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Large-scale gene-centric meta-analysis across 32 studies identifies multiple lipid loci
Asselbergs, Folkert W; Guo, Yiran; van Iperen, Erik P A; Sivapalaratnam, Suthesh; Tragante, Vinicius; Lanktree, Matthew B; Lange, Leslie A; Almoguera, Berta; Appelman, Yolande E; Barnard, John; Baumert, Jens; Beitelshees, Amber L; Bhangale, Tushar R; Chen, Yii-Der Ida; Gaunt, Tom R; Gong, Yan; Hopewell, Jemma C; Johnson, Toby; Kleber, Marcus E; Langaee, Taimour Y; Li, Mingyao; Li, Yun R; Liu, Kiang; McDonough, Caitrin W; Meijs, Matthijs F L; Middelberg, Rita P S; Musunuru, Kiran; Nelson, Christopher P; O'Connell, Jeffery R; Padmanabhan, Sandosh; Pankow, James S; Pankratz, Nathan; Rafelt, Suzanne; Rajagopalan, Ramakrishnan; Romaine, Simon P R; Schork, Nicholas J; Shaffer, Jonathan; Shen, Haiqing; Smith, Erin N; Tischfield, Sam E; van der Most, Peter J; van Vliet-Ostaptchouk, Jana V; Verweij, Niek; Volcik, Kelly A; Zhang, Li; Bailey, Kent R; Bailey, Kristian M; Bauer, Florianne; Boer, Jolanda M A; Braund, Peter S; Burt, Amber; Burton, Paul R; Buxbaum, Sarah G; Chen, Wei; Cooper-Dehoff, Rhonda M; Cupples, L Adrienne; deJong, Jonas S; Delles, Christian; Duggan, David; Fornage, Myriam; Furlong, Clement E; Glazer, Nicole; Gums, John G; Hastie, Claire; Holmes, Michael V; Illig, Thomas; Kirkland, Susan A; Kivimaki, Mika; Klein, Ronald; Klein, Barbara E; Kooperberg, Charles; Kottke-Marchant, Kandice; Kumari, Meena; LaCroix, Andrea Z; Mallela, Laya; Murugesan, Gurunathan; Ordovas, Jose; Ouwehand, Willem H; Post, Wendy S; Saxena, Richa; Scharnagl, Hubert; Schreiner, Pamela J; Shah, Tina; Shields, Denis C; Shimbo, Daichi; Srinivasan, Sathanur R; Stolk, Ronald P; Swerdlow, Daniel I; Taylor, Herman A; Topol, Eric J; Toskala, Elina; van Pelt, Joost L; van Setten, Jessica; Yusuf, Salim; Whittaker, John C; Zwinderman, A H; Anand, Sonia S; Balmforth, Anthony J; Berenson, Gerald S; Bezzina, Connie R; Boehm, Bernhard O; Boerwinkle, Eric; Casas, Juan P; Caulfield, Mark J; Clarke, Robert; Connell, John M; Cruickshanks, Karen J; Davidson, Karina W; Day, Ian N M; de Bakker, Paul I W; Doevendans, Pieter A; Dominiczak, Anna F; Hall, Alistair S; Hartman, Catharina A; Hengstenberg, Christian; Hillege, Hans L; Hofker, Marten H; Humphries, Steve E; Jarvik, Gail P; Johnson, Julie A; Kaess, Bernhard M; Kathiresan, Sekar; Koenig, Wolfgang; Lawlor, Debbie A; März, Winfried; Melander, Olle; Mitchell, Braxton D; Montgomery, Grant W; Munroe, Patricia B; Murray, Sarah S; Newhouse, Stephen J; Onland-Moret, N Charlotte; Poulter, Neil; Psaty, Bruce; Redline, Susan; Rich, Stephen S; Rotter, Jerome I; Schunkert, Heribert; Sever, Peter; Shuldiner, Alan R; Silverstein, Roy L; Stanton, Alice; Thorand, Barbara; Trip, Mieke D; Tsai, Michael Y; van der Harst, Pim; van der Schoot, Ellen; van der Schouw, Yvonne T; Verschuren, W M Monique; Watkins, Hugh; Wilde, Arthur A M; Wolffenbuttel, Bruce H R; Whitfield, John B; Hovingh, G Kees; Ballantyne, Christie M; Wijmenga, Cisca; Reilly, Muredach P; Martin, Nicholas G; Wilson, James G; Rader, Daniel J; Samani, Nilesh J; Reiner, Alex P; Hegele, Robert A; Kastelein, John J P; Hingorani, Aroon D; Talmud, Philippa J; Hakonarson, Hakon; Elbers, Clara C; Keating, Brendan J; Drenos, Fotios
Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering ∼2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids.
PMCID:3487124
PMID: 23063622
ISSN: 1537-6605
CID: 5477922
Genetic association studies in pre-eclampsia: systematic meta-analyses and field synopsis
Staines-Urias, Eleonora; Paez, María C; Doyle, Pat; Dudbridge, Frank; Serrano, Norma C; Ioannidis, John P A; Keating, Brendan J; Hingorani, Aroon D; Casas, Juan P
BACKGROUND:Pre-eclampsia is thought to have a polygenic basis, but the identification of susceptibility genes and the quantification of associated risks have been elusive owing to lack of replication from published genetic association studies. OBJECTIVE:To perform a systematic review and meta-analysis of genetic association studies to evaluate the evidence for the associations of various candidate genes with pre-eclampsia. METHODS:For inclusion, studies had to involve unrelated subjects and examine the associations between pre-eclampsia (excluding publications without a measurement of proteinuria) and any candidate variant. Authors were contacted to obtain unpublished data when necessary. A meta-analysis was conducted for all variants with three or more independent samples available. Summary odds ratios (ORs), 99% confidence intervals (CIs) and P-values were calculated using random effects models. RESULTS:Data from 192 genetic association studies met the selection criteria and were included in 25 independent meta-analyses. There was some evidence of association for F5 rs6025 (OR = 1.74; 99% CI 1.43-2.12), F2 rs1799963 (OR = 1.72; 99% CI 1.31-2.26), ACE rs4646994 (OR = 1.17; 99% CI 0.99-1.40), AGT rs699 (OR = 1.26; 99% CI 1.00-1.59) and AGTR1 rs5186 (OR = 1.22; 99% CI 0.96-1.56), but only the first two associations reached moderate epidemiological credibility. Possible bias resulting from small study size and poor reporting of individual studies were the most important factors affecting the reported associations. CONCLUSION/CONCLUSIONS:To date, candidate gene studies in pre-eclampsia have not robustly documented any associations with strong epidemiological credibility. Large-scale replication of the most promising associations, exhibited by two genetic variants, and incorporation of agnostic high-throughput data may improve our genetic knowledge base for this complex phenotype.
PMID: 23132613
ISSN: 1464-3685
CID: 5477932
Novel loci associated with PR interval in a genome-wide association study of 10 African American cohorts
Butler, Anne M; Yin, Xiaoyan; Evans, Daniel S; Nalls, Michael A; Smith, Erin N; Tanaka, Toshiko; Li, Guo; Buxbaum, Sarah G; Whitsel, Eric A; Alonso, Alvaro; Arking, Dan E; Benjamin, Emelia J; Berenson, Gerald S; Bis, Josh C; Chen, Wei; Deo, Rajat; Ellinor, Patrick T; Heckbert, Susan R; Heiss, Gerardo; Hsueh, Wen-Chi; Keating, Brendan J; Kerr, Kathleen F; Li, Yun; Limacher, Marian C; Liu, Yongmei; Lubitz, Steven A; Marciante, Kristin D; Mehra, Reena; Meng, Yan A; Newman, Anne B; Newton-Cheh, Christopher; North, Kari E; Palmer, Cameron D; Psaty, Bruce M; Quibrera, P Miguel; Redline, Susan; Reiner, Alex P; Rotter, Jerome I; Schnabel, Renate B; Schork, Nicholas J; Singleton, Andrew B; Smith, J Gustav; Soliman, Elsayed Z; Srinivasan, Sathanur R; Zhang, Zhu-ming; Zonderman, Alan B; Ferrucci, Luigi; Murray, Sarah S; Evans, Michele K; Sotoodehnia, Nona; Magnani, Jared W; Avery, Christy L
BACKGROUND:The PR interval, as measured by the resting, standard 12-lead ECG, reflects the duration of atrial/atrioventricular nodal depolarization. Substantial evidence exists for a genetic contribution to PR, including genome-wide association studies that have identified common genetic variants at 9 loci influencing PR in populations of European and Asian descent. However, few studies have examined loci associated with PR in African Americans. METHODS AND RESULTS/RESULTS:We present results from the largest genome-wide association study to date of PR in 13 415 adults of African descent from 10 cohorts. We tested for association between PR (ms) and ≈2.8 million genotyped and imputed single-nucleotide polymorphisms. Imputation was performed using HapMap 2 YRI and CEU panels. Study-specific results, adjusted for global ancestry and clinical correlates of PR, were meta-analyzed using the inverse variance method. Variation in genome-wide test statistic distributions was noted within studies (λ range: 0.9-1.1), although not after genomic control correction was applied to the overall meta-analysis (λ: 1.008). In addition to generalizing previously reported associations with MEIS1, SCN5A, ARHGAP24, CAV1, and TBX5 to African American populations at the genome-wide significance level (P<5.0 × 10(-8)), we also identified a novel locus: ITGA9, located in a region previously implicated in SCN5A expression. The 3p21 region harboring SCN5A also contained 2 additional independent secondary signals influencing PR (P<5.0 × 10(-8)). CONCLUSIONS:This study demonstrates the ability to map novel loci in African Americans as well as the generalizability of loci associated with PR across populations of African, European, and Asian descent.
PMCID:3560365
PMID: 23139255
ISSN: 1942-3268
CID: 5477942
Gene-centric meta-analysis of lipid traits in African, East Asian and Hispanic populations
Elbers, Clara C; Guo, Yiran; Tragante, Vinicius; van Iperen, Erik P A; Lanktree, Matthew B; Castillo, Berta Almoguera; Chen, Fang; Yanek, Lisa R; Wojczynski, Mary K; Li, Yun R; Ferwerda, Bart; Ballantyne, Christie M; Buxbaum, Sarah G; Chen, Yii-Der Ida; Chen, Wei-Min; Cupples, L Adrienne; Cushman, Mary; Duan, Yanan; Duggan, David; Evans, Michele K; Fernandes, Jyotika K; Fornage, Myriam; Garcia, Melissa; Garvey, W Timothy; Glazer, Nicole; Gomez, Felicia; Harris, Tamara B; Halder, Indrani; Howard, Virginia J; Keller, Margaux F; Kamboh, M Ilyas; Kooperberg, Charles; Kritchevsky, Stephen B; LaCroix, Andrea; Liu, Kiang; Liu, Yongmei; Musunuru, Kiran; Newman, Anne B; Onland-Moret, N Charlotte; Ordovas, Jose; Peter, Inga; Post, Wendy; Redline, Susan; Reis, Steven E; Saxena, Richa; Schreiner, Pamela J; Volcik, Kelly A; Wang, Xingbin; Yusuf, Salim; Zonderland, Alan B; Anand, Sonia S; Becker, Diane M; Psaty, Bruce; Rader, Daniel J; Reiner, Alex P; Rich, Stephen S; Rotter, Jerome I; Sale, Michèle M; Tsai, Michael Y; Borecki, Ingrid B; Hegele, Robert A; Kathiresan, Sekar; Nalls, Michael A; Taylor, Herman A; Hakonarson, Hakon; Sivapalaratnam, Suthesh; Asselbergs, Folkert W; Drenos, Fotios; Wilson, James G; Keating, Brendan J
Meta-analyses of European populations has successfully identified genetic variants in over 100 loci associated with lipid levels, but our knowledge in other ethnicities remains limited. To address this, we performed dense genotyping of ∼2,000 candidate genes in 7,657 African Americans, 1,315 Hispanics and 841 East Asians, using the IBC array, a custom ∼50,000 SNP genotyping array. Meta-analyses confirmed 16 lipid loci previously established in European populations at genome-wide significance level, and found multiple independent association signals within these lipid loci. Initial discovery and in silico follow-up in 7,000 additional African American samples, confirmed two novel loci: rs5030359 within ICAM1 is associated with total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) (p = 8.8×10(-7) and p = 1.5×10(-6) respectively) and a nonsense mutation rs3211938 within CD36 is associated with high-density lipoprotein cholesterol (HDL-C) levels (p = 13.5×10(-12)). The rs3211938-G allele, which is nearly absent in European and Asian populations, has been previously found to be associated with CD36 deficiency and shows a signature of selection in Africans and African Americans. Finally, we have evaluated the effect of SNPs established in European populations on lipid levels in multi-ethnic populations and show that most known lipid association signals span across ethnicities. However, differences between populations, especially differences in allele frequency, can be leveraged to identify novel signals, as shown by the discovery of ICAM1 and CD36 in the current report.
PMCID:3517599
PMID: 23236364
ISSN: 1932-6203
CID: 5477962
Examination of genetic variants influencing lipid traits in pediatric populations
Wang, Kai; Zhang, Haitao; Mentch, Frank D; Bradfield, Jonathan P; Glessner, Joseph T; Qiu, Haijun; Guo, Yiran; Hou, Cuiping; Frackelton, Edward C; Thomas, Kelly; Bender, Amber; Albano, Anthony; Otieno, George; Garris, Maria; Seidler, Kallyn; Moy, Alexander; Kim, Cecilia E; Keating, Brendan; Chiavacci, Rosetta M; Grundmeier, Robert; Sleiman, Patrick A; Grant, Struan F A; Hakonarson, Hakon
Previous large-scale genome-wide association studies in adult populations have implicated ∽100 loci in determining high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, or triglyceride levels. However, whether these loci also contribute to variations of lipid traits in pediatric populations remain unknown. Here we assayed a population of Philadelphia children by high-density single nucleotide polymorphism arrays, and performed association analysis on lipid traits ascertained from lipid measurements stored in electronic medical records. We examined previously reported lipid trait associations, and found that most of them show identical direction of association in our pediatric cohorts, including genome-wide significant association on cholesteryl ester transfer protein with HDL-C levels (rs3764261, P = 2.1 × 10(-8)) and other significant associations on oxysterol-binding protein-like protein 7, low-density lipoprotein receptor-related protein 4 and low-density lipoprotein receptor-related protein 1. Additionally, we identified suggestive association on low-density lipoprotein receptor-related protein 1B with HDL-C levels (rs17736712, P = 2.1 × 10(-7)), but this signal is not supported by previous meta-analysis on adult cohorts. Finally, we examined rare copy number variants and identified deletions encompassing tetratricopeptide repeat domain 39B in two children with extreme lipid measures. Our results highlight the commonalities and differences of genetic components in determining lipid traits in pediatric versus adult populations. Furthermore, our study demonstrates the unique utility of automated information retrieval from electronic medical records in facilitating the identification of genotype-phenotype associations.
PMCID:5020926
PMID: 27625808
ISSN: 2146-4596
CID: 5478512
Large-Scale Gene-Centric Meta-Analysis across 39 Studies Identifies Type 2 Diabetes Loci (vol 90, pg 410, 2012) [Correction]
Saxena, Richa; Elbers, Clara C.; Guo, Yiran; Peter, Inga; Gaunt, Tom R.; Mega, Jessica L.; Lanktree, Matthew B.; Tare, Archana; Castillo, Berta Almoguera; Li, Yun R.; Johnson, Toby; Bruinenberg, Marcel; Gilbert-Diamond, Diane; Rajagopalan, Ramakrishnan; Voight, Benjamin F.; Balasubramanyam, Ashok; Barnard, John; Bauer, Florianne; Baumert, Jens; Bhangale, Tushar; Boehm, Bernhard O.; Braund, Peter S.; Burton, Paul R.; Chandrupatla, Hareesh R.; Clarke, Robert; Cooper-DeHoff, Rhonda M.; Crook, Errol D.; Davey-Smith, George; Day, Ian N.; de Boer, Anthonius; de Groot, Mark C. H.; Drenos, Fotios; Ferguson, Jane; Fox, Caroline S.; Furlong, Clement E.; Gibson, Quince; Gieger, Christian; Gilhuijs-Pederson, Lisa A.; Glessner, Joseph T.; Goel, Anuj; Gong, Yan; Grant, Struan F. A.; Grobbee, Diederick E.; Hastie, Claire; Humphries, Steve E.; Kim, Cecilia E.; Kivimaki, Mika; Kleber, Marcus; Meisinger, Christa; Kumari, Meena; Langaee, Taimour Y.; Lawlor, Debbie A.; Li, Mingyao; Lobmeyer, Maximilian T.; Maitland-van der Zee, Anke-Hilse; Meijs, Matthijs F. L.; Molony, Cliona M.; Morrow, David A.; Murugesan, Gurunathan; Musani, Solomon K.; Nelson, Christopher P.; Newhouse, Stephen J.; O\Connell, Jeffery R.; Padmanabhan, Sandosh; Palmen, Jutta; Patel, Sanjey R.; Pepine, Carl J.; Pettinger, Mary; Price, Thomas S.; Rafelt, Suzanne; Ranchalis, Jane; Rasheed, Asif; Rosenthal, Elisabeth; Ruczinski, Ingo; Shah, Sonia; Shen, Haiqing; Silbernagel, Guenther; Smith, Erin N.; Spijkerman, Annemieke W. M.; Stanton, Alice; Steffes, Michael W.; Thorand, Barbara; Trip, Mieke; van der Harst, Pim; van der A, Daphne L.; van Iperen, Erik P. A.; van Setten, Jessica; van Vliet-Ostaptchouk, Jana V.; Verweij, Niek; Wolffenbuttel, Bruce H. R.; Young, Taylor; Zafarmand, M. Hadi; Zmuda, Joseph M.; Boehnke, Michael; Altshuler, David; McCarthy, Mark; Kao, W. H. Linda; Pankow, James S.; Cappola, Thomas P.; Sever, Peter; Poulter, Neil; Caulfield, Mark; Dominiczak, Anna; Shields, Denis C.; Bhatt, Deepak L.; Zhang, Li; Curtis, Sean P.; Danesh, John; Casas, Juan P.; van der Schouw, Yvonne T.; Onland-Moret, N. Charlotte; Doevendans, Pieter A.; Dorn, Gerald W., II; Farrall, Martin; FitzGerald, Garret A.; Hegele, Anders Hamsten Robert; Hingorani, Aroon D.; Hofker, Marten H.; Huggins, Gordon S.; Illig, Thomas; Jarvik, Gail P.; Johnson, Julie A.; Klungel, Olaf H.; Knowler, William C.; Koenig, Wolfgang; Maerz, Winfried; Meigs, James B.; Melander, Olle; Munroe, Patricia B.; Mitchell, Braxton D.; Bielinski, Susan J.; Rader, Daniel J.; Reilly, Muredach R.; Rich, Stephen S.; Rotter, Jerome I.; Saleheen, Danish; Samani, Nilesh J.; Schadt, Eric E.; Shuldiner, Alan R.; Silverstein, Roy; Kottke-Marchant, Kandice; Talmud, Philippa J.; Watkins, Hugh; Asselbergs, Folkert W.; de Bakker, Paul I. W.; McCaffery, Jeanne; Wijmenga, Cisca; Sabatine, Marc S.; Wilson, James G.; Reiner, Alex; Bowden, Donald W.; Hakonarson, Hakon; Siscovick, David S.; Keating, Brendan J.
ISI:000302833400022
ISSN: 0002-9297
CID: 5479082
Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height (vol 88, pg 6, 2010) [Correction]
Lanktree, Matthew B.; Guo, Yiran; Murtaza, Muhammed; Glessner, Joseph T.; Bailey, Swneke D.; Onland-Moret, N. Charlotte; Lettre, Guillaume; Ongen, Halit; Rajagopalan, Ramakrishnan; Johnson, Toby; Shen, Haiqing; Nelson, Christopher P.; Klopp, Norman; Baumert, Jens; Padmanabhan, Sandosh; Pankratz, Nathan; Pankow, James S.; Shah, Sonia; Taylor, Kira; Barnard, John; Peters, Bas J.; Maloney, Cliona M.; Lobmeyer, Maximilian T.; Stanton, Alice; Zafarmand, M. Hadi; Romaine, Simon P. R.; Mehta, Amar; van Iperen, Erik P. A.; Gong, Yan; Price, Tom S.; Smith, Erin N.; Kim, Cecilia E.; Li, Yun R.; Asselbergs, Folkert W.; Atwood, Larry D.; Bailey, Kristian M.; Bhatt, Deepak; Bauer, Florianne; Behr, Elijah R.; Bhangale, Tushar; Boer, Jolanda M. A.; Boehm, Bernhard O.; Bradfield, Jonathan P.; Brown, Morris; Braund, Peter S.; Burton, Paul R.; Carty, Cara; Chandrupatla, Hareesh R.; Chen, Wei; Connell, John; Dalgeorgou, Chrysoula; de Boer, Anthonius; Drenos, Fotios; Elbers, Clara C.; Fang, James C.; Fox, Caroline S.; Frackelton, Edward C.; Fuchs, Barry; Furlong, Clement E.; Gibson, Quince; Gieger, Christian; Goel, Anuj; Grobbee, Diederik E.; Hastie, Claire; Howard, Philip J.; Huang, Guan-Hua; Johnson, W. Craig; Li, Oing; Kleber, Marcus E.; Klein, Barbara E. K.; Klein, Ronald; Kooperberg, Charles; Ky, Bonnie; LaCroix, Andrea; Lanken, Paul; Lathrop, Mark; Li, Mingyao; Marshall, Vanessa; Melander, Olle; Mentch, Frank D.; Meyer, Nuala J.; Monda, Ken I. L.; Montpetit, Alexandre; Murugesan, Gurunathan; Nakayama, Karen; Nondahl, Dave; Onipinla, Abiodun; Rafelt, Suzanne; Newhouse, Stephen J.; Otieno, F. George; Patel, Sanjey R.; Putt, Mary E.; Rodriguez, Santiago; Safa, Radwan N.; Sawyer, Douglas B.; Schreiner, Pamela J.; Simpson, Claire; Sivapalaratnam, Suthesh; Srinivasan, Sathanur R.; Suver, Christine; Swergold, Gary; Sweitzer, Nancy K.; Thomas, Kelly A.; Thorand, Barbara; Timpson, Nicholas J.; Tischfield, Sam; Tobin, Martin; Tomaszewski, Maciej; Verschuren, W. M. Monique; Wallace, Chris; Winkelmann, Bernhard; Zhang, Haitao; Zheng, Dongling; Zhang, Li; Zmuda, Joseph M.; Clarke, Robert; Balmforth, Anthony J.; Danesh, John; Day, Ian N.; Schork, Nicholas J.; de Bakker, Paul I. W.; Delles, Christian; Duggan, David; Hingorani, Aroon D.; Hirschhorn, Joel N.; Hofker, Marten H.; Humphries, Steve E.; Kivimaki, Mika; Lawlor, Debbie A.; Kottke-Marchant, Kandice; Mega, Jessica L.; Mitchell, Braxton D.; Morrow, David A.; Palmen, Jutta; Redline, Susan; Shields, Denis C.; Shuldiner, Alan R.; Sleiman, Patrick M.; Smith, George Davey; Farrall, Martin; Jamshidi, Yalda; Christiani, David C.; Casas, Juan P.; Hall, Alistair S.; Doevendans, Pieter A.; Christie, Jason D.; Berenson, Gerald S.; Murray, Sarah S.; Illig, Thomas; Dorn, Gerald W.; Cappola, Thomas P.; Boerwinkle, Eric; Sever, Peter; Rader, Daniel J.; Reilly, Muredach P.; Caulfield, Mark; Talmud, Philippa J.; Topol, Eric; Engert, James C.; Wang, Kai; Dominiczak, Anna; Hamsten, Anders; Curtis, Sean P.; Silverstein, Roy L.; Lange, Leslie A.; Sabatine, Marc S.; Trip, Mieke; Saleheen, Danish; Peden, John F.; Cruickshanks, Karen J.; Maerz, Winfried; O\Connell, Jeffrey R.; Klungel, Olaf H.; Wijmenga, Cisca; Maitland-van der Zee, Anke Hilse; Schadt, Eric E.; Johnson, Julie A.; Jarvik, Gail P.; Papanicolaou, George J.; Watkins, Hugh; Grant, Struan F. A.; Munroe, Patricia B.; North, Karl E.; Samani, Nilesh J.; Koenig, Wolfgang; Gaunt, Tom R.; Anand, Sonia S.; van der Schouw, Yvonne T.; Kumari, Meena; Soranzo, Nicole; FitzGerald, Garret A.; Reiner, Alex; Hegele, Robert A.; Hakonarson, Hakon; Keating, Brendan J.
ISI:000305262600018
ISSN: 0002-9297
CID: 5479092
Large-scale gene-centric analysis identifies novel variants for coronary artery disease
Butterworth, Adam S; Braund, Peter S; Farrall, Martin; Hardwick, Robert J; Saleheen, Danish; Peden, John F; Soranzo, Nicole; Chambers, John C; Sivapalaratnam, Suthesh; Kleber, Marcus E; Keating, Brendan; Qasim, Atif; Klopp, Norman; Erdmann, Jeanette; Assimes, Themistocles L; Ball, Stephen G; Balmforth, Anthony J; Barnes, Timothy A; Basart, Hanneke; Baumert, Jens; Bezzina, Connie R; Boerwinkle, Eric; Boehm, Bernhard O; Brocheton, Jessy; Bugert, Peter; Cambien, Francois; Clarke, Robert; Codd, Veryan; Collins, Rory; Couper, David; Cupples, L Adrienne; de Jong, Jonas S; Diemert, Patrick; Ejebe, Kenechi; Elbers, Clara C; Elliott, Paul; Fornage, Myriam; Franzosi, Maria-Grazia; Frossard, Philippe; Garner, Stephen; Goel, Anuj; Goodall, Alison H; Hengstenberg, Christian; Hunt, Sarah E; Kastelein, John J P; Klungel, Olaf H; Klüter, Harald; Koch, Kerstin; König, Inke R; Kooner, Angad S; Laaksonen, Reijo; Lathrop, Mark; Li, Mingyao; Liu, Kiang; McPherson, Ruth; Musameh, Muntaser D; Musani, Solomon; Nelson, Christopher P; O'Donnell, Christopher J; Ongen, Halit; Papanicolaou, George; Peters, Annette; Peters, Bas J M; Potter, Simon; Psaty, Bruce M; Qu, Liming; Rader, Daniel J; Rasheed, Asif; Rice, Catherine; Scott, James; Seedorf, Udo; Sehmi, Joban S; Sotoodehnia, Nona; Stark, Klaus; Stephens, Jonathan; van der Schoot, C Ellen; van der Schouw, Yvonne T; Thorsteinsdottir, Unnur; Tomaszewski, Maciej; van der Harst, Pim; Vasan, Ramachandran S; Wilde, Arthur A M; Willenborg, Christina; Winkelmann, Bernhard R; Zaidi, Moazzam; Zhang, Weihua; Ziegler, Andreas; de Bakker, Paul I W; Koenig, Wolfgang; Mätz, Winfried; Trip, Mieke D; Reilly, Muredach P; Kathiresan, Sekar; Schunkert, Heribert; Hamsten, Anders; Hall, Alistair S; Kooner, Jaspal S; Thompson, Simon G; Thompson, John R; Deloukas, Panos; Ouwehand, Willem H; Watkins, Hugh; Danesh, John; Samani, Nilesh J; Barnes, Timothy; Rafelt, Suzanne; Codd, Veryan; Tomaszewski, Maciej; Ouwehand, Willem H; Bruinsma, Nienke; Dekker, Lukas R; Henriques, José P; Koch, Karel T; de Winter, Robbert J; Alings, Marco; Allaart, Cor F; Gorgels, Anton P; Verheugt, Freek W; Braund, Peter S; Thompson, John R; Samani, Nilesh J; Mueller, Martina; Meisinger, Christa; DerOhannessian, Stephanie; Mehta, Nehal N; Ferguson, Jane; Hakonarson, Hakon; Matthai, William; Wilensky, Robert; Hopewell, J C; Parish, S; Linksted, P; Notman, J; Gonzalez, H; Young, A; Ostley, T; Munday, A; Goodwin, N; Verdon, V; Shah, S; Cobb, L; Edwards, C; Mathews, C; Gunter, R; Benham, J; Davies, C; Cobb, M; Cobb, L; Crowther, J; Richards, A; Silver, M; Tochlin, S; Mozley, S; Clark, S; Radley, M; Kourellias, K; Silveira, Angela; Söderholm, Birgitta; Olsson, Per; Barlera, Simona; Tognoni, Gianni; Rust, Stephan; Assmann, Gerd; Heath, Simon; Zelenika, Diana; Gut, Ivo; Green, Fiona; Farrall, Martin; Peden, John; Goel, Anuj; Ongen, Halit; Franzosi, Maria-Grazia; Lathrop, Mark; Seedorf, Udo; Clarke, Robert; Collins, Rory; Hamsten, Anders; Watkins, Hugh; Aly, Anette; Anner, Karolina; Björklund, Karin; Blomgren, Gun; Cederschiöld, Barbro; Danell-Toverud, Karin; Eriksson, Per; Grundstedt, Ulla; Hamsten, Anders; Heinonen, Merja; Hellénius, Mai-Lis; van't Hooft, Ferdinand; Husman, Karin; Lagercrantz, Jacob; Larsson, Anita; Larsson, Malin; Mossfeldt, Magnus; Mälarstig, Anders; Olsson, Gunnar; Sabater-Lleal, Maria; Sennblad, Bengt; Silveira, Angela; Strawbridge, Rona; Söderholm, Birgitta; Öhrvik, John; Zaman, Khan Shah; Mallick, Nadeem Hayat; Azhar, Muhammad; Samad, Abdus; Ishaq, Mohammad; Shah, Nabi; Samuel, Maria; Schunkert, Heribert; König, Inke R; Kathiresan, Sekar; Reilly, Muredach; Assimes, Themistocles L; Holm, Hilma; Preuss, Michael; Stewart, Alexandre F R; Barbalic, Maja; Gieger, Christian; Absher, Devin; Aherrahrou, Zouhair; Allayee, Hooman; Altshuler, David; Anand, Sonia; Andersen, Karl; Anderson, Jeffrey L; Ardissino, Diego; Ball, Stephen G; Balmforth, Anthony J; Barnes, Timothy A; Becker, Lewis C; Becker, Diane M; Berger, Klaus; Bis, Joshua C; Boekholdt, S Matthijs; Boerwinkle, Eric; Braund, Peter S; Brown, Morris J; Burnett, Mary Susan; Buysschaert, Ian; Carlquist, John F; Chen, Li; Codd, Veryan; Davies, Robert W; Dedoussis, George; Dehghan, Abbas; Demissie, Serkalem; Devaney, Joseph; Do, Ron; Doering, Angela; El Mokhtari, Nour Eddine; Ellis, Stephen G; Elosua, Roberto; Engert, James C; Epstein, Stephen; de Faire, Ulf; Fischer, Marcus; Folsom, Aaron R; Freyer, Jennifer; Gigante, Bruna; Girelli, Domenico; Gretarsdottir, Solveig; Gudnason, Vilmundur; Gulcher, Jeffrey R; Tennstedt, Stephanie; Halperin, Eran; Hammond, Naomi; Hazen, Stanley L; Hofman, Albert; Horne, Benjamin D; Illig, Thomas; Iribarren, Carlos; Jones, Gregory T; Jukema, J Wouter; Kaiser, Michael A; Kaplan, Lee M; Kastelein, John J P; Khaw, Kay-Tee; Knowles, Joshua W; Kolovou, Genovefa; Kong, Augustine; Laaksonen, Reijo; Lambrechts, Diether; Leander, Karin; Li, Mingyao; Lieb, Wolfgang; Diemert, Patrick; Lettre, Guillaume; Loley, Christina; Lotery, Andrew J; Mannucci, Pier M; Maouche, Seraya; Martinelli, Nicola; McKeown, Pascale P; Meisinger, Christa; Meitinger, Thomas; Melander, Olle; Merlini, Pier Angelica; Mooser, Vincent; Morgan, Thomas; Mühleisen, Thomas W; Muhlestein, Joseph B; Musunuru, Kiran; Nahrstaedt, Janja; Nelson, Christopher P; Nöthen, Markus M; Olivieri, Oliviero; Peyvandi, Flora; Patel, Riyaz S; Patterson, Chris C; Peters, Annette; Qu, Liming; Quyyumi, Arshed A; Rader, Daniel J; Rallidis, Loukianos S; Rice, Catherine; Rosendaal, Frits R; Rubin, Diana; Salomaa, Veikko; Sampietro, M Lourdes; Sandhu, Manj S; Schadt, Eric; Schäfer, Arne; Schillert, Arne; Schreiber, Stefan; Schrezenmeir, Jürgen; Schwartz, Stephen M; Siscovick, David S; Sivananthan, Mohan; Sivapalaratnam, Suthesh; Smith, Albert V; Smith, Tamara B; Snoep, Jaapjan D; Soranzo, Nicole; Spertus, John A; Stark, Klaus; Stefansson, Kari; Stirrups, Kathy; Stoll, Monika; Tang, W H Wilson; Thorgeirsson, Gudmundur; Thorleifsson, Gudmar; Tomaszewski, Maciej; Uitterlinden, Andre G; van Rij, Andre M; Voight, Benjamin F; Wareham, Nick J; AWells, George; Wichmann, H-Erich; Willenborg, Christina; Witteman, Jaqueline C M; Wright, Benjamin J; Ye, Shu; Ziegler, Andreas; Cambien, Francois; Goodall, Alison H; Cupples, L Adrienne; Quertermous, Thomas; März, Winfried; Hengstenberg, Christian; Blankenberg, Stefan; Ouwehand, Willem H; Hall, Alistair S; Deloukas, Panos; Thorsteinsdottir, Unnur; Roberts, Robert; Thompson, John R; O'Donnell, Christopher J; McPherson, Ruth; Erdmann, Jeanette; Samani, Nilesh J; Onland-Moret, N Charlotte; van Setten, Jessica; de Bakker, Paul I W; Verschuren, W M Monique; Boer, Jolanda M A; Wijmenga, Cisca; Hofker, Marten H; Maitland-van der Zee, Anke-Hilse; de Boer, Anthonius; Grobbee, Diederick E; Attwood, Tony; Belz, Stephanie; Braund, Peter; Cambien, François; Cooper, Jason; Crisp-Hihn, Abi; Diemert, Patrick; Deloukas, Panos; Foad, Nicola; Erdmann, Jeanette; Goodall, Alison H; Gracey, Jay; Gray, Emma; Gwilliams, Rhian; Heimerl, Susanne; Hengstenberg, Christian; Jolley, Jennifer; Krishnan, Unni; Lloyd-Jones, Heather; Lugauer, Ingrid; Lundmark, Per; Maouche, Seraya; Moore, Jasbir S; Muir, David; Murray, Elizabeth; Nelson, Chris P; Neudert, Jessica; Niblett, David; O'Leary, Karen; Ouwehand, Willem H; Pollard, Helen; Rankin, Angela; Rice, Catherine M; Sager, Hendrik; Samani, Nilesh J; Sambrook, Jennifer; Schmitz, Gerd; Scholz, Michael; Schroeder, Laura; Schunkert, Heribert; Syvannen, Ann-Christine; Tennstedt, Stephanie; Wallace, Chris
Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. We examined 49,094 genetic variants in ∼2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin). We attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. Potential mechanisms through which the novel variants could affect CAD risk were explored through association tests with vascular risk factors and gene expression. We confirmed associations of several previously known CAD susceptibility loci (eg, 9p21.3:p<10(-33); LPA:p<10(-19); 1p13.3:p<10(-17)) as well as three recently discovered loci (COL4A1/COL4A2, ZC3HC1, CYP17A1:p<5×10(-7)). However, we found essentially null results for most previously suggested CAD candidate genes. In our replication study of 24 promising common variants, we identified novel associations of variants in or near LIPA, IL5, TRIB1, and ABCG5/ABCG8, with per-allele odds ratios for CAD risk with each of the novel variants ranging from 1.06-1.09. Associations with variants at LIPA, TRIB1, and ABCG5/ABCG8 were supported by gene expression data or effects on lipid levels. Apart from the previously reported variants in LPA, none of the other ∼4,500 low frequency and functional variants showed a strong effect. Associations in South Asians did not differ appreciably from those in Europeans, except for 9p21.3 (per-allele odds ratio: 1.14 versus 1.27 respectively; P for heterogeneity = 0.003). This large-scale gene-centric analysis has identified several novel genes for CAD that relate to diverse biochemical and cellular functions and clarified the literature with regard to many previously suggested genes.
PMID: 21966275
ISSN: 1553-7404
CID: 5479352
Association of genomic loci from a cardiovascular gene SNP array with fibrinogen levels in European Americans and African-Americans from six cohort studies: the Candidate Gene Association Resource (CARe)
Wassel, Christina L; Lange, Leslie A; Keating, Brendan J; Taylor, Kira C; Johnson, Andrew D; Palmer, Cameron; Ho, Lindsey A; Smith, Nicholas L; Lange, Ethan M; Li, Yun; Yang, Qiong; Delaney, Joseph A; Tang, Weihong; Tofler, Geoffrey; Redline, Susan; Taylor, Herman A; Wilson, James G; Tracy, Russell P; Jacobs, David R; Folsom, Aaron R; Green, David; O'Donnell, Christopher J; Reiner, Alexander P
Several common genomic loci, involving various immunity- and metabolism-related genes, have been associated with plasma fibrinogen in European Americans (EAs). The genetic determinants of fibrinogen in African Americans (AAs) are poorly characterized. Using a vascular gene-centric array in 23,634 EA and 6657 AA participants from 6 studies comprising the Candidate Gene Association Resource project, we examined the association of 47,539 common and lower frequency variants with fibrinogen concentration. We identified a rare Pro265Leu variant in FGB (rs6054) associated with lower fibrinogen. Common fibrinogen gene single nucleotide polymorphisms (FGB rs1800787 and FGG rs2066861) significantly associated with fibrinogen in EAs were prevalent in AAs and showed consistent associations. Several fibrinogen locus single nucleotide polymorphism associated with lower fibrinogen were exclusive to AAs; these include a newly reported association with FGA rs10050257. For IL6R, IL1RN, and NLRP3 inflammatory gene loci, associations with fibrinogen were concordant between EAs and AAs, but not at other loci (CPS1, PCCB, and SCL22A5-IRF1). The association of FGG rs2066861 with fibrinogen differed according to assay type used to measure fibrinogen. Further characterization of common and lower-frequency genetic variants that contribute to interpopulation differences in fibrinogen phenotype may help refine our understanding of the contribution of hemostasis and inflammation to atherothrombotic risk.
PMCID:3037748
PMID: 20978265
ISSN: 1528-0020
CID: 5477792
Genetic association analysis highlights new loci that modulate hematological trait variation in Caucasians and African Americans
Lo, Ken Sin; Wilson, James G; Lange, Leslie A; Folsom, Aaron R; Galarneau, Geneviève; Ganesh, Santhi K; Grant, Struan F A; Keating, Brendan J; McCarroll, Steven A; Mohler, Emile R; O'Donnell, Christopher J; Palmas, Walter; Tang, Weihong; Tracy, Russell P; Reiner, Alexander P; Lettre, Guillaume
Red blood cell, white blood cell, and platelet measures, including their count, sub-type and volume, are important diagnostic and prognostic clinical parameters for several human diseases. To identify novel loci associated with hematological traits, and compare the architecture of these phenotypes between ethnic groups, the CARe Project genotyped 49,094 single nucleotide polymorphisms (SNPs) that capture variation in ~2,100 candidate genes in DNA of 23,439 Caucasians and 7,112 African Americans from five population-based cohorts. We found strong novel associations between erythrocyte phenotypes and the glucose-6 phosphate dehydrogenase (G6PD) A-allele in African Americans (rs1050828, P<2.0×10(-13), T-allele associated with lower red blood cell count, hemoglobin, and hematocrit, and higher mean corpuscular volume), and between platelet count and a SNP at the tropomyosin-4 (TPM4) locus (rs8109288, P=3.0×10(-7) in Caucasians; P=3.0×10(-7) in African Americans, T-allele associated with lower platelet count). We strongly replicated many genetic associations to blood cell phenotypes previously established in Caucasians. A common variant of the α-globin (HBA2-HBA1) locus was associated with red blood cell traits in African Americans, but not in Caucasians (rs1211375, P<7×10(-8), A-allele associated with lower hemoglobin, mean corpuscular hemoglobin, and mean corpuscular volume). Our results show similarities but also differences in the genetic regulation of hematological traits in European- and African-derived populations, and highlight the role of natural selection in shaping these differences.
PMCID:3442357
PMID: 21153663
ISSN: 1432-1203
CID: 5477802
