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Trans-ethnic genome-wide association studies: advantages and challenges of mapping in diverse populations

Li, Yun R; Keating, Brendan J
Genome-wide association studies (GWASs) are the method most often used by geneticists to interrogate the human genome, and they provide a cost-effective way to identify the genetic variants underpinning complex traits and diseases. Most initial GWASs have focused on genetically homogeneous cohorts from European populations given the limited availability of ethnic minority samples and so as to limit population stratification effects. Transethnic studies have been invaluable in explaining the heritability of common quantitative traits, such as height, and in examining the genetic architecture of complex diseases, such as type 2 diabetes. They provide an opportunity for large-scale signal replication in independent populations and for cross-population meta-analyses to boost statistical power. In addition, transethnic GWASs enable prioritization of candidate genes, fine-mapping of functional variants, and potentially identification of SNPs associated with disease risk in admixed populations, by taking advantage of natural differences in genomic linkage disequilibrium across ethnically diverse populations. Recent efforts to assess the biological function of variants identified by GWAS have highlighted the need for large-scale replication, meta-analyses and fine-mapping across worldwide populations of ethnically diverse genetic ancestries. Here, we review recent advances and new approaches that are important to consider when performing, designing or interpreting transethnic GWASs, and we highlight existing challenges, such as the limited ability to handle heterogeneity in linkage disequilibrium across populations and limitations in dissecting complex architectures, such as those found in recently admixed populations.
PMCID:4254423
PMID: 25473427
ISSN: 1756-994x
CID: 5478222

Secretory phospholipase A(2)-IIA and cardiovascular disease: a mendelian randomization study

Holmes, Michael V; Simon, Tabassome; Exeter, Holly J; Folkersen, Lasse; Asselbergs, Folkert W; Guardiola, Montse; Cooper, Jackie A; Palmen, Jutta; Hubacek, Jaroslav A; Carruthers, Kathryn F; Horne, Benjamin D; Brunisholz, Kimberly D; Mega, Jessica L; van Iperen, Erik P A; Li, Mingyao; Leusink, Maarten; Trompet, Stella; Verschuren, Jeffrey J W; Hovingh, G Kees; Dehghan, Abbas; Nelson, Christopher P; Kotti, Salma; Danchin, Nicolas; Scholz, Markus; Haase, Christiane L; Rothenbacher, Dietrich; Swerdlow, Daniel I; Kuchenbaecker, Karoline B; Staines-Urias, Eleonora; Goel, Anuj; van 't Hooft, Ferdinand; Gertow, Karl; de Faire, Ulf; Panayiotou, Andrie G; Tremoli, Elena; Baldassarre, Damiano; Veglia, Fabrizio; Holdt, Lesca M; Beutner, Frank; Gansevoort, Ron T; Navis, Gerjan J; Mateo Leach, Irene; Breitling, Lutz P; Brenner, Hermann; Thiery, Joachim; Dallmeier, Dhayana; Franco-Cereceda, Anders; Boer, Jolanda M A; Stephens, Jeffrey W; Hofker, Marten H; Tedgui, Alain; Hofman, Albert; Uitterlinden, André G; Adamkova, Vera; Pitha, Jan; Onland-Moret, N Charlotte; Cramer, Maarten J; Nathoe, Hendrik M; Spiering, Wilko; Klungel, Olaf H; Kumari, Meena; Whincup, Peter H; Morrow, David A; Braund, Peter S; Hall, Alistair S; Olsson, Anders G; Doevendans, Pieter A; Trip, Mieke D; Tobin, Martin D; Hamsten, Anders; Watkins, Hugh; Koenig, Wolfgang; Nicolaides, Andrew N; Teupser, Daniel; Day, Ian N M; Carlquist, John F; Gaunt, Tom R; Ford, Ian; Sattar, Naveed; Tsimikas, Sotirios; Schwartz, Gregory G; Lawlor, Debbie A; Morris, Richard W; Sandhu, Manjinder S; Poledne, Rudolf; Maitland-van der Zee, Anke H; Khaw, Kay-Tee; Keating, Brendan J; van der Harst, Pim; Price, Jackie F; Mehta, Shamir R; Yusuf, Salim; Witteman, Jaqueline C M; Franco, Oscar H; Jukema, J Wouter; de Knijff, Peter; Tybjaerg-Hansen, Anne; Rader, Daniel J; Farrall, Martin; Samani, Nilesh J; Kivimaki, Mika; Fox, Keith A A; Humphries, Steve E; Anderson, Jeffrey L; Boekholdt, S Matthijs; Palmer, Tom M; Eriksson, Per; Paré, Guillaume; Hingorani, Aroon D; Sabatine, Marc S; Mallat, Ziad; Casas, Juan P; Talmud, Philippa J
OBJECTIVES/OBJECTIVE:This study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease. BACKGROUND:Higher circulating levels of sPLA2-IIA mass or sPLA2 enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA2 inhibitor (varespladib) was stopped prematurely for lack of efficacy. METHODS:We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA2-IIA isoenzyme, as an instrumental variable. RESULTS:PLA2G2A rs11573156 C allele associated with lower circulating sPLA2-IIA mass (38% to 44%) and sPLA2 enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA2-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE. CONCLUSIONS:Reducing sPLA2-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.
PMID: 23916927
ISSN: 1558-3597
CID: 5478022

The Electronic Medical Records and Genomics (eMERGE) Network: past, present, and future

Gottesman, Omri; Kuivaniemi, Helena; Tromp, Gerard; Faucett, W Andrew; Li, Rongling; Manolio, Teri A; Sanderson, Saskia C; Kannry, Joseph; Zinberg, Randi; Basford, Melissa A; Brilliant, Murray; Carey, David J; Chisholm, Rex L; Chute, Christopher G; Connolly, John J; Crosslin, David; Denny, Joshua C; Gallego, Carlos J; Haines, Jonathan L; Hakonarson, Hakon; Harley, John; Jarvik, Gail P; Kohane, Isaac; Kullo, Iftikhar J; Larson, Eric B; McCarty, Catherine; Ritchie, Marylyn D; Roden, Dan M; Smith, Maureen E; Böttinger, Erwin P; Williams, Marc S; Harley, John; Kohane, Isaac; Holm, Ingrid; Hutton, John; Cobb, Beth L; Perry, Cassandra; Namjou, Bahram; Bickel, Julie; Prows, Cindy; Solti, Imre; Savova, Guergana; Chen, Pei; Lindgren, Todd; Marsolo, Keith; Bickel, John; Wagner, Michael; Vinks, Alexander; Wolf, Wendy; Hakonarson, Hakon; Keating, Brendan; Sleiman, Patrick; Connolly, John; Chiavacci, Rosetta; Mentch, Frank; Qiu, Haijun; Behr, Meckenzie; Carey, David J; Williams, Marc S; Tromp, Gerard; Kuivaniemi, Helena; Faucett, W Andrew; Ledbetter, David H; Gerhard, Glenn S; Smelser, Diane T; Borthwick, Kenneth; Colonie, Ryan; Bock, Jonathan; Fetterolf, Samantha; Wood, G Craig; Williams, Janet L; Rogers, Laura; Packard-Smith, Bethanny; Chu, Xin; Ryer, Evan J; Elmore, James R; Still, Christopher D; Vrabec, Tamara R; Shellenberger, M Joshua; Steinhubl, Steven R; Sundaresan, Agnes; Elston, Robert C; Shuldiner, Alan R; Mitchell, Braxton D; Larson, Eric B; Jarvik, Gail; Ralson, James; Hartzler, Andrea; Carrell, David S; Crane, Paul; Crosslin, David; Kim, Daniel S; Gallego, Carlos J; Mukherjee, Shubhabrata; Fullerton, Stephanie Malia; Brown, Susan; Leppig, Kathleen A; Carlson, Christopher S; McCarty, Catherine A; Brilliant, Murray; Lin, Simon; Brautbar, Ariel S; Patchett, Richard; Peissig, Peggy; Berg, Richard; Strenn, Rob; Linneman, James; Rottscheit, Carla; Kitchner, Terrie; Ritchie, Marylyn; Verma, Shefali Setia; Armstrong, Gretta D; Kullo, Iftikhar J; Chute, Christopher G; Koenig, Barbara A; de Andrade, Mariza; Bielinski, Suzette; Pathak, Jyotishman; Heit, John A; Bottinger, Erwin; Gottesman, Omri; Scott, Stuart; Hulot, Jean-Sebastien; Kannry, Joseph; Ellis, Steve; Keppel, Yolanda; Purcell, Shaun; Zhang, Weijia; Peter, Inga; Nadukuru, Rajiv; Lotay, Vaneet; Parides, Michael; Horowitz, Carol; Rhodes, Rosamond; Sanderson, Saskia; Zinberg, Randi; Lin, Jennifer; Ullman, Thomas; Dieterich, Douglas; Friedman, Scott; Brown, Tanisha; Mejia, Ana; Cooper, Richard; Kathiresan, Sekar; Hripsak, George; Friedman, Carol; Weng, Chunhua; Overby, Casey Lynette; Chisholm, Rex L; Smith, Maureen E; Kho, Abel; Hayes, M Geoffrey; Rasmussen-Torvik, Laura; Starren, Justin; Christensen, Carl; Persell, Stephen; Aufox, Sharon; Pacheco, Jennifer; Rasmussen, Luke; Thompson, William L; Pan, Vivian; Wicklund, Catherine; Roden, Dan M; Clayton, Ellen; Crawford, Dana; Denny, Joshua C; Malin, Bradley A; Peterson, Josh F; Schildcrout, Jonathan S; Wilke, Russ; Bastarache, Lisa; Danciu, Ioana; Delaney, Jessica; Dumitrescu, Logan; Goodloe, Robert; Heatherly, Raymond; Hinz, Eugenia McPeek; Jeff, Janina; Karnes, Jason; Malinowski, Jennifer; McCall, A Scott; Mosley, Jonathan; Saip, Alexander; Stallings, Sarah; Van Driest, Sara; Wang, Xiaoming; Westbrook, Matthew; Haines, Jonathan L; Denny, Joshua C; Malin, Bradley A; Ritchie, Marylyn D; Basford, Melissa; Armstrong, Gretta; Bradford, Yuki; Cowan, James; Kirby, Jacqueline; Melancon, Lauren; Mapes, Brandy; Speltz, Peter; Verma, Anurag; Verma, Shefali; Xia, Weiyi
The Electronic Medical Records and Genomics Network is a National Human Genome Research Institute-funded consortium engaged in the development of methods and best practices for using the electronic medical record as a tool for genomic research. Now in its sixth year and second funding cycle, and comprising nine research groups and a coordinating center, the network has played a major role in validating the concept that clinical data derived from electronic medical records can be used successfully for genomic research. Current work is advancing knowledge in multiple disciplines at the intersection of genomics and health-care informatics, particularly for electronic phenotyping, genome-wide association studies, genomic medicine implementation, and the ethical and regulatory issues associated with genomics research and returning results to study participants. Here, we describe the evolution, accomplishments, opportunities, and challenges of the network from its inception as a five-group consortium focused on genotype-phenotype associations for genomic discovery to its current form as a nine-group consortium pivoting toward the implementation of genomic medicine.
PMCID:3795928
PMID: 23743551
ISSN: 1530-0366
CID: 5479322

Genetic variance in nitric oxide synthase and endothelin genes among children with and without endothelial dysfunction

Chatsuriyawong, Siriporn; Gozal, David; Kheirandish-Gozal, Leila; Bhattacharjee, Rakesh; Khalyfa, Ahamed A; Wang, Yang; Hakonarson, Hakon; Keating, Brendan; Sukhumsirichart, Wasana; Khalyfa, Abdelnaby
BACKGROUND:The presence of endothelial dysfunction (ED) constitutes an early risk factor for cardiovascular disease (CVD) in children. Nitric oxide (NO) and endothelin (EDN) are generated in endothelial cells and are critical regulators of vascular function, with ED resulting from an imbalance between these two molecules. We hypothesized that genetic variants in NO synthase and EDN isoforms and its receptors (EDNRA and EDNRB) may account for a proportion of the risk for ED in developing children. METHODS:Consecutive children (ages 5-10 years) were prospectively recruited from the community. Time to peak post-occlusive reperfusion (Tmax) was considered as the indicator of either normal endothelial function (NEF; Tmax < 45 sec) or ED (Tmax ≥ 45 sec). Lipid profiles, high sensitivity C-reactive protein (hsCRP), fasting glucose and insulin were assayed using ELISA. Genomic DNA from peripheral blood was extracted and genotyped for NOS1 (209 SNPs), NOS2 (122 SNPs), NOS3 (50 SNPs), EDN1 (43 SNPs), EDN2 (48 SNPs), EDN3 (14 SNPs), EDNRA (27 SNPs), and EDNRB (23 SNPs) using a custom SNPs array. Linkage disequilibrium was analyzed using Haploview version 4.2 software. RESULTS:The relative frequencies of SNPs were evaluated in 122 children, 84 with NEF and 38 with ED. The frequencies of NOS1 (11 SNPs), and EDN1 (2 SNPs) were differentially distributed between NEF vs. ED, and no significant differences emerged for all other genes. Significant SNPs for NOS1 and EDN1 SNPs were further validated with RT-PCR. CONCLUSIONS:Genetic variants in the NOS1 and EDN1 genes appear to account for important components of the variance in endothelial function, particularly when concurrent risk factors such as obesity exist. Thus, analysis of genotype-phenotype interactions in children at risk for ED will be critical for more accurate formulation of categorical CVD risk estimates.
PMCID:3849009
PMID: 24063765
ISSN: 1479-5876
CID: 5478052

Genome-wide association analysis of blood-pressure traits in African-ancestry individuals reveals common associated genes in African and non-African populations

Franceschini, Nora; Fox, Ervin; Zhang, Zhaogong; Edwards, Todd L; Nalls, Michael A; Sung, Yun Ju; Tayo, Bamidele O; Sun, Yan V; Gottesman, Omri; Adeyemo, Adebawole; Johnson, Andrew D; Young, J Hunter; Rice, Ken; Duan, Qing; Chen, Fang; Li, Yun; Tang, Hua; Fornage, Myriam; Keene, Keith L; Andrews, Jeanette S; Smith, Jennifer A; Faul, Jessica D; Guangfa, Zhang; Guo, Wei; Liu, Yu; Murray, Sarah S; Musani, Solomon K; Srinivasan, Sathanur; Velez Edwards, Digna R; Wang, Heming; Becker, Lewis C; Bovet, Pascal; Bochud, Murielle; Broeckel, Ulrich; Burnier, Michel; Carty, Cara; Chasman, Daniel I; Ehret, Georg; Chen, Wei-Min; Chen, Guanjie; Chen, Wei; Ding, Jingzhong; Dreisbach, Albert W; Evans, Michele K; Guo, Xiuqing; Garcia, Melissa E; Jensen, Rich; Keller, Margaux F; Lettre, Guillaume; Lotay, Vaneet; Martin, Lisa W; Moore, Jason H; Morrison, Alanna C; Mosley, Thomas H; Ogunniyi, Adesola; Palmas, Walter; Papanicolaou, George; Penman, Alan; Polak, Joseph F; Ridker, Paul M; Salako, Babatunde; Singleton, Andrew B; Shriner, Daniel; Taylor, Kent D; Vasan, Ramachandran; Wiggins, Kerri; Williams, Scott M; Yanek, Lisa R; Zhao, Wei; Zonderman, Alan B; Becker, Diane M; Berenson, Gerald; Boerwinkle, Eric; Bottinger, Erwin; Cushman, Mary; Eaton, Charles; Nyberg, Fredrik; Heiss, Gerardo; Hirschhron, Joel N; Howard, Virginia J; Karczewsk, Konrad J; Lanktree, Matthew B; Liu, Kiang; Liu, Yongmei; Loos, Ruth; Margolis, Karen; Snyder, Michael; Psaty, Bruce M; Schork, Nicholas J; Weir, David R; Rotimi, Charles N; Sale, Michele M; Harris, Tamara; Kardia, Sharon L R; Hunt, Steven C; Arnett, Donna; Redline, Susan; Cooper, Richard S; Risch, Neil J; Rao, D C; Rotter, Jerome I; Chakravarti, Aravinda; Reiner, Alex P; Levy, Daniel; Keating, Brendan J; Zhu, Xiaofeng
High blood pressure (BP) is more prevalent and contributes to more severe manifestations of cardiovascular disease (CVD) in African Americans than in any other United States ethnic group. Several small African-ancestry (AA) BP genome-wide association studies (GWASs) have been published, but their findings have failed to replicate to date. We report on a large AA BP GWAS meta-analysis that includes 29,378 individuals from 19 discovery cohorts and subsequent replication in additional samples of AA (n = 10,386), European ancestry (EA) (n = 69,395), and East Asian ancestry (n = 19,601). Five loci (EVX1-HOXA, ULK4, RSPO3, PLEKHG1, and SOX6) reached genome-wide significance (p < 1.0 x 10(-8)) for either systolic or diastolic BP in a transethnic meta-analysis after correction for multiple testing. Three of these BP loci (EVX1-HOXA, RSPO3, and PLEKHG1) lack previous associations with BP. We also identified one independent signal in a known BP locus (SOX6) and provide evidence for fine mapping in four additional validated BP loci. We also demonstrate that validated EA BP GWAS loci, considered jointly, show significant effects in AA samples. Consequently, these findings suggest that BP loci might have universal effects across studied populations, demonstrating that multiethnic samples are an essential component in identifying, fine mapping, and understanding their trait variability.
PMCID:3769920
PMID: 23972371
ISSN: 1537-6605
CID: 2747032

Loci influencing blood pressure identified using a cardiovascular gene-centric array (vol 22, pg 1663, 2013) [Correction]

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 MIH; Gieger, Christian; Gong, Yan; Isaacs, Aaron; Kleber, Marcus E; Leach, Irene Mateo; McDonough, Caitrin W; Meijs, Matthijs FL; 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 PA; Van Setten, Jessica; Vonk, Judith M; Zhang, Li; Beitelshees, Amber L; Berenson, Gerald S; Bhatt, Deepak L; Boer, Jolanda MA; 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, GKees; 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; OConnell, Jeffery R; Onland-Moret, NCharlotte; 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, WMonique; Wijmenga, Cisca; Winkelmann, Bernhard R; Wyatt, Sharon; Young, JHunter; 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 JP; Koenig, Wolfgang; Maerz, 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, Andre G; van der Harst, Pim; van der Schouw, Yvonne T; Samani, Nilesh J; Johnson, Andrew D; Munroe, Patricia B; de Bakker, Paul IW; Zhu, Xiaofeng; Levy, Daniel; Keating, Brendan J; Asselbergs, Folkert W; CARDIOGRAM METASTROKE; LifeLines Cohort Study
ISI:000322341300019
ISSN: 0964-6906
CID: 2748282

Genome-wide and gene-centric analyses of circulating myeloperoxidase levels in the charge and care consortia

Reiner, Alexander P; Hartiala, Jaana; Zeller, Tanja; Bis, Joshua C; Dupuis, Josée; Fornage, Myriam; Baumert, Jens; Kleber, Marcus E; Wild, Philipp S; Baldus, Stephan; Bielinski, Suzette J; Fontes, João D; Illig, Thomas; Keating, Brendan J; Lange, Leslie A; Ojeda, Francisco; Müller-Nurasyid, Martina; Munzel, Thomas F; Psaty, Bruce M; Rice, Kenneth; Rotter, Jerome I; Schnabel, Renate B; Tang, W H Wilson; Thorand, Barbara; Erdmann, Jeanette; Jacobs, David R; Wilson, James G; Koenig, Wolfgang; Tracy, Russell P; Blankenberg, Stefan; März, Winfried; Gross, Myron D; Benjamin, Emelia J; Hazen, Stanley L; Allayee, Hooman
Increased systemic levels of myeloperoxidase (MPO) are associated with the risk of coronary artery disease (CAD). To identify the genetic factors that are associated with circulating MPO levels, we carried out a genome-wide association study (GWAS) and a gene-centric analysis in subjects of European ancestry and African Americans (AAs). A locus on chromosome 1q31.1 containing the complement factor H (CFH) gene was strongly associated with serum MPO levels in 9305 subjects of European ancestry (lead SNP rs800292; P = 4.89 × 10(-41)) and in 1690 AA subjects (rs505102; P = 1.05 × 10(-8)). Gene-centric analyses in 8335 subjects of European ancestry additionally identified two rare MPO coding sequence variants that were associated with serum MPO levels (rs28730837, P = 5.21 × 10(-12); rs35897051, P = 3.32 × 10(-8)). A GWAS for plasma MPO levels in 9260 European ancestry subjects identified a chromosome 17q22 region near MPO that was significantly associated (lead SNP rs6503905; P = 2.94 × 10(-12)), but the CFH locus did not exhibit evidence of association with plasma MPO levels. Functional analyses revealed that rs800292 was associated with levels of complement proteins in serum. Variants at chromosome 17q22 also had pleiotropic cis effects on gene expression. In a case-control analysis of ∼80 000 subjects from CARDIoGRAM, none of the identified single-nucleotide polymorphisms (SNPs) were associated with CAD. These results suggest that distinct genetic factors regulate serum and plasma MPO levels, which may have relevance for various acute and chronic inflammatory disorders. The clinical implications for CAD and a better understanding of the functional basis for the association of CFH and MPO variants with circulating MPO levels require further study.
PMCID:3723315
PMID: 23620142
ISSN: 1460-2083
CID: 5478002

Genome-wide association analysis of red blood cell traits in African Americans: the COGENT Network

Chen, Zhao; Tang, Hua; Qayyum, Rehan; Schick, Ursula M; Nalls, Michael A; Handsaker, Robert; Li, Jin; Lu, Yingchang; Yanek, Lisa R; Keating, Brendan; Meng, Yan; van Rooij, Frank J A; Okada, Yukinori; Kubo, Michiaki; Rasmussen-Torvik, Laura; Keller, Margaux F; Lange, Leslie; Evans, Michele; Bottinger, Erwin P; Linderman, Michael D; Ruderfer, Douglas M; Hakonarson, Hakon; Papanicolaou, George; Zonderman, Alan B; Gottesman, Omri; Thomson, Cynthia; Ziv, Elad; Singleton, Andrew B; Loos, Ruth J F; Sleiman, Patrick M A; Ganesh, Santhi; McCarroll, Steven; Becker, Diane M; Wilson, James G; Lettre, Guillaume; Reiner, Alexander P
Laboratory red blood cell (RBC) measurements are clinically important, heritable and differ among ethnic groups. To identify genetic variants that contribute to RBC phenotypes in African Americans (AAs), we conducted a genome-wide association study in up to ~16 500 AAs. The alpha-globin locus on chromosome 16pter [lead SNP rs13335629 in ITFG3 gene; P < 1E-13 for hemoglobin (Hgb), RBC count, mean corpuscular volume (MCV), MCH and MCHC] and the G6PD locus on Xq28 [lead SNP rs1050828; P < 1E - 13 for Hgb, hematocrit (Hct), MCV, RBC count and red cell distribution width (RDW)] were each associated with multiple RBC traits. At the alpha-globin region, both the common African 3.7 kb deletion and common single nucleotide polymorphisms (SNPs) appear to contribute independently to RBC phenotypes among AAs. In the 2p21 region, we identified a novel variant of PRKCE distinctly associated with Hct in AAs. In a genome-wide admixture mapping scan, local European ancestry at the 6p22 region containing HFE and LRRC16A was associated with higher Hgb. LRRC16A has been previously associated with the platelet count and mean platelet volume in AAs, but not with Hgb. Finally, we extended to AAs the findings of association of erythrocyte traits with several loci previously reported in Europeans and/or Asians, including CD164 and HBS1L-MYB. In summary, this large-scale genome-wide analysis in AAs has extended the importance of several RBC-associated genetic loci to AAs and identified allelic heterogeneity and pleiotropy at several previously known genetic loci associated with blood cell traits in AAs.
PMCID:3658166
PMID: 23446634
ISSN: 1460-2083
CID: 5477982

Mutations in PDGFRB cause autosomal-dominant infantile myofibromatosis

Martignetti, John A; Tian, Lifeng; Li, Dong; Ramirez, Maria Celeste M; Camacho-Vanegas, Olga; Camacho, Sandra Catalina; Guo, Yiran; Zand, Dina J; Bernstein, Audrey M; Masur, Sandra K; Kim, Cecilia E; Otieno, Frederick G; Hou, Cuiping; Abdel-Magid, Nada; Tweddale, Ben; Metry, Denise; Fournet, Jean-Christophe; Papp, Eniko; McPherson, Elizabeth W; Zabel, Carrie; Vaksmann, Guy; Morisot, Cyril; Keating, Brendan; Sleiman, Patrick M; Cleveland, Jeffrey A; Everman, David B; Zackai, Elaine; Hakonarson, Hakon
Infantile myofibromatosis (IM) is a disorder of mesenchymal proliferation characterized by the development of nonmetastasizing tumors in the skin, muscle, bone, and viscera. Occurrence within families across multiple generations is suggestive of an autosomal-dominant (AD) inheritance pattern, but autosomal-recessive (AR) modes of inheritance have also been proposed. We performed whole-exome sequencing (WES) in members of nine unrelated families clinically diagnosed with AD IM to identify the genetic origin of the disorder. In eight of the families, we identified one of two disease-causing mutations, c.1978C>A (p.Pro660Thr) and c.1681C>T (p.Arg561Cys), in PDGFRB. Intriguingly, one family did not have either of these PDGFRB mutations but all affected individuals had a c.4556T>C (p.Leu1519Pro) mutation in NOTCH3. Our studies suggest that mutations in PDGFRB are a cause of IM and highlight NOTCH3 as a candidate gene. Further studies of the crosstalk between PDGFRB and NOTCH pathways may offer new opportunities to identify mutations in other genes that result in IM and is a necessary first step toward understanding the mechanisms of both tumor growth and regression and its targeted treatment.
PMID: 23731542
ISSN: 1537-6605
CID: 5478012

A meta-analysis identifies new loci associated with body mass index in individuals of African ancestry

Monda, Keri L; Chen, Gary K; Taylor, Kira C; Palmer, Cameron; Edwards, Todd L; Lange, Leslie A; Ng, Maggie C Y; Adeyemo, Adebowale A; Allison, Matthew A; Bielak, Lawrence F; Chen, Guanjie; Graff, Mariaelisa; Irvin, Marguerite R; Rhie, Suhn K; Li, Guo; Liu, Yongmei; Liu, Youfang; Lu, Yingchang; Nalls, Michael A; Sun, Yan V; Wojczynski, Mary K; Yanek, Lisa R; Aldrich, Melinda C; Ademola, Adeyinka; Amos, Christopher I; Bandera, Elisa V; Bock, Cathryn H; Britton, Angela; Broeckel, Ulrich; Cai, Quiyin; Caporaso, Neil E; Carlson, Chris S; Carpten, John; Casey, Graham; Chen, Wei-Min; Chen, Fang; Chen, Yii-Der I; Chiang, Charleston W K; Coetzee, Gerhard A; Demerath, Ellen; Deming-Halverson, Sandra L; Driver, Ryan W; Dubbert, Patricia; Feitosa, Mary F; Feng, Ye; Freedman, Barry I; Gillanders, Elizabeth M; Gottesman, Omri; Guo, Xiuqing; Haritunians, Talin; Harris, Tamara; Harris, Curtis C; Hennis, Anselm J M; Hernandez, Dena G; McNeill, Lorna H; Howard, Timothy D; Howard, Barbara V; Howard, Virginia J; Johnson, Karen C; Kang, Sun J; Keating, Brendan J; Kolb, Suzanne; Kuller, Lewis H; Kutlar, Abdullah; Langefeld, Carl D; Lettre, Guillaume; Lohman, Kurt; Lotay, Vaneet; Lyon, Helen; Manson, Joann E; Maixner, William; Meng, Yan A; Monroe, Kristine R; Morhason-Bello, Imran; Murphy, Adam B; Mychaleckyj, Josyf C; Nadukuru, Rajiv; Nathanson, Katherine L; Nayak, Uma; N'diaye, Amidou; Nemesure, Barbara; Wu, Suh-Yuh; Leske, M Cristina; Neslund-Dudas, Christine; Neuhouser, Marian; Nyante, Sarah; Ochs-Balcom, Heather; Ogunniyi, Adesola; Ogundiran, Temidayo O; Ojengbede, Oladosu; Olopade, Olufunmilayo I; Palmer, Julie R; Ruiz-Narvaez, Edward A; Palmer, Nicholette D; Press, Michael F; Rampersaud, Evandine; Rasmussen-Torvik, Laura J; Rodriguez-Gil, Jorge L; Salako, Babatunde; Schadt, Eric E; Schwartz, Ann G; Shriner, Daniel A; Siscovick, David; Smith, Shad B; Wassertheil-Smoller, Sylvia; Speliotes, Elizabeth K; Spitz, Margaret R; Sucheston, Lara; Taylor, Herman; Tayo, Bamidele O; Tucker, Margaret A; Van Den Berg, David J; Edwards, Digna R Velez; Wang, Zhaoming; Wiencke, John K; Winkler, Thomas W; Witte, John S; Wrensch, Margaret; Wu, Xifeng; Yang, James J; Levin, Albert M; Young, Taylor R; Zakai, Neil A; Cushman, Mary; Zanetti, Krista A; Zhao, Jing Hua; Zhao, Wei; Zheng, Yonglan; Zhou, Jie; Ziegler, Regina G; Zmuda, Joseph M; Fernandes, Jyotika K; Gilkeson, Gary S; Kamen, Diane L; Hunt, Kelly J; Spruill, Ida J; Ambrosone, Christine B; Ambs, Stefan; Arnett, Donna K; Atwood, Larry; Becker, Diane M; Berndt, Sonja I; Bernstein, Leslie; Blot, William J; Borecki, Ingrid B; Bottinger, Erwin P; Bowden, Donald W; Burke, Gregory; Chanock, Stephen J; Cooper, Richard S; Ding, Jingzhong; Duggan, David; Evans, Michele K; Fox, Caroline; Garvey, W Timothy; Bradfield, Jonathan P; Hakonarson, Hakon; Grant, Struan F A; Hsing, Ann; Chu, Lisa; Hu, Jennifer J; Huo, Dezheng; Ingles, Sue A; John, Esther M; Jordan, Joanne M; Kabagambe, Edmond K; Kardia, Sharon L R; Kittles, Rick A; Goodman, Phyllis J; Klein, Eric A; Kolonel, Laurence N; Le Marchand, Loic; Liu, Simin; McKnight, Barbara; Millikan, Robert C; Mosley, Thomas H; Padhukasahasram, Badri; Williams, L Keoki; Patel, Sanjay R; Peters, Ulrike; Pettaway, Curtis A; Peyser, Patricia A; Psaty, Bruce M; Redline, Susan; Rotimi, Charles N; Rybicki, Benjamin A; Sale, Michèle M; Schreiner, Pamela J; Signorello, Lisa B; Singleton, Andrew B; Stanford, Janet L; Strom, Sara S; Thun, Michael J; Vitolins, Mara; Zheng, Wei; Moore, Jason H; Williams, Scott M; Ketkar, Shamika; Zhu, Xiaofeng; Zonderman, Alan B; Kooperberg, Charles; Papanicolaou, George J; Henderson, Brian E; Reiner, Alex P; Hirschhorn, Joel N; Loos, Ruth J F; North, Kari E; Haiman, Christopher A
Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one new locus at 5q33 (GALNT10, rs7708584, P = 3.4 × 10(-11)) and another at 7p15 when we included data from the GIANT consortium (MIR148A-NFE2L3, rs10261878, P = 1.2 × 10(-10)). We also found suggestive evidence of an association at a third locus at 6q16 in the African-ancestry sample (KLHL32, rs974417, P = 6.9 × 10(-8)). Thirty-two of the 36 previously established BMI variants showed directionally consistent effect estimates in our GWAS (binomial P = 9.7 × 10(-7)), five of which reached genome-wide significance. These findings provide strong support for shared BMI loci across populations, as well as for the utility of studying ancestrally diverse populations.
PMCID:3694490
PMID: 23583978
ISSN: 1546-1718
CID: 5477992