has not been explored.
Materials and Methods
Four common single nucleotide polymorphisms (SNPs) in the Gas6 gene were genotyped in 984 participants from the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) family cohort. An insulin suppression test was performed to determine IR based on steady-state plasma glucose (SSPG). Associations between IR indices and obesity, and SNP genotypes, based on previously-reported data for this cohort (Phase I), were analyzed. In the present follow-up study (Phase II), the effects of gene variants of Gas6 on the progression to T2D were explored in individuals who were free of T2D in Phase I. The mean follow-up period for Phase II was 5.7 years.
Results
The mean age of the study population in Phase I was 49.5 years and 16.7% of individuals developed T2D during follow-up. After adjusting for covariates, three SNPs (rs8191973, rs8197974, and rs7323932) were found to be associated with SSPG levels (p = 0.007, p = 0.03, and p = 0.011, respectively). This association remained significant after multiple testing and showed a significant interaction with physical activity for SNP rs8191973. However, no other significant correlations were observed between Gas6 polymorphisms and other indices of IR or obesity. A specific haplotype, AACG (from rs8191974, rs7323932, rs7331124, and rs8191973), was positively associated with SSPG levels (p = 0.0098). None of the polymorphisms were associated with an increased risk of T2D development.
Conclusions
Our results suggest that Gas6 gene variants are associated with IR, although their effects on subsequent progression to T2D were minimal in this prospective Asian cohort.
doi:10.1371/journal.pone.0135681
PMCID: PMC4540485  PMID: 26284522
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
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
PLoS Genetics  2015;11(5):e1005155.
Recent genome wide association studies have identified a number of genes that contribute to the risk for coronary heart disease. One such gene, TCF21, encodes a basic-helix-loop-helix transcription factor believed to serve a critical role in the development of epicardial progenitor cells that give rise to coronary artery smooth muscle cells (SMC) and cardiac fibroblasts. Using reporter gene and immunolocalization studies with mouse and human tissues we have found that vascular TCF21 expression in the adult is restricted primarily to adventitial cells associated with coronary arteries and also medial SMC in the proximal aorta of mouse. Genome wide RNA-Seq studies in human coronary artery SMC (HCASMC) with siRNA knockdown found a number of putative TCF21 downstream pathways identified by enrichment of terms related to CAD, including “vascular disease,” “disorder of artery,” and “occlusion of artery,” as well as disease-related cellular functions including “cellular movement” and “cellular growth and proliferation.” In vitro studies in HCASMC demonstrated that TCF21 expression promotes proliferation and migration and inhibits SMC lineage marker expression. Detailed in situ expression studies with reporter gene and lineage tracing revealed that vascular wall cells expressing Tcf21 before disease initiation migrate into vascular lesions of ApoE-/- and Ldlr-/- mice. While Tcf21 lineage traced cells are distributed throughout the early lesions, in mature lesions they contribute to the formation of a subcapsular layer of cells, and others become associated with the fibrous cap. The lineage traced fibrous cap cells activate expression of SMC markers and growth factor receptor genes. Taken together, these data suggest that TCF21 may have a role regulating the differentiation state of SMC precursor cells that migrate into vascular lesions and contribute to the fibrous cap and more broadly, in view of the association of this gene with human CAD, provide evidence that these processes may be a mechanism for CAD risk attributable to the vascular wall.
Author Summary
Coronary artery disease (CAD) is responsible for the majority of deaths in the Western world, and is due in part to environmental and metabolic factors. However, half of the risk for developing heart disease is genetically predetermined. Genome-wide association studies in human populations have identified over 100 sites in the genome that appear to be associated with CAD, however, the mechanisms by which variation in these regions are responsible for predisposition to CAD remain largely unknown. We have begun to study a gene that contributes to CAD risk, the TCF21 gene. Through genomic studies we show that this gene is involved in processes related to alterations in vascular gene expression, and in particular those related to the smooth muscle cell biology. With cell culture models, we show that TCF21 regulates the differentiation state of this cell type, which is believed critical for vascular disease. Using mouse genetic models of atherosclerotic vascular disease we provide evidence that this gene is expressed in precursor cells that migrate into the disease lesions and contribute to the formation of the fibrous cap that is believed to stabilize these lesions and prevent heart attacks.
doi:10.1371/journal.pgen.1005155
PMCID: PMC4447275  PMID: 26020946
PLoS Genetics  2015;11(5):e1005202.
To functionally link coronary artery disease (CAD) causal genes identified by genome wide association studies (GWAS), and to investigate the cellular and molecular mechanisms of atherosclerosis, we have used chromatin immunoprecipitation sequencing (ChIP-Seq) with the CAD associated transcription factor TCF21 in human coronary artery smooth muscle cells (HCASMC). Analysis of identified TCF21 target genes for enrichment of molecular and cellular annotation terms identified processes relevant to CAD pathophysiology, including “growth factor binding,” “matrix interaction,” and “smooth muscle contraction.” We characterized the canonical binding sequence for TCF21 as CAGCTG, identified AP-1 binding sites in TCF21 peaks, and by conducting ChIP-Seq for JUN and JUND in HCASMC confirmed that there is significant overlap between TCF21 and AP-1 binding loci in this cell type. Expression quantitative trait variation mapped to target genes of TCF21 was significantly enriched among variants with low P-values in the GWAS analyses, suggesting a possible functional interaction between TCF21 binding and causal variants in other CAD disease loci. Separate enrichment analyses found over-representation of TCF21 target genes among CAD associated genes, and linkage disequilibrium between TCF21 peak variation and that found in GWAS loci, consistent with the hypothesis that TCF21 may affect disease risk through interaction with other disease associated loci. Interestingly, enrichment for TCF21 target genes was also found among other genome wide association phenotypes, including height and inflammatory bowel disease, suggesting a functional profile important for basic cellular processes in non-vascular tissues. Thus, data and analyses presented here suggest that study of GWAS transcription factors may be a highly useful approach to identifying disease gene interactions and thus pathways that may be relevant to complex disease etiology.
Author Summary
While coronary artery disease (CAD) is due in part to environmental and metabolic factors, about half of the risk is genetically predetermined. Genome-wide association studies in human populations have identified approximately 150 sites in the genome that appear to be associated with CAD. The mechanisms by which mutations in these regions are responsible for predisposition to CAD remain largely unknown. To begin to explore how disease-specific gene sequences and disease gene function promotes pathology, we have mapped the loci and genes that are downstream of the transcription factor TCF21, which is strongly associated with CAD. By identifying genes that are regulated by TCF21 we have been able to link together multiple other CAD associated genes and begin to identify the critical molecular processes that mediate atherosclerosis in the blood vessel wall and contribute to the genesis of ischemic cardiovascular events.
doi:10.1371/journal.pgen.1005202
PMCID: PMC4447360  PMID: 26020271
Large-scale genome wide association studies (GWAS) have identified 46 loci that are associated with coronary heart disease (CHD). Additionally, 104 independent candidate variants (false discovery rate of 5%) have been identified.1–3 A majority of the causal genes in these loci function independently of conventional risk factors, and it is postulated that a number of the CHD associated genes regulate basic processes in the vascular cells involved in atherosclerosis, and that study of the signaling pathways that are modulated in this cell type by causal regulatory variation will provide critical new insights for targeting the initiation and progression of disease. In this review we will discuss the types of experimental approaches and data that are critical for understanding of molecular processes that underlie the disease risk at 9p21.3, TCF21, SORT1, and other CHD associated loci.
doi:10.1007/s11883-014-0406-4
PMCID: PMC4015632  PMID: 24623178
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
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
Nature  2014;514(7520):102-106.
Summary
The role of long noncoding RNA (lncRNA) in adult hearts is unknown; also unclear is how lncRNA modulates nucleosome remodeling. An estimated 70% of mouse genes undergo antisense transcription1, including myosin heavy chain 7 (Myh7) that encodes molecular motor proteins for heart contraction2. Here, we identify a cluster of lncRNA transcripts from Myh7 loci and show a new lncRNA–chromatin mechanism for heart failure. In mice, these transcripts, which we named Myosin Heavy Chain Associated RNA Transcripts (MyHEART or Mhrt), are cardiac-specific and abundant in adult hearts. Pathological stress activates the Brg1-Hdac-Parp chromatin repressor complex3 to inhibit Mhrt transcription in the heart. Such stress-induced Mhrt repression is essential for cardiomyopathy to develop: restoring Mhrt to the pre-stress level protects the heart from hypertrophy and failure. Mhrt antagonizes the function of Brg1, a chromatin-remodeling factor that is activated by stress to trigger aberrant gene expression and cardiac myopathy3. Mhrt prevents Brg1 from recognizing its genomic DNA targets, thus inhibiting chromatin targeting and gene regulation by Brg1. Mhrt binds to the helicase domain of Brg1, and this domain is crucial for tethering Brg1 to chromatinized DNA targets. Brg1 helicase has dual nucleic acid-binding specificities: it is capable of binding lncRNA (Mhrt) and chromatinized—but not naked—DNA. This dual-binding feature of helicase enables a competitive inhibition mechanism by which Mhrt sequesters Brg1 from its genomic DNA targets to prevent chromatin remodeling. A Mhrt-Brg1 feedback circuit is thus crucial for heart function. Human MHRT also originates from MYH7 loci and is repressed in various types of myopathic hearts, suggesting a conserved lncRNA mechanism in human cardiomyopathy. Our studies identify the first cardioprotective lncRNA, define a new targeting mechanism for ATP-dependent chromatin-remodeling factors, and establish a new paradigm for lncRNA–chromatin interaction.
doi:10.1038/nature13596
PMCID: PMC4184960  PMID: 25119045
lncRNA; Mhrt; Brg1; BAF; chromatin; gene regulation; myosin heavy chain; cardiomyocyte; cardiac hypertrophy; cardiomyopathy; heart failure
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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
The Journal of Clinical Investigation  2015;125(4):1739-1751.
Decreased insulin sensitivity, also referred to as insulin resistance (IR), is a fundamental abnormality in patients with type 2 diabetes and a risk factor for cardiovascular disease. While IR predisposition is heritable, the genetic basis remains largely unknown. The GENEticS of Insulin Sensitivity consortium conducted a genome-wide association study (GWAS) for direct measures of insulin sensitivity, such as euglycemic clamp or insulin suppression test, in 2,764 European individuals, with replication in an additional 2,860 individuals. The presence of a nonsynonymous variant of N-acetyltransferase 2 (NAT2) [rs1208 (803A>G, K268R)] was strongly associated with decreased insulin sensitivity that was independent of BMI. The rs1208 “A” allele was nominally associated with IR-related traits, including increased fasting glucose, hemoglobin A1C, total and LDL cholesterol, triglycerides, and coronary artery disease. NAT2 acetylates arylamine and hydrazine drugs and carcinogens, but predicted acetylator NAT2 phenotypes were not associated with insulin sensitivity. In a murine adipocyte cell line, silencing of NAT2 ortholog Nat1 decreased insulin-mediated glucose uptake, increased basal and isoproterenol-stimulated lipolysis, and decreased adipocyte differentiation, while Nat1 overexpression produced opposite effects. Nat1-deficient mice had elevations in fasting blood glucose, insulin, and triglycerides and decreased insulin sensitivity, as measured by glucose and insulin tolerance tests, with intermediate effects in Nat1 heterozygote mice. Our results support a role for NAT2 in insulin sensitivity.
doi:10.1172/JCI74692
PMCID: PMC4409020  PMID: 25798622
Cardiology; Endocrinology; Genetics; Metabolism

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