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3. Cross-ancestry investigation of venousc genomic predictors

Author

Thibord, F., Klarin, D., Brody, J.A., Chen, M.H., Levin, M.G., Chasman, D.I., Goode, E.L., Hveem, K., Teder-Laving, M., Martinez-Perez, A., Aissi, D., Daian-Bacq, D., Ito, K., Natarajan, P., Lutsey, P.L., Nadkarni, G.N., Vries, P.S. de, Cuellar-Partida, G., Wolford, B.N., Pattee, J.W., Kooperberg, C., Braekkan, S.K., Li-Gao, R.F., Saut, N., Sept, C., Germain, M., Judy, R.L., Wiggins, K.L., Ko, D., O'Donnell, C.J., Taylor, K.D., Giulianini, F., Andrade, M. de, Nost, T.H., Boland, A., Empana, J.P., Koyama, S., Gilliland, T., R. do, Huffman, J.E., Wang, X., Zhou, W., Soria, J.M., Souto, J.C., Pankratz, N., Haessler, J., Hindberg, K., Rosendaal, F.R., Turman, C., Olaso, R., Kember, R.L., Bartz, T.M., Lynch, J.A., Heckbert, S.R., Armasu, S.M., Brumpton, B., Smadja, D.M., Jouven, X., Komuro, I., Clapham, K.R., Loos, R.J.F., Willer, C.J., Sabater-Lleal, M., Pankow, J.S., Reiner, A.P., Morelli, V.M., Ridker, P.M., Vlieg, A.V., Deleuze, J.F., Kraft, P., Rader, D.J., Lee, K.M., Psaty, B.M., Skogholt, A.H., Emmerich, J., Suchon, P., Rich, S.S., Vy, H.T., Tang, W.H., Jackson, R.D., Hansen, J.B., Morange, P.E., Kabrhel, C., Tregouet, D.A., Damrauer, S.M., Johnson, A.D., and Smith, N.L.

Subjects
meta-analysis, genome-wide association study, venous thromboembolism, genetics, venous thrombosis
Abstract

Background: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources. Methods: We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations. Results: In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis. Conclusions: Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.

Published
2022

8. Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging.

Author

McCartney D.L., Min J.L., Richmond R.C., Lu A.T., Sobczyk M.K., Davies G., Broer L., Guo X., Jeong A., Jung J., Kasela S., Katrinli S., Kuo P.-L., Matias-Garcia P.R., Mishra P.P., Nygaard M., Palviainen T., Patki A., Raffield L.M., Ratliff S.M., Richardson T.G., Robinson O., Soerensen M., Sun D., Tsai P.-C., van der Zee M.D., Walker R.M., Wang X., Wang Y., Xia R., Xu Z., Yao J., Zhao W., Correa A., Boerwinkle E., Dugue P.-A., Durda P., Elliott H.R., Gieger C., de Geus E.J.C., Harris S.E., Hemani G., Imboden M., Kahonen M., Kardia S.L.R., Kresovich J.K., Li S., Lunetta K.L., Mangino M., Mason D., McIntosh A.M., Mengel-From J., Moore A.Z., Murabito J.M., Ollikainen M., Pankow J.S., Pedersen N.L., Peters A., Polidoro S., Porteous D.J., Raitakari O., Rich S.S., Sandler D.P., Sillanpaa E., Smith A.K., Southey M.C., Strauch K., Tiwari H., Tanaka T., Tillin T., Uitterlinden A.G., Van Den Berg D.J., van Dongen J., Wilson J.G., Wright J., Yet I., Arnett D., Bandinelli S., Bell J.T., Binder A.M., Boomsma D.I., Chen W., Christensen K., Conneely K.N., Elliott P., Ferrucci L., Fornage M., Hagg S., Hayward C., Irvin M., Kaprio J., Lawlor D.A., Lehtimaki T., Lohoff F.W., Milani L., Milne R.L., Probst-Hensch N., Reiner A.P., Ritz B., Rotter J.I., Smith J.A., Taylor J.A., van Meurs J.B.J., Vineis P., Waldenberger M., Deary I.J., Relton C.L., Horvath S., Marioni R.E., McCartney D.L., Min J.L., Richmond R.C., Lu A.T., Sobczyk M.K., Davies G., Broer L., Guo X., Jeong A., Jung J., Kasela S., Katrinli S., Kuo P.-L., Matias-Garcia P.R., Mishra P.P., Nygaard M., Palviainen T., Patki A., Raffield L.M., Ratliff S.M., Richardson T.G., Robinson O., Soerensen M., Sun D., Tsai P.-C., van der Zee M.D., Walker R.M., Wang X., Wang Y., Xia R., Xu Z., Yao J., Zhao W., Correa A., Boerwinkle E., Dugue P.-A., Durda P., Elliott H.R., Gieger C., de Geus E.J.C., Harris S.E., Hemani G., Imboden M., Kahonen M., Kardia S.L.R., Kresovich J.K., Li S., Lunetta K.L., Mangino M., Mason D., McIntosh A.M., Mengel-From J., Moore A.Z., Murabito J.M., Ollikainen M., Pankow J.S., Pedersen N.L., Peters A., Polidoro S., Porteous D.J., Raitakari O., Rich S.S., Sandler D.P., Sillanpaa E., Smith A.K., Southey M.C., Strauch K., Tiwari H., Tanaka T., Tillin T., Uitterlinden A.G., Van Den Berg D.J., van Dongen J., Wilson J.G., Wright J., Yet I., Arnett D., Bandinelli S., Bell J.T., Binder A.M., Boomsma D.I., Chen W., Christensen K., Conneely K.N., Elliott P., Ferrucci L., Fornage M., Hagg S., Hayward C., Irvin M., Kaprio J., Lawlor D.A., Lehtimaki T., Lohoff F.W., Milani L., Milne R.L., Probst-Hensch N., Reiner A.P., Ritz B., Rotter J.I., Smith J.A., Taylor J.A., van Meurs J.B.J., Vineis P., Waldenberger M., Deary I.J., Relton C.L., Horvath S., and Marioni R.E.

Abstract

Background: Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. Result(s): Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. Conclusion(s): This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.Copyright © 2021, The Author(s).

Published
2021

11. Allelic Heterogeneity at the CRP Locus Identified by Whole-Genome Sequencing in Multi-ancestry Cohorts

Author

Gaynor, S.M., Lee, S., Lee, J., Yanek, L.R., Correa, A., Metcalf, G.A., Rotter, J.I., TOPMed Inflammation Working Group, Kowalski, M.H., Mohlke, K.L., Kral, B.G., Seo, D., Rockville, MD 20850, United States, Dupuis, J., Cruz, P., Bis, J.C., Tracy, R.P., Lange, L.A., Park, C.J., Comellas, A.P., Larson, M.G., Raffield, L.M., Lin, X., Pankratz, N., Polfus, L.M., Jain, D., Gogarten, S.M., Benjamin, E.J., Muzny, D.M., Kim, R.W., Rockville, MD 20850, United States, Zhong, X., Durda, P., Choi, W.J., Mitchell, B.D., Iyengar, A.K., Zhao, L.P., Bowler, R., Rich, S.S., Reiner, A.P., Ryan, K., Spracklen, C.N., Doddapaneni, H., NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Viaud-Martinez, K.A., Wang, B., Momin, Z., Li, B., Laurie, C., Salimi, S., Cade, B.E., Li, Y., Lewis, J.P., and Auer, P.L.

Subjects
Black People, Medical and Health Sciences, Linkage Disequilibrium, White People, Cohort Studies, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Gene Frequency, Asian People, c-reactive protein, Clinical Research, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Polymorphism, Aetiology, Genetics & Heredity, Whole Genome Sequencing, TOPMed Inflammation Working Group, Human Genome, Single Nucleotide, Biological Sciences, Good Health and Well Being, whole-genome sequencing, Genome-Wide Association Study, Biotechnology
Abstract

Whole-genome sequencing (WGS) can improve assessment of low-frequency and rare variants, particularly in non-European populations that have been underrepresented in existing genomic studies. The genetic determinants of C-reactive protein (CRP), a biomarker of chronic inflammation, have been extensively studied, with existing genome-wide association studies (GWASs) conducted in >200,000 individuals of European ancestry. In order to discover novel loci associated with CRP levels, we examined a multi-ancestry population (n = 23,279) with WGS (∼38× coverage) from the Trans-Omics for Precision Medicine (TOPMed) program. We found evidence for eight distinct associations at the CRP locus, including two variants that have not been identified previously (rs11265259 and rs181704186), both of which are non-coding and more common in individuals of African ancestry (∼10% and ∼1% minor allele frequency, respectively, and rare or monomorphic in 1000 Genomes populations of East Asian, South Asian, and European ancestry). We show that the minor (G) allele of rs181704186 is associated with lower CRP levels and decreased transcriptional activity and protein binding invitro, providing a plausible molecular mechanism for this African ancestry-specific signal. The individuals homozygous for rs181704186-G have a mean CRP level of 0.23mg/L, in contrast to individuals heterozygous for rs181704186 with mean CRP of 2.97mg/L and major allele homozygotes with mean CRP of 4.11mg/L. This study demonstrates the utility of WGS in multi-ethnic populations to drive discovery of complex trait associations of large effect and to identify functional alleles in noncoding regulatory regions.

Published
2020

14. The Polygenic and Monogenic Basis of Blood Traits and Diseases

Author

Vuckovic, D. (Dragana), Bao, E.L. (Erik L.), Akbari, P. (Parsa), Lareau, C.A. (Caleb A.), Mousas, A. (Abdou), Jiang, T. (Tao), Chen, M.-H. (Ming-Huei), Raffield, L.M. (Laura M.), Tardaguila, M. (Manuel), Huffman, J.E. (Jennifer E.), Ritchie, S.C. (Scott C.), Megy, K. (Karyn), Ponstingl, H. (Hannes), Penkett, C.J. (Christopher J.), Albers, P.K. (Patrick K.), Wigdor, E.M. (Emilie M.), Sakaue, S. (Saori), Moscati, A. (Arden), Manansala, R. (Regina), Lo, K.S., Qian, H. (Huijun), Akiyama, M. (Masato), Bartz, T.M. (Traci M.), Ben-Shlomo, Y. (Yoav), Beswick, A. (Andrew), Bork-Jensen, J. (Jette), Bottinger, E.P. (Erwin), Brody, J.A. (Jennifer A.), Rooij, F.J.A. (Frank) van, Chitrala, K.N. (Kumaraswamy N.), Wilson, P.W.F. (Peter W.F.), Choquet, H. (Hélène), Danesh, J. (John), Angelantonio, E. (Emanuele) di, Dimou, N. (Niki), Ding, J. (Jingzhong), Elliott, P. (Paul), Esko, T. (Tõnu), Evans, M.K. (Michele), Felix, S.B. (Stephan Burkhard), Floyd, J.S. (James S.), Broer, L. (Linda), Grarup, N. (Niels), Guo, M.H. (Michael H.), Guo, Q. (Qi), Greinacher, A. (Andreas), Haessler, J. (Jeff), Hansen, T. (Torben), Howson, J.M.M. (Joanna M.M.), Huang, W. (Wei), Jorgenson, E. (Eric), Kacprowski, T. (Tim), Kähönen, M. (Mika), Kamatani, Y. (Yoichiro), Kanai, M. (Masahiro), Karthikeyan, S. (Savita), Koskeridis, F. (Fotios), Lange, L.A. (Leslie A.), Lehtimäki, T. (Terho), Linneberg, A. (Allan), Liu, Y. (YongMei), Lyytikäinen, L.-P. (Leo-Pekka), Manichaikul, A. (Ani), Matsuda, K. (Koichi), Mohlke, K.L. (Karen L.), Mononen, N. (Nina), Murakami, Y. (Yoshinori), Nadkarni, G. (Girish), Nikus, K. (Kjell), Pankratz, V.S. (Shane), Pedersen, O. (Oluf), Preuss, M. (Michael), Psaty, B.M. (Bruce), Raitakari, O. (Olli), Rich, S.S. (Stephen), Rodriguez, B.A.T. (Benjamin A.T.), Rosen, J.D. (Jonathan D.), Rotter, J.I. (Jerome I.), Schubert, P. (Petra), Spracklen, C.N. (Cassandra N.), Surendran, P. (Praveen), Tang, H. (Hua), Tardif, J.-C. (Jean-Claude), Ghanbari, M. (Mohsen), Völker, U. (Uwe), Völzke, H. (Henry), Watkins, N.A. (Nicholas A.), Weiss, S. (Stefan), Cai, N. (Na), Kundu, K. (Kousik), Watt, S.B. (Stephen B.), Walter, K. (Klaudia), Zonderman, A.B. (Alan B.), Cho, K. (Kelly), Li, Y. (Yun), Loos, R.J.F. (Ruth), Knight, J.C. (Julian), Georges, M. (Michel), Stegle, O. (Oliver), Evangelou, E. (Evangelos), Okada, Y. (Yukinori), Roberts, D.J. (David J.), Inouye, M. (Michael), Johnson, A.D. (Andrew), Auer, P.L. (Paul L.), Astle, W.J. (William J.), Reiner, A.P. (Alexander P.), Butterworth, A.S. (Adam S.), Ouwehand, W.H. (Willem), Lettre, G. (Guillaume), Sankaran, V.G. (Vijay G.), Soranzo, N. (Nicole), Vuckovic, D. (Dragana), Bao, E.L. (Erik L.), Akbari, P. (Parsa), Lareau, C.A. (Caleb A.), Mousas, A. (Abdou), Jiang, T. (Tao), Chen, M.-H. (Ming-Huei), Raffield, L.M. (Laura M.), Tardaguila, M. (Manuel), Huffman, J.E. (Jennifer E.), Ritchie, S.C. (Scott C.), Megy, K. (Karyn), Ponstingl, H. (Hannes), Penkett, C.J. (Christopher J.), Albers, P.K. (Patrick K.), Wigdor, E.M. (Emilie M.), Sakaue, S. (Saori), Moscati, A. (Arden), Manansala, R. (Regina), Lo, K.S., Qian, H. (Huijun), Akiyama, M. (Masato), Bartz, T.M. (Traci M.), Ben-Shlomo, Y. (Yoav), Beswick, A. (Andrew), Bork-Jensen, J. (Jette), Bottinger, E.P. (Erwin), Brody, J.A. (Jennifer A.), Rooij, F.J.A. (Frank) van, Chitrala, K.N. (Kumaraswamy N.), Wilson, P.W.F. (Peter W.F.), Choquet, H. (Hélène), Danesh, J. (John), Angelantonio, E. (Emanuele) di, Dimou, N. (Niki), Ding, J. (Jingzhong), Elliott, P. (Paul), Esko, T. (Tõnu), Evans, M.K. (Michele), Felix, S.B. (Stephan Burkhard), Floyd, J.S. (James S.), Broer, L. (Linda), Grarup, N. (Niels), Guo, M.H. (Michael H.), Guo, Q. (Qi), Greinacher, A. (Andreas), Haessler, J. (Jeff), Hansen, T. (Torben), Howson, J.M.M. (Joanna M.M.), Huang, W. (Wei), Jorgenson, E. (Eric), Kacprowski, T. (Tim), Kähönen, M. (Mika), Kamatani, Y. (Yoichiro), Kanai, M. (Masahiro), Karthikeyan, S. (Savita), Koskeridis, F. (Fotios), Lange, L.A. (Leslie A.), Lehtimäki, T. (Terho), Linneberg, A. (Allan), Liu, Y. (YongMei), Lyytikäinen, L.-P. (Leo-Pekka), Manichaikul, A. (Ani), Matsuda, K. (Koichi), Mohlke, K.L. (Karen L.), Mononen, N. (Nina), Murakami, Y. (Yoshinori), Nadkarni, G. (Girish), Nikus, K. (Kjell), Pankratz, V.S. (Shane), Pedersen, O. (Oluf), Preuss, M. (Michael), Psaty, B.M. (Bruce), Raitakari, O. (Olli), Rich, S.S. (Stephen), Rodriguez, B.A.T. (Benjamin A.T.), Rosen, J.D. (Jonathan D.), Rotter, J.I. (Jerome I.), Schubert, P. (Petra), Spracklen, C.N. (Cassandra N.), Surendran, P. (Praveen), Tang, H. (Hua), Tardif, J.-C. (Jean-Claude), Ghanbari, M. (Mohsen), Völker, U. (Uwe), Völzke, H. (Henry), Watkins, N.A. (Nicholas A.), Weiss, S. (Stefan), Cai, N. (Na), Kundu, K. (Kousik), Watt, S.B. (Stephen B.), Walter, K. (Klaudia), Zonderman, A.B. (Alan B.), Cho, K. (Kelly), Li, Y. (Yun), Loos, R.J.F. (Ruth), Knight, J.C. (Julian), Georges, M. (Michel), Stegle, O. (Oliver), Evangelou, E. (Evangelos), Okada, Y. (Yukinori), Roberts, D.J. (David J.), Inouye, M. (Michael), Johnson, A.D. (Andrew), Auer, P.L. (Paul L.), Astle, W.J. (William J.), Reiner, A.P. (Alexander P.), Butterworth, A.S. (Adam S.), Ouwehand, W.H. (Willem), Lettre, G. (Guillaume), Sankaran, V.G. (Vijay G.), and Soranzo, N. (Nicole)

Abstract

Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation. Analysis of blood cell traits in the UK Biobank and other cohorts illuminates the full genetic architecture of hematopoietic phenotypes, with evidence supporting the omnigenic model for complex traits and linking polygenic burden with monogenic blood diseases.

Published
2020
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15. Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction

Author

Ntalla, I. (Ioanna), Weng, L.-C., Cartwright, J.H. (James H.), Hall, A.W. (Amelia Weber), Sveinbjornsson, G. (Gardar), Tucker, N.R. (Nathan R.), Choi, S.H. (Seung Hoan), Chaffin, M.D. (Mark D.), Roselli, C. (Carolina), Barnes, M.J. (Michael), Mifsud, B. (Borbala), Warren, H.R. (Helen R.), Hayward, C. (Caroline), Marten, J. (Jonathan), Cranley, J.J. (James J.), Concas, M.P. (Maria Pina), Gasparini, P. (Paolo), Boutin, T. (Thibaud), Kolcic, I. (Ivana), Polasek, O. (Ozren), Rudan, I. (Igor), Araujo, N.M. (Nathalia M.), Lima-Costa, M.F. (Maria Fernanda), Ribeiro, A.L. (Antonio), Souza, R.P. (Renan P.), Tarazona-Santos, E. (Eduardo), Giedraitis, V. (Vilmantas), Ingelsson, E. (Erik), Mahajan, A. (Anubha), Morris, A.P. (Andrew), Del Greco M, F. (Fabiola), Foco, L. (Luisa), Gögele, M. (Martin), Hicks, A.A. (Andrew A.), Cook, J.P. (James P.), Kao, W.H.L. (Wen), Lindgren, C.M. (Cecilia M.), Sundström, J. (Johan), Nelson, C.P. (Christopher P.), Riaz, M.B. (Muhammad B.), Samani, N.J. (Nilesh), Sinagra, G. (Gianfranco), Ulivi, S. (Shelia), Kähönen, M. (Mika), Mishra, P.P. (Pashupati P.), Mononen, N. (Nina), Nikus, K. (Kjell), Caulfield, M. (Mark), Dominiczak, A. (Anna), Padmanabhan, S. (Sandosh), Montasser, M.E. (May E.), O’Connell, J.R. (Jeff R.), Ryan, K. (Kathleen), Shuldiner, A.R. (Alan R.), Aeschbacher, S. (Stefanie), Conen, D. (David), Risch, L. (Lorenz), Thériault, S. (Sébastien), Hutri-Kähönen, N. (Nina), Lehtimäki, T. (Terho), Lyytikäinen, L.-P. (Leo-Pekka), Raitakari, O. (Olli), Barnes, C.L.K. (Catriona L. K.), Campbell, H. (Harry), Joshi, P.K. (Peter), Wilson, J.F. (James), Isaacs, A.J. (Aaron), Kors, J.A. (Jan), Duijn, C.M. (Cornelia) van, Huang, P.L. (Paul L.), Gudnason, V. (Vilmundur), Harris, T.B. (Tamara B.), Launer, L.J. (Lenore), Smith, A.V. (Albert), Bottinger, E.P. (Erwin), Loos, R.J.F. (Ruth), Nadkarni, G. (Girish), Preuss, M. (Michael), Correa, D.D., Mei, H. (Hao), Meitinger, T. (Thomas), Müller-Nurasyid, M. (Martina), Peters, A. (Annette), Waldenberger, M. (Melanie), Mangino, M. (Massimo), Spector, T.D. (Timothy), Rienstra, S.A., van de Vegte, Y.J. (Yordi J.), Harst, P. (Pim) van der, Verweij, N. (Niek), Kääb, S. (Stefan), Schramm, K. (Katharina), Sinner, M.F. (Moritz), Strauch, K. (Konstantin), Cutler, M.J. (Michael J.), Fatkin, D. (Diane), London, B. (Barry), Olesen, M.S. (Morten S.), Roden, D.M. (Dan M.), Benjamin Shoemaker, M. (M.), Gustav Smith, J. (J.), Biggs, M.L. (M.), Bis, J.C. (Joshua), Brody, J.A. (Jennifer A.), Psaty, B.M. (Bruce), Rice, K.M. (Kenneth), Sotoodehnia, N. (Nona), Grandi, A. (Alessandro) de, Fuchsberger, C. (Christian), Penninx, B.W.J.H., Pramstaller, P.P. (Peter Paul), Ford, I. (Ian), Jukema, J.W. (Jan Wouter), Macfarlane, P.W. (Peter W.), Trompet, S. (Stella), Dörr, M. (Marcus), Felix, S.B. (Stephan B.), Völker, U. (Uwe), Weiss, S. (Stefan), Havulinna, A.S. (Aki), Jula, A. (Antti), Sääksjärvi, K. (K.), Salomaa, V. (Veikko), Guo, X. (Xiuqing), Heckbert, S.R. (Susan), Lin, H.J. (Henry J.), Rotter, J.I. (Jerome I.), Taylor, K.D. (Kent), Yao, J. (Jie), Mutsert, R. (Reneé) de, Maan, A.C. (Arie C.), Mook-Kanamori, D.O. (Dennis O.), Noordam, R. (Raymond), Cucca, F. (Francesco), Ding, J. (Jun), Lakatta, E. (Edward), Qian, Y. (Yong), Tarasov, K.V. (Kirill V.), Levy, D. (Daniel), Lin, H. (Honghuang), Newton-Cheh, C. (Christopher), Lunetta, K.L. (Kathryn), Murray, A.D. (Alison D.), Porteous, D.J. (David J.), Smith, B.H. (Blair), Stricker, B.H.Ch. (Bruno), Uitterlinden, A.G. (André), Berg, M.E. (Marten) van den, Haessler, J. (Jeff), Jackson, R.D. (Rebecca), Kooperberg, C. (Charles), Peters, U. (Ulrike), Reiner, A.P. (Alexander P.), Whitsel, E.A. (Eric), Alonso, A. (Alvaro), Arking, D.E. (Dan E.), Boerwinkle, E.A. (Eric), Ehret, G.B. (Georg B.), Soliman, E.Z. (Elsayed Z.), Avery, C.L., Gogarten, S.M., Kerr, K.F. (Kathleen), Laurie, C.C. (Cathy C.), Seyerle, A.A. (Amanda A.), Stilp, A. (Adrienne), Assa, S. (Solmaz), Abdullah Said, M. (M.), Yldau van der Ende, M. (M.), Lambiase, P.D. (Pier), Orini, M. (Michele), Ramirez, J. (Julia), Van Duijvenboden, S. (Stefan), Arnar, D.O. (David O.), Gudbjartsson, D.F. (Daniel), Holm, H. (Hilma), Sulem, P. (Patrick), Thorleifsson, G. (Gudmar), Thorolfsdottir, R.B. (Rosa B.), Thorsteinsdottir, U. (Unnur), Benjamin, E.J. (Emelia J.), Tinker, A. (Andrew), Zwart, J-A. (John-Anker), Ellinor, P.T. (Patrick), Jamshidi, Y. (Yalda), Lubitz, S.A. (Steven), Munroe, P. (Patricia), Ntalla, I. (Ioanna), Weng, L.-C., Cartwright, J.H. (James H.), Hall, A.W. (Amelia Weber), Sveinbjornsson, G. (Gardar), Tucker, N.R. (Nathan R.), Choi, S.H. (Seung Hoan), Chaffin, M.D. (Mark D.), Roselli, C. (Carolina), Barnes, M.J. (Michael), Mifsud, B. (Borbala), Warren, H.R. (Helen R.), Hayward, C. (Caroline), Marten, J. (Jonathan), Cranley, J.J. (James J.), Concas, M.P. (Maria Pina), Gasparini, P. (Paolo), Boutin, T. (Thibaud), Kolcic, I. (Ivana), Polasek, O. (Ozren), Rudan, I. (Igor), Araujo, N.M. (Nathalia M.), Lima-Costa, M.F. (Maria Fernanda), Ribeiro, A.L. (Antonio), Souza, R.P. (Renan P.), Tarazona-Santos, E. (Eduardo), Giedraitis, V. (Vilmantas), Ingelsson, E. (Erik), Mahajan, A. (Anubha), Morris, A.P. (Andrew), Del Greco M, F. (Fabiola), Foco, L. (Luisa), Gögele, M. (Martin), Hicks, A.A. (Andrew A.), Cook, J.P. (James P.), Kao, W.H.L. (Wen), Lindgren, C.M. (Cecilia M.), Sundström, J. (Johan), Nelson, C.P. (Christopher P.), Riaz, M.B. (Muhammad B.), Samani, N.J. (Nilesh), Sinagra, G. (Gianfranco), Ulivi, S. (Shelia), Kähönen, M. (Mika), Mishra, P.P. (Pashupati P.), Mononen, N. (Nina), Nikus, K. (Kjell), Caulfield, M. (Mark), Dominiczak, A. (Anna), Padmanabhan, S. (Sandosh), Montasser, M.E. (May E.), O’Connell, J.R. (Jeff R.), Ryan, K. (Kathleen), Shuldiner, A.R. (Alan R.), Aeschbacher, S. (Stefanie), Conen, D. (David), Risch, L. (Lorenz), Thériault, S. (Sébastien), Hutri-Kähönen, N. (Nina), Lehtimäki, T. (Terho), Lyytikäinen, L.-P. (Leo-Pekka), Raitakari, O. (Olli), Barnes, C.L.K. (Catriona L. K.), Campbell, H. (Harry), Joshi, P.K. (Peter), Wilson, J.F. (James), Isaacs, A.J. (Aaron), Kors, J.A. (Jan), Duijn, C.M. (Cornelia) van, Huang, P.L. (Paul L.), Gudnason, V. (Vilmundur), Harris, T.B. (Tamara B.), Launer, L.J. (Lenore), Smith, A.V. (Albert), Bottinger, E.P. (Erwin), Loos, R.J.F. (Ruth), Nadkarni, G. (Girish), Preuss, M. (Michael), Correa, D.D., Mei, H. (Hao), Meitinger, T. (Thomas), Müller-Nurasyid, M. (Martina), Peters, A. (Annette), Waldenberger, M. (Melanie), Mangino, M. (Massimo), Spector, T.D. (Timothy), Rienstra, S.A., van de Vegte, Y.J. (Yordi J.), Harst, P. (Pim) van der, Verweij, N. (Niek), Kääb, S. (Stefan), Schramm, K. (Katharina), Sinner, M.F. (Moritz), Strauch, K. (Konstantin), Cutler, M.J. (Michael J.), Fatkin, D. (Diane), London, B. (Barry), Olesen, M.S. (Morten S.), Roden, D.M. (Dan M.), Benjamin Shoemaker, M. (M.), Gustav Smith, J. (J.), Biggs, M.L. (M.), Bis, J.C. (Joshua), Brody, J.A. (Jennifer A.), Psaty, B.M. (Bruce), Rice, K.M. (Kenneth), Sotoodehnia, N. (Nona), Grandi, A. (Alessandro) de, Fuchsberger, C. (Christian), Penninx, B.W.J.H., Pramstaller, P.P. (Peter Paul), Ford, I. (Ian), Jukema, J.W. (Jan Wouter), Macfarlane, P.W. (Peter W.), Trompet, S. (Stella), Dörr, M. (Marcus), Felix, S.B. (Stephan B.), Völker, U. (Uwe), Weiss, S. (Stefan), Havulinna, A.S. (Aki), Jula, A. (Antti), Sääksjärvi, K. (K.), Salomaa, V. (Veikko), Guo, X. (Xiuqing), Heckbert, S.R. (Susan), Lin, H.J. (Henry J.), Rotter, J.I. (Jerome I.), Taylor, K.D. (Kent), Yao, J. (Jie), Mutsert, R. (Reneé) de, Maan, A.C. (Arie C.), Mook-Kanamori, D.O. (Dennis O.), Noordam, R. (Raymond), Cucca, F. (Francesco), Ding, J. (Jun), Lakatta, E. (Edward), Qian, Y. (Yong), Tarasov, K.V. (Kirill V.), Levy, D. (Daniel), Lin, H. (Honghuang), Newton-Cheh, C. (Christopher), Lunetta, K.L. (Kathryn), Murray, A.D. (Alison D.), Porteous, D.J. (David J.), Smith, B.H. (Blair), Stricker, B.H.Ch. (Bruno), Uitterlinden, A.G. (André), Berg, M.E. (Marten) van den, Haessler, J. (Jeff), Jackson, R.D. (Rebecca), Kooperberg, C. (Charles), Peters, U. (Ulrike), Reiner, A.P. (Alexander P.), Whitsel, E.A. (Eric), Alonso, A. (Alvaro), Arking, D.E. (Dan E.), Boerwinkle, E.A. (Eric), Ehret, G.B. (Georg B.), Soliman, E.Z. (Elsayed Z.), Avery, C.L., Gogarten, S.M., Kerr, K.F. (Kathleen), Laurie, C.C. (Cathy C.), Seyerle, A.A. (Amanda A.), Stilp, A. (Adrienne), Assa, S. (Solmaz), Abdullah Said, M. (M.), Yldau van der Ende, M. (M.), Lambiase, P.D. (Pier), Orini, M. (Michele), Ramirez, J. (Julia), Van Duijvenboden, S. (Stefan), Arnar, D.O. (David O.), Gudbjartsson, D.F. (Daniel), Holm, H. (Hilma), Sulem, P. (Patrick), Thorleifsson, G. (Gudmar), Thorolfsdottir, R.B. (Rosa B.), Thorsteinsdottir, U. (Unnur), Benjamin, E.J. (Emelia J.), Tinker, A. (Andrew), Zwart, J-A. (John-Anker), Ellinor, P.T. (Patrick), Jamshidi, Y. (Yalda), Lubitz, S.A. (Steven), and Munroe, P. (Patricia)

Abstract

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduc

Published
2020
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16. Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism

Author

Lindstrom, S., Wang, L., Smith, E.N., Gordon, W., Vlieg, A.V., Andrade, M. de, Brody, J.A., Pattee, J.W., Haessler, J., Brumpton, B., Chasman, D.I., Suchon, P., Chen, M.H., Turman, C., Germain, M., Wiggins, K.L., MacDonald, J., Braekkan, S.K., Armasu, S.M., Pankratz, N., Jackson, R.D., Nielsen, J.B., Giulianini, F., Puurunen, M.K., Ibrahim, M., Heckbert, S.R., Damrauer, S.M., Natarajan, P., Klarin, D., Vries, P.S. de, Sabater-Lleal, M., Huffman, J.E., Bammler, T.K., Frazer, K.A., McCauley, B.M., Taylor, K., Pankow, J.S., Reiner, A.P., Gabrielsen, M.E., Deleuze, J.F., O'Donnell, C.J., Kim, J., McKnight, B., Kraft, P., Hansen, J.B., Rosendaal, F.R., Heit, J.A., Psaty, B.M., Tang, W.H., Kooperberg, C., Hveem, K., Ridker, P.M., Morange, P.E., Johnson, A.D., Kabrhel, C., Tregouet, D.A., Smith, N.L., Busenkell, E., Judy, R., Lynch, J., Levin, M., Aragam, J.H.K., Chaffin, M., Haas, M., Assimes, T.L., Huang, J., Lee, K.M., Shao, Q., Huang, Y.F., Sun, Y.V., Vujkovic, M., Saleheen, D., Miller, D.R., Reaven, P., DuVall, S., Boden, W., Pyarajan, S., Henke, P., Gaziano, J.M., Concato, J., Rader, D.J., Cho, K., Chang, K.M., Wilson, P.W.F., Tsao, P.S., Kathiresan, S., Obi, A., Million Veteran Program, CHARGE Hemostasis Working Grp, INVENT Consortium, Program in Genetic Epidemiology and Statistical Genetics (PGESG - BOSTON), Harvard School of Public Health, University of Washington [Seattle], The Scripps Translational Science Institute and Scripps Health, Department of Thrombosis and Haemostasis, Leiden University Medical Center (LUMC), Department of Health Sciences Research [Mayo Clinic] (HSR), Mayo Clinic, University of Minnesota System, Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Brigham and Women's Hospital [Boston], Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire d'hématologie biologique [Hôpital de la Timone - Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), National Institutes of Health [Bethesda] (NIH), Harvard T.H. Chan School of Public Health, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Biorobotics Lab (University of Washington), University of South-Eastern Norway (USN), Department of Health Sciences Research, Ohio State University [Columbus] (OSU), Nutrition, obésité et risque thrombotique (NORT), Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Los Angeles Biomedical Research Institute (LA BioMed), University of Augsburg [Augsburg], Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Department of Epidemiology, Division of Cardiovascular Diseases, Mayo Clinic College of Medicine, University of Minnesota [Twin Cities] (UMN), Norwegian University of Science and Technology [Trondheim] (NTNU), Norwegian University of Science and Technology (NTNU), Department of Emergency Medicine, Massachusetts General Hospital [Boston], Universiteit Leiden-Universiteit Leiden, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Augsburg (UNIA), and Universiteit Leiden

Subjects
0301 basic medicine, Genetics, [SDV]Life Sciences [q-bio], Immunology, Genome-wide association study, Cell Biology, Hematology, 030204 cardiovascular system & hematology, Biology, equipment and supplies, Biochemistry, 3. Good health, Transcriptome, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Mendelian randomization, Expression quantitative trait loci, Gene expression, cardiovascular diseases, Gene, Genetic association, Whole blood
Abstract

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality. To advance our understanding of the biology contributing to VTE, we conducted a genome-wide association study (GWAS) of VTE and a transcriptome-wide association study (TWAS) based on imputed gene expression from whole blood and liver. We meta-analyzed GWAS data from 18 studies for 30 234 VTE cases and 172 122 controls and assessed the association between 12 923 718 genetic variants and VTE. We generated variant prediction scores of gene expression from whole blood and liver tissue and assessed them for association with VTE. Mendelian randomization analyses were conducted for traits genetically associated with novel VTE loci. We identified 34 independent genetic signals for VTE risk from GWAS meta-analysis, of which 14 are newly reported associations. This included 11 newly associated genetic loci (C1orf198, PLEK, OSMR-AS1, NUGGC/SCARA5, GRK5, MPHOSPH9, ARID4A, PLCG2, SMG6, EIF5A, and STX10) of which 6 replicated, and 3 new independent signals in 3 known genes. Further, TWAS identified 5 additional genetic loci with imputed gene expression levels differing between cases and controls in whole blood (SH2B3, SPSB1, RP11-747H7.3, RP4-737E23.2) and in liver (ERAP1). At some GWAS loci, we found suggestive evidence that the VTE association signal for novel and previously known regions colocalized with expression quantitative trait locus signals. Mendelian randomization analyses suggested that blood traits may contribute to the underlying risk of VTE. To conclude, we identified 16 novel susceptibility loci for VTE; for some loci, the association signals are likely mediated through gene expression of nearby genes.

Published
2019

19. Admixture mapping of ankle-arm index: identification of a candidate locus associated with peripheral arterial disease

Author

Scherer, M.L., Nalls, M.A., Pawlikowska, L., Ziv, E., Mitchell, G., Huntsman, S., Hu, D., Sutton-Tyrrell, K., Lakatta, E.G., Hsueh, W.-C., Newman, A.B., Tandon, A., Kim, L., Kwok, P.-Y., Sung, A., Li, R., Psaty, B., Reiner, A.P., and Harris, T.

Subjects
Peripheral vascular diseases -- Genetic aspects, Peripheral vascular diseases -- Demographic aspects, Peripheral vascular diseases -- Research, African Americans -- Genetic aspects, African Americans -- Health aspects, African Americans -- Research, Chromosome mapping -- Research, Peripheral circulation -- Measurement, Peripheral circulation -- Genetic aspects, Peripheral circulation -- Research, Health
Published
2010

20. Use of >100,000 NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium whole genome sequences improves imputation quality and detection of rare variant associations in admixed African and Hispanic/Latino populations

Author

Cai, J., NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Qian, H., Montgomery, C., Kelly, T.N., Cho, M.H., Weiss, S.T., Loos, R.J.F., Johnson, A.D., de Vries, P.S., Li, Y., Becker, L.C., Peralta, J.M., Wiggins, K.L., Bowden, D.W., Lasky-Su, J.A., Buyske, S., Shan, Y., Moon, J.-Y., Jorgenson, E., Cushman, M., Tiwari, H.K., Kooperberg, C., Faraday, N., Tapia, A.L., TOPMed Hematology & Hemostasis Working Group, Thornton, T.A., Choquet, H., Barnes, K.C., Bis, J.C., Hodonsky, C.J., Mathias, R.A., Wang, T., Taylor, K.D., He, J., Kaplan, R., Gupta, N., Lubitz, S.A., Smith, N.L., Daya, M., Rich, S.S., Peyser, P.A., Palmer, N.D., Silverman, E.K., Arnett, D.K., Choi, S.H., Cupples, L. A., Reiner, A.P., Argos, M., Boerwinkle, E., Hou, Z., Auer, P.L., Bien, S.A., Hidalgo, B., Ellinor, P.T., Heckbert, S.R., Gabriel, S., Tracy, R.P., Avery, C., Yanek, L.R., Raffield, L.M., Papanicolaou, G.J., Fornage, M., Z��llner, S., Graff, M., Wilson, J.G., Smith, J.A., Weng, L.-C., Morrison, A.C., Rosen, J.D., Irvin, M.R., North, K.E., Kardia, S.L.R., Pankratz, N., Rotter, J.I., Blangero, J., McHugh, C.P., Jain, D., Kowalski, M.H., and Ganesh, S.K.

Abstract

Most genome-wide association and fine-mapping studies to date have been conducted in individuals of European descent, and genetic studies of populations of Hispanic/Latino and African ancestry are limited. In addition, these populations have more complex linkage disequilibrium structure. In order to better define the genetic architecture of these understudied populations, we leveraged >100,000 phased sequences available from deep-coverage whole genome sequencing through the multi-ethnic NHLBI Trans-Omics for Precision Medicine (TOPMed) program to impute genotypes into admixed African and Hispanic/Latino samples with genome-wide genotyping array data. We demonstrated that using TOPMed sequencing data as the imputation reference panel improves genotype imputation quality in these populations, which subsequently enhanced gene-mapping power for complex traits. For rare variants with minor allele frequency (MAF) < 0.5%, we observed a 2.3- to 6.1-fold increase in the number of well-imputed variants, with 11-34% improvement in average imputation quality, compared to the state-of-the-art 1000 Genomes Project Phase 3 and Haplotype Reference Consortium reference panels. Impressively, even for extremely rare variants with minor allele count 86%. Subsequent association analyses of TOPMed reference panel-imputed genotype data with hematological traits (hemoglobin (HGB), hematocrit (HCT), and white blood cell count (WBC)) in ~21,600 African-ancestry and ~21,700 Hispanic/Latino individuals identified associations with two rare variants in the HBB gene (rs33930165 with higher WBC [p = 8.8x10-15] in African populations, rs11549407 with lower HGB [p = 1.5x10-12] and HCT [p = 8.8x10-10] in Hispanics/Latinos). By comparison, neither variant would have been genome-wide significant if either 1000 Genomes Project Phase 3 or Haplotype Reference Consortium reference panels had been used for imputation. Our findings highlight the utility of the TOPMed imputation reference panel for identification of novel rare variant associations not previously detected in similarly sized genome-wide studies of under-represented African and Hispanic/Latino populations.

Published
2019
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21. Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions

Author

Vries, P.S. (Paul) de, Brown, M.R., Bentley, A.R. (Amy), Sung, Y.J. (Yun J.), Winkler, T.W. (Thomas W.), Ntalla, I. (Ioanna), Schwander, K., Kraja, A. (Aldi), Guo, X. (Xiuqing), Franceschini, N. (Nora), Cheng, C.-Y. (Ching-Yu), Sim, X. (Xueling), Vojinović, D. (Dina), Huffman, J.E. (Jennifer E.), Musani, S.K. (Solomon K.), Li, C. (Changwei), Feitosa, M.F. (Mary Furlan), Richard, M.A. (Melissa A.), Noordam, R. (Raymond), Aschard, H. (Hugues), Bartz, T.M. (Traci M.), Bielak, L.F. (Lawrence F.), Deng, X. (Xuan), Dorajoo, R. (Rajkumar), Lohman, K.K. (Kurt K.), Manning, A.K. (Alisa), Rankinen, T. (Tuomo), Smith, A.V. (Albert), Tajuddin, S.M. (Salman M.), Evangelou, E. (Evangelos), Graff, M.J. (Maud J.L.), Alver, M. (Maris), Boissel, M. (Mathilde), Chai, J.F. (Jin Fang), Chen, X. (Xu), Divers, J. (Jasmin), Gandin, I. (Ilaria), Gao, C. (Chuan), Goel, A. (Anuj), Hagemeijer, Y. (Yanick), Harris, S.E. (Sarah), Hartwig, F.P. (Fernando P.), He, M. (Meian), Horimoto, A.R.V.R. (Andrea R V R), Hsu, F.-C. (Fang-Chi), Jackson, A.U. (Anne), Kasturiratne, A. (Anuradhani), Komulainen, P. (Pirjo), Kuhnel, B. (Brigitte), Laguzzi, F. (Federica), Lee, J.H. (Joseph H.), Luan, J. (Jian'an), Lyytikäinen, L.-P. (Leo-Pekka), Matoba, N. (Nana), Nolte, I.M. (Ilja), Pietzner, M. (Maik), Riaz, M. (Muhammad), Said, M.A. (M Abdullah), Scott, R.A. (Robert), Sofer, T. (Tamar), Stancáková, A. (Alena), Takeuchi, F. (Fumihiko), Tayo, B. (Bamidele), Most, P.J. (Peter) van der, Varga, T.V. (Tibor V.), Wang, Y. (Yajuan), Ware, E.B. (Erin B.), Wen, W. (Wanqing), Yanek, L.R. (Lisa), Zhang, W. (Weihua), Zhao, J.H. (Jing Hua), Afaq, S. (Saima), Amin, N. (Najaf), Amini, M. (Marzyeh), Arking, D.E. (Dan), Aung, T. (Tin), Ballantyne, C. (Christie), Boerwinkle, E.A. (Eric), Broeckel, U. (Ulrich), Campbell, A. (Archie), Canouil, M. (Mickaël), Charumathi, S. (Sabanayagam), Chen, Y.D.I. (Yii-Der Ida), Connell, J. (John), Faire, U. (Ulf) de, de Las Fuentes, L. (Lisa), Mutsert, R. (Reneé) de, de Silva, H.J. (H Janaka), Ding, J. (Jingzhong), Dominiczak, A.F. (Anna F.), Duan, Q. (Qing), Eaton, C.B. (Charles B.), Eppinga, R.N. (Ruben N.), Faul, J.D. (Jessica D.), Fisher, V. (Virginia), Forrester, T. (Terrence), Franco, O.H. (Oscar), Friedlander, Y. (Yechiel), Ghanbari, M. (Mohsen), Giulianini, F. (Franco), Grabe, H.J. (Hans Jörgen), Grove, M.L. (Megan), Gu, C. (Charles), Harris, T.B. (Tamara), Heikkinen, S. (Sami), Heng, C.K. (Chew-Kiat), Hirata, M. (Makoto), Hixson, J.E. (James E.), Howard, B.V. (Barbara V.), Ikram, M.A. (Arfan), Jacobs, D.R. (David R.), Johnson, C. (Craig), Jonas, J.B., Kammerer, C.M. (Candace), Katsuya, T. (Tomohiro), Khor, C.C., Kilpeläinen, T.O. (Tuomas O.), Koh, W.-P. (Woon-Puay), Koistinen, H.A. (Heikki A.), Kolcic, I. (Ivana), Kooperberg, C. (Charles), Krieger, J.E. (José), Kritchevsky, S.B. (Steve B.), Kubo, M. (Michiaki), Kuusisto, J. (Johanna), Lakka, T.A. (Timo), Langefeld, C.D. (Carl), Langenberg, C. (Claudia), Launer, L.J. (Lenore), Lehne, B. (Benjamin), Lemaitre, R.N. (Rozenn ), Li, Y. (Yize), Liang, J. (Jingjing), Liu, J. (Jianjun), Liu, K. (Kiang), Loh, M. (Marie), Louie, T. (Tin), Mägi, R. (Reedik), Manichaikul, A.W. (Ani W.), McKenzie, C.A. (Colin A.), Meitinger, T. (Thomas), Metspalu, A. (Andres), Milaneschi, Y. (Yuri), Milani, L. (Lili), Mohlke, K.L. (Karen L.), Mosley, T.H. (Thomas H.), Mukamal, K. (Kenneth), Nalls, M.A. (Michael), Nauck, M. (Matthias), Nelson, C.P. (Christopher P.), Sotoodehnia, N. (Nona), O´Connell, J.R., Palmer, N.D. (Nicholette), Pazoki, R. (Raha), Pedersen, N.L. (Nancy), Peters, A. (Annette), Peyser, P.A. (Patricia A.), Polasek, O. (Ozren), Poulter, N.R. (Neil), Raffel, L.J. (Leslie J.), Raitakari, O. (Olli), Reiner, A.P. (Alex P.), Rice, T.K. (Treva K.), Rich, S.S. (Stephen), Robino, A. (Antonietta), Robinson, J.G. (Jennifer), Rose, L.M. (Lynda M.), Rudan, I. (Igor), Schmidt, C.O. (Carsten O.), Schreiner, P.J. (Pamela), Scott, W.R. (William R.), Sever, P. (Peter), Shi, Y. (Yuan), Sidney, S. (Stephen), Sims, M. (Mario), Smith, B.H. (Blair), Smith, J.A. (Jennifer A), Snieder, H. (Harold), Starr, J.M. (John), Strauch, K. (Konstantin), Tan, N. (Nicholas), Taylor, K.D. (Kent), Teo, Y.Y. (Yik Ying), Tham, Y.C. (Yih Chung), Uitterlinden, A.G. (André), Heemst, D. (Diana) van, Vuckovic, D. (Dragana), Waldenberger, M. (Melanie), Wang, L. (Lihua), Wang, Y. (Yujie), Wang, Z. (Zhe), Wei, W.B. (Wen Bin), Williams, C. (Christine), Wilson, G. (Gregory), Wojczynski, M.K. (Mary ), Yao, J. (Jie), Yu, B. (Bing), Yu, C. (Caizheng), Yuan, J.-M. (Jian-Min), Zhao, W. (Wei), Zonderman, A.B., Becker, D.M. (Diane), Boehnke, M. (Michael), Bowden, D.W. (Donald W.), Chambers, J.C. (John C.), Deary, I.J. (Ian), Esko, T. (Tõnu), Farrall, M. (Martin), Franks, P.W. (Paul W.), Freedman, B.I. (Barry), Froguel, P. (Philippe), Gasparini, P. (Paolo), Gieger, C. (Christian), Horta, B.L. (Bernardo L.), Kamatani, Y. (Yoichiro), Kato, N. (Norihiro), Kooner, J.S. (Jaspal S.), Laakso, M. (Markku), Leander, K. (Karin), Lehtimäki, T. (Terho), Magnusson, P.K. (Patrik), Penninx, B.W.J.H. (Brenda), Pereira, A.C. (Alexandre C.), Rauramaa, R. (Rainer), Samani, N.J. (Nilesh), Scott, J. (James), Shu, X.-O. (Xiao-Ou), Harst, P. (Pim) van der, Wagenknecht, L.E. (Lynne), Wang, Y.X. (Ya Xing), Wareham, N.J. (Nick), Watkins, H. (Hugh), Weir, D.R. (David R.), Wickremasinghe, A.R. (Ananda R.), Zheng, W. (Wei), Elliott, P. (Paul), North, K.E. (Kari), Bouchard, C. (Claude), Evans, M.K. (Michele), Gudnason, V. (Vilmundur), Liu, C.-T. (Ching-Ti), Liu, Y. (YongMei), Psaty, B.M. (Bruce M.), Jarvelin, M.-R. (Marjo-Riitta), Dam, R.M. (Rob) van, Kardia, S.L.R. (Sharon), Dominiczak, A. (Anna), Rotimi, C. (Charles), Mook-Kanamori, D.O. (Dennis O.), Fornage, M. (Myriam), Kelly, T.N. (Tanika N.), Fox, E.R. (Ervin R.), Hayward, C. (Caroline), Duijn, C.M. (Cornelia) van, Tai, E.S. (Shyong), Wong, T.Y. (Tien Yin), Liu, J. (Jingmin), Rotter, J.I. (Jerome I.), Gauderman, W.J. (W James), Province, M.A. (Michael A.), Munroe, P. (Patricia), Rice, K. (Kenneth), Chasman, D.I. (Daniel), Cupples, L.A. (L Adrienne), Tobin, M.D. (Martin), Morrison, A.C. (Alanna), Vries, P.S. (Paul) de, Brown, M.R., Bentley, A.R. (Amy), Sung, Y.J. (Yun J.), Winkler, T.W. (Thomas W.), Ntalla, I. (Ioanna), Schwander, K., Kraja, A. (Aldi), Guo, X. (Xiuqing), Franceschini, N. (Nora), Cheng, C.-Y. (Ching-Yu), Sim, X. (Xueling), Vojinović, D. (Dina), Huffman, J.E. (Jennifer E.), Musani, S.K. (Solomon K.), Li, C. (Changwei), Feitosa, M.F. (Mary Furlan), Richard, M.A. (Melissa A.), Noordam, R. (Raymond), Aschard, H. (Hugues), Bartz, T.M. (Traci M.), Bielak, L.F. (Lawrence F.), Deng, X. (Xuan), Dorajoo, R. (Rajkumar), Lohman, K.K. (Kurt K.), Manning, A.K. (Alisa), Rankinen, T. (Tuomo), Smith, A.V. (Albert), Tajuddin, S.M. (Salman M.), Evangelou, E. (Evangelos), Graff, M.J. (Maud J.L.), Alver, M. (Maris), Boissel, M. (Mathilde), Chai, J.F. (Jin Fang), Chen, X. (Xu), Divers, J. (Jasmin), Gandin, I. (Ilaria), Gao, C. (Chuan), Goel, A. (Anuj), Hagemeijer, Y. (Yanick), Harris, S.E. (Sarah), Hartwig, F.P. (Fernando P.), He, M. (Meian), Horimoto, A.R.V.R. (Andrea R V R), Hsu, F.-C. (Fang-Chi), Jackson, A.U. (Anne), Kasturiratne, A. (Anuradhani), Komulainen, P. (Pirjo), Kuhnel, B. (Brigitte), Laguzzi, F. (Federica), Lee, J.H. (Joseph H.), Luan, J. (Jian'an), Lyytikäinen, L.-P. (Leo-Pekka), Matoba, N. (Nana), Nolte, I.M. (Ilja), Pietzner, M. (Maik), Riaz, M. (Muhammad), Said, M.A. (M Abdullah), Scott, R.A. (Robert), Sofer, T. (Tamar), Stancáková, A. (Alena), Takeuchi, F. (Fumihiko), Tayo, B. (Bamidele), Most, P.J. (Peter) van der, Varga, T.V. (Tibor V.), Wang, Y. (Yajuan), Ware, E.B. (Erin B.), Wen, W. (Wanqing), Yanek, L.R. (Lisa), Zhang, W. (Weihua), Zhao, J.H. (Jing Hua), Afaq, S. (Saima), Amin, N. (Najaf), Amini, M. (Marzyeh), Arking, D.E. (Dan), Aung, T. (Tin), Ballantyne, C. (Christie), Boerwinkle, E.A. (Eric), Broeckel, U. (Ulrich), Campbell, A. (Archie), Canouil, M. (Mickaël), Charumathi, S. (Sabanayagam), Chen, Y.D.I. (Yii-Der Ida), Connell, J. (John), Faire, U. (Ulf) de, de Las Fuentes, L. (Lisa), Mutsert, R. (Reneé) de, de Silva, H.J. (H Janaka), Ding, J. (Jingzhong), Dominiczak, A.F. (Anna F.), Duan, Q. (Qing), Eaton, C.B. (Charles B.), Eppinga, R.N. (Ruben N.), Faul, J.D. (Jessica D.), Fisher, V. (Virginia), Forrester, T. (Terrence), Franco, O.H. (Oscar), Friedlander, Y. (Yechiel), Ghanbari, M. (Mohsen), Giulianini, F. (Franco), Grabe, H.J. (Hans Jörgen), Grove, M.L. (Megan), Gu, C. (Charles), Harris, T.B. (Tamara), Heikkinen, S. (Sami), Heng, C.K. (Chew-Kiat), Hirata, M. (Makoto), Hixson, J.E. (James E.), Howard, B.V. (Barbara V.), Ikram, M.A. (Arfan), Jacobs, D.R. (David R.), Johnson, C. (Craig), Jonas, J.B., Kammerer, C.M. (Candace), Katsuya, T. (Tomohiro), Khor, C.C., Kilpeläinen, T.O. (Tuomas O.), Koh, W.-P. (Woon-Puay), Koistinen, H.A. (Heikki A.), Kolcic, I. (Ivana), Kooperberg, C. (Charles), Krieger, J.E. (José), Kritchevsky, S.B. (Steve B.), Kubo, M. (Michiaki), Kuusisto, J. (Johanna), Lakka, T.A. (Timo), Langefeld, C.D. (Carl), Langenberg, C. (Claudia), Launer, L.J. (Lenore), Lehne, B. (Benjamin), Lemaitre, R.N. (Rozenn ), Li, Y. (Yize), Liang, J. (Jingjing), Liu, J. (Jianjun), Liu, K. (Kiang), Loh, M. (Marie), Louie, T. (Tin), Mägi, R. (Reedik), Manichaikul, A.W. (Ani W.), McKenzie, C.A. (Colin A.), Meitinger, T. (Thomas), Metspalu, A. (Andres), Milaneschi, Y. (Yuri), Milani, L. (Lili), Mohlke, K.L. (Karen L.), Mosley, T.H. (Thomas H.), Mukamal, K. (Kenneth), Nalls, M.A. (Michael), Nauck, M. (Matthias), Nelson, C.P. (Christopher P.), Sotoodehnia, N. (Nona), O´Connell, J.R., Palmer, N.D. (Nicholette), Pazoki, R. (Raha), Pedersen, N.L. (Nancy), Peters, A. (Annette), Peyser, P.A. (Patricia A.), Polasek, O. (Ozren), Poulter, N.R. (Neil), Raffel, L.J. (Leslie J.), Raitakari, O. (Olli), Reiner, A.P. (Alex P.), Rice, T.K. (Treva K.), Rich, S.S. (Stephen), Robino, A. (Antonietta), Robinson, J.G. (Jennifer), Rose, L.M. (Lynda M.), Rudan, I. (Igor), Schmidt, C.O. (Carsten O.), Schreiner, P.J. (Pamela), Scott, W.R. (William R.), Sever, P. (Peter), Shi, Y. (Yuan), Sidney, S. (Stephen), Sims, M. (Mario), Smith, B.H. (Blair), Smith, J.A. (Jennifer A), Snieder, H. (Harold), Starr, J.M. (John), Strauch, K. (Konstantin), Tan, N. (Nicholas), Taylor, K.D. (Kent), Teo, Y.Y. (Yik Ying), Tham, Y.C. (Yih Chung), Uitterlinden, A.G. (André), Heemst, D. (Diana) van, Vuckovic, D. (Dragana), Waldenberger, M. (Melanie), Wang, L. (Lihua), Wang, Y. (Yujie), Wang, Z. (Zhe), Wei, W.B. (Wen Bin), Williams, C. (Christine), Wilson, G. (Gregory), Wojczynski, M.K. (Mary ), Yao, J. (Jie), Yu, B. (Bing), Yu, C. (Caizheng), Yuan, J.-M. (Jian-Min), Zhao, W. (Wei), Zonderman, A.B., Becker, D.M. (Diane), Boehnke, M. (Michael), Bowden, D.W. (Donald W.), Chambers, J.C. (John C.), Deary, I.J. (Ian), Esko, T. (Tõnu), Farrall, M. (Martin), Franks, P.W. (Paul W.), Freedman, B.I. (Barry), Froguel, P. (Philippe), Gasparini, P. (Paolo), Gieger, C. (Christian), Horta, B.L. (Bernardo L.), Kamatani, Y. (Yoichiro), Kato, N. (Norihiro), Kooner, J.S. (Jaspal S.), Laakso, M. (Markku), Leander, K. (Karin), Lehtimäki, T. (Terho), Magnusson, P.K. (Patrik), Penninx, B.W.J.H. (Brenda), Pereira, A.C. (Alexandre C.), Rauramaa, R. (Rainer), Samani, N.J. (Nilesh), Scott, J. (James), Shu, X.-O. (Xiao-Ou), Harst, P. (Pim) van der, Wagenknecht, L.E. (Lynne), Wang, Y.X. (Ya Xing), Wareham, N.J. (Nick), Watkins, H. (Hugh), Weir, D.R. (David R.), Wickremasinghe, A.R. (Ananda R.), Zheng, W. (Wei), Elliott, P. (Paul), North, K.E. (Kari), Bouchard, C. (Claude), Evans, M.K. (Michele), Gudnason, V. (Vilmundur), Liu, C.-T. (Ching-Ti), Liu, Y. (YongMei), Psaty, B.M. (Bruce M.), Jarvelin, M.-R. (Marjo-Riitta), Dam, R.M. (Rob) van, Kardia, S.L.R. (Sharon), Dominiczak, A. (Anna), Rotimi, C. (Charles), Mook-Kanamori, D.O. (Dennis O.), Fornage, M. (Myriam), Kelly, T.N. (Tanika N.), Fox, E.R. (Ervin R.), Hayward, C. (Caroline), Duijn, C.M. (Cornelia) van, Tai, E.S. (Shyong), Wong, T.Y. (Tien Yin), Liu, J. (Jingmin), Rotter, J.I. (Jerome I.), Gauderman, W.J. (W James), Province, M.A. (Michael A.), Munroe, P. (Patricia), Rice, K. (Kenneth), Chasman, D.I. (Daniel), Cupples, L.A. (L Adrienne), Tobin, M.D. (Martin), and Morrison, A.C. (Alanna)

Abstract

A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2-degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10-6) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10-8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models.

Published
2019
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22. Genome-wide association study and meta-analysis identify loci associated with ventricular and supraventricular ectopy

Author

Bartz, T.M., Taylor, K.D., Highland, H.M., Wilhelmsen, K.C., Brody, J.A., Liao, D., Yao, J., Guo, X., Zhang, Z.-M., Avery, C.L., Psaty, B.M., Sitlani, C.M., Roach, J., Méndez-Giráldez, R., Gondalia, R., Tinker, L.F., Lin, H.J., Whitsel, E.A., Franceschini, N., Gogarten, S.M., Seyerle, A.A., Stewart, J.D., Yan, S., Duan, Q., Napier, M.D., Rotter, J.I., Li, Y., Laurie, C.C., Reiner, A.P., Heckbert, S.R., Sotoodehnia, N., North, K.E., and Soliman, E.Z.

Abstract

The genetic basis of supraventricular and ventricular ectopy (SVE, VE) remains largely uncharacterized, despite established genetic mechanisms of arrhythmogenesis. To identify novel genetic variants associated with SVE/VE in ancestrally diverse human populations, we conducted a genome-wide association study of electrocardiographically identified SVE and VE in five cohorts including approximately 43,000 participants of African, European and Hispanic/Latino ancestry. In thirteen ancestry-stratified subgroups, we tested multivariable-adjusted associations of SVE and VE with single nucleotide polymorphism (SNP) dosage. We combined subgroup-specific association estimates in inverse variance-weighted, fixed-effects and Bayesian meta-analyses. We also combined fixed-effects meta-analytic t-test statistics for SVE and VE in multi-trait SNP association analyses. No loci reached genome-wide significance in trans-ethnic meta-analyses. However, we found genome-wide significant SNPs intronic to an apoptosis-enhancing gene previously associated with QRS interval duration (FAF1; lead SNP rs7545860; effect allele frequency = 0.02; P = 2.0 × 10-8) in multi-trait analysis among European ancestry participants and near a locus encoding calcium-dependent glycoproteins (DSC3; lead SNP rs8086068; effect allele frequency = 0.17) in meta-analysis of SVE (P = 4.0 × 10-8) and multi-trait analysis (P = 2.9 × 10-9) among African ancestry participants. The novel findings suggest several mechanisms by which genetic variation may predispose to ectopy in humans and highlight the potential value of leveraging pleiotropy in future studies of ectopy-related phenotypes.

Published
2018
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23. Erratum to: Discovery and refinement of genetic loci associated with cardiometabolic risk using dense imputation maps

Author

Iotchkova, V. (Valentina), Huang, J. (Jie), Morris, J.A. (John A), Jain, D. (Deepti), Barbieri, C. (Caterina), Walter, K. (Klaudia), Min, J. (Josine), Chen, L. (Lu), Astle, W. (William), Cocca, M. (Massimilian), Deelen, P. (Patrick), Elding, H. (Heather), Farmaki, A.-E. (Aliki-Eleni), Franklin, C.S. (Christopher), Frånberg, M. (Mattias), Gaunt, T.R. (Tom), Hofman, A. (Albert), Jiang, T. (Tao), Kleber, M.E. (Marcus), Lachance, G. (Genevieve), Luan, J., Malerba, G. (Giovanni), Matchan, A. (Angela), Mead, D. (Daniel), Memari, Y. (Yasin), Ntalla, I. (Ioanna), Panoutsopoulou, K. (Kalliope), Pazoki, R. (Raha), Perry, J.R.B. (John R B), Rivadeneira Ramirez, F. (Fernando), Sabater-Lleal, M. (Maria), Sennblad, B. (Bengt), Shin, S.-Y., Southam, L. (Lorraine), Traglia, M. (Michela), Dijk, F. (Freerk) van, Leeuwen, E.M. (Elisa) van, Zaza, G. (Gianluigi), Zhang, W. (Weihua), Amin, N. (Najaf), Butterworth, A. (Adam), Chambers, J.C. (John C), Dedoussis, G.V. (George), Dehghan, A. (Abbas), Franco, O.H. (Oscar), Franke, L. (Lude), Frontini, M. (Mattia), Gambaro, G. (Giovanni), Gasparini, P. (Paolo), Hamsten, A. (Anders), Isaacs, A.J. (Aaron), Kooner, J.S. (Jaspal S.), Kooperberg, C. (Charles), Langenberg, C. (Claudia), März, W. (Winfried), Scott, R.A. (Robert), Swertz, M.A. (Morris A), Toniolo, D. (Daniela), Uitterlinden, A.G. (André), Duijn, C.M. (Cornelia) van, Watkins, H. (Hugh), Zeggini, E. (Eleftheria), Maurano, M.T. (Matthew T.), Timpson, N.J. (Nicholas), Reiner, A.P. (Alexander P), Auer, P.L. (Paul L), Soranzo, N. (Nicole), Iotchkova, V. (Valentina), Huang, J. (Jie), Morris, J.A. (John A), Jain, D. (Deepti), Barbieri, C. (Caterina), Walter, K. (Klaudia), Min, J. (Josine), Chen, L. (Lu), Astle, W. (William), Cocca, M. (Massimilian), Deelen, P. (Patrick), Elding, H. (Heather), Farmaki, A.-E. (Aliki-Eleni), Franklin, C.S. (Christopher), Frånberg, M. (Mattias), Gaunt, T.R. (Tom), Hofman, A. (Albert), Jiang, T. (Tao), Kleber, M.E. (Marcus), Lachance, G. (Genevieve), Luan, J., Malerba, G. (Giovanni), Matchan, A. (Angela), Mead, D. (Daniel), Memari, Y. (Yasin), Ntalla, I. (Ioanna), Panoutsopoulou, K. (Kalliope), Pazoki, R. (Raha), Perry, J.R.B. (John R B), Rivadeneira Ramirez, F. (Fernando), Sabater-Lleal, M. (Maria), Sennblad, B. (Bengt), Shin, S.-Y., Southam, L. (Lorraine), Traglia, M. (Michela), Dijk, F. (Freerk) van, Leeuwen, E.M. (Elisa) van, Zaza, G. (Gianluigi), Zhang, W. (Weihua), Amin, N. (Najaf), Butterworth, A. (Adam), Chambers, J.C. (John C), Dedoussis, G.V. (George), Dehghan, A. (Abbas), Franco, O.H. (Oscar), Franke, L. (Lude), Frontini, M. (Mattia), Gambaro, G. (Giovanni), Gasparini, P. (Paolo), Hamsten, A. (Anders), Isaacs, A.J. (Aaron), Kooner, J.S. (Jaspal S.), Kooperberg, C. (Charles), Langenberg, C. (Claudia), März, W. (Winfried), Scott, R.A. (Robert), Swertz, M.A. (Morris A), Toniolo, D. (Daniela), Uitterlinden, A.G. (André), Duijn, C.M. (Cornelia) van, Watkins, H. (Hugh), Zeggini, E. (Eleftheria), Maurano, M.T. (Matthew T.), Timpson, N.J. (Nicholas), Reiner, A.P. (Alexander P), Auer, P.L. (Paul L), and Soranzo, N. (Nicole)

Abstract

In the version of the article published, the surname of author Aaron Isaacs is misspelled as Issacs.

Published
2018
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24. GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes

Author

Franceschini, N. (Nora), Giambartolomei, C. (Claudia), Vries, P.S. (Paul) de, Finan, C. (Chris), Bis, J.C. (Joshua), Huntley, R.P. (Rachael P.), Lovering, R.C. (Ruth C.), Tajuddin, S.M. (Salman M.), Winkler, T.W. (Thomas W.), Graff, M. (Misa), Kavousi, M. (Maryam), Dale, C. (Caroline), Smith, A.V. (Albert), Hofer, E. (Edith), Leeuwen, E.M. (Elisa) van, Nolte, I.M. (Ilja), Lu, L. (Lingyi), Scholz, M. (Markus), Sargurupremraj, M. (Muralidharan), Pitkanen, N. (Niina), Franzén, O. (Oscar), Joshi, P.K. (Peter), Noordam, R. (Raymond), Marioni, R.E. (Riccardo), Hwang, S.-J. (Shih-Jen), Musani, S.K. (Solomon K.), Schminke, U. (Ulf), Palmas, W. (Walter), Isaacs, A.J. (Aaron), Correa, D.D., Zonderman, A.B., Hofman, A. (Albert), Teumer, A. (Alexander), Cox, A.J. (Amanda J.), Uitterlinden, A.G. (André), Wong, A. (Andrew), Smit, A.J. (Andries), Newman, A.B. (Anne B.), Britton, A.R., Ruusalepp, A. (Arno), Sennblad, B. (Bengt), Hedblad, B. (Bo), Pasaniuc, B. (Bogdan), Penninx, B.W.J.H. (Brenda), Langefeld, C.D. (Carl D.), Wassel, C.L. (Christina), Tzourio, C. (Christophe), Fava, C. (Cristiano), Baldassarre, D. (Damiano), O’Leary, D.H. (Daniel H.), Teupser, D. (Daniel), Kuh, D. (Diana), Tremoli, E. (Elena), Mannarino, E. (Elmo), Grossi, E. (Enzo), Boerwinkle, E.A. (Eric), Schadt, E.E. (Eric E.), Ingelsson, E. (Erik), Veglia, F. (Fabrizio), Rivadeneira Ramirez, F. (Fernando), Beutner, F. (Frank), Chauhan, G. (Ganesh), Heiss, G. (Gerardo), Snieder, H. (Harold), Campbell, H. (Harry), Völzke, H. (Henry), Markus, H.S. (Hugh), Deary, I.J. (Ian), Jukema, J.W. (Jan Wouter), Graaf, J. (Jacqueline) de, Price, J. (Jacqueline), Pott, J. (Janne), Hopewell, J., Liang, J. (Jingjing), Thiery, J.P. (Joachim), Engmann, J. (Jorgen), Gertow, K. (Karl), Rice, K.M. (Kenneth), Taylor, K.D. (Kent), Dhana, K. (Klodian), Kiemeney, L.A.L.M. (Lambertus A. L. M.), Kao, W.H.L. (Wen), Raffield, L.M. (Laura M.), Launer, L.J. (Lenore), Holdt, L.M. (Lesca), Dörr, M. (Marcus), Kubisch, C. (Christian), Traylor, M. (Matthew), Sitzer, M. (Matthias), Kumari, M. (Meena), Kivimaki, M. (Mika), Nalls, M.A. (Michael), Melander, O. (Olle), Raitakari, O. (Olli), Franco, O.H. (Oscar), Rueda-Ochoa, O.L. (Oscar), Roussos, A. (Alexandra), Whincup, P.H. (Peter), Amouyel, P. (Philippe), Giral, P. (Philippe), Anugu, P. (Pramod), Wong, Q. (Quenna), Malik, R. (Rainer), Rauramaa, R. (Rainer), Burkhardt, R. (Ralph), Hardy, R. (Rebecca), Schmidt, R. (Reinhold), Mutsert, R. (Reneé) de, Strawbridge, R.J. (Rona), Wannamethee, S.G. (Goya), Hägg, S. (Sara), Shah, S. (Sonia), McLachlan, S. (Stela), Trompet, S. (Stella), Seshadri, S. (Sudha), Kurl, S. (Sudhir), Heckbert, S.R. (Susan), Ring, S.M. (Susan), Harris, T.B. (Tamara B.), Lehtimäki, T. (Terho), Galesloot, T.E. (Tessel), Shah, T. (Tina), Faire, U. (Ulf) de, Plagnol, V. (Vincent), Rosamond, W.D. (Wayne), Post, W.S. (Wendy S.), Zhu, X. (Xiaofeng), Zhang, X. (Xiaoling), Guo, X. (Xiuqing), Saba, Y. (Yasaman), Okada, Y. (Yukinori), Mishra, A. (Aniket), Rutten-Jacobs, L. (Loes), Giese, A.-K. (Anne-Katrin), van der Laan, S.W. (Sander W.), Gretarsdottir, S. (Solveig), Anderson, C.D. (Christopher D.), Chong, M. (Michael), Adams, H.H.H. (Hieab), Ago, T. (Tetsuro), Almgren, P. (Peter), Ay, H. (Hakan), Bartz, T.M. (Traci M.), Benavente, O.R. (Oscar R.), Bevan, S. (Steve), Boncoraglio, G. (Giorgio Battista), Brown, R.D. (Robert D.), Butterworth, A.S. (Adam S.), Carrera, C. (Caty), Carty, C.L. (Cara L.), Chasman, D.I. (Daniel), Chen, W-M., Cole, J.W. (John W.), Cotlarciuc, I. (Ioana), Cruchaga, C. (Carlos), Danesh, J. (John), Bakker, P.I.W. (Paul) de, DeStefano, A.L. (Anita), Hoed, M. (Marcel) den, Duan, Q. (Qing), Engelter, S.T. (Stefan), Falcone, G.J. (Guido J.), Gottesman, R.F. (Rebecca), Grewal, R.P. (Raji P.), Gustafsson, S. (Stefan), Haessler, J. (Jeff), Harris, T.B. (Tamara), Hassan, A. (Ahamad), Havulinna, A.S. (Aki), Holliday, E.G. (Elizabeth), Howard, G. (George), Hsu, F.-C. (Fang-Chi), Hyacinth, H.I. (Hyacinth I.), Ikram, M.A. (Arfan), Irvin, M.R. (Marguerite R.), Jian, X. (Xueqiu), Jimenez-Conde, J. (Jordi), Johnson, J.A. (Julie A.), Jukema, J.W. (J. Wouter), Kanai, M. (Masahiro), Keene, K.L. (Keith), Kissela, B.M. (Brett M.), Kleindorfer, D.O. (Dawn O.), Kooperberg, C. (Charles), Kubo, M. (Michiaki), Lange, L.A. (Leslie), Langefeld, C.D. (Carl), Langenberg, C. (Claudia), Lee, J.-M. (Jin-Moo), Lemmens, R. (Robin), Leys, D. (Didier), Lewis, C.M. (Cathryn), Lin, W.-Y. (Wei-Yu), Lindgren, A.G. (Arne G.), Lorentzen, E. (Erik), Magnusson, P.K. (Patrik), Maguire, J.M. (Jane), Manichaikul, A. (Ani), McArdle, P.F. (Patrick), Meschia, J.F. (James F.), Mosley, T.H. (Thomas H.), Ninomiya, T. (Toshiharu), O’Donnell, M.J. (Martin J.), Pulit, S.L. (Sara), Rannikmäe, K. (Kristiina), Reiner, A.P. (Alexander P.), Rexrode, K. (Kathryn), Rich, S.S. (Stephen), Ridker, P.M. (Paul), Rost, N.S. (Natalia), Rothwell, P.M. (Peter), Rundek, T. (Tatjana), Muir, K.W. (Keith), Sakaue, S. (Saori), Sale, M.M. (Michele M.), Salomaa, V. (Veikko), Sapkota, B.R. (Bishwa R.), Schmidt, C.O. (Carsten O.), Sharma, P. (Pankaj), Slowik, A. (Agnieszka), Sudlow, C. (Cathie), Tanislav, C. (Christian), Tatlisumak, T. (Turgut), Thijs, V. (Vincent), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnur), Tiedt, S. (Steffen), Walters, M. (Matthew), Wareham, N.J. (Nick), Wassertheil-Smoller, S. (Sylvia), Wiggins, K.L. (Kerri), Yang, Q. (Qiong Fang), Yusuf, S. (Salim), Pastinen, T. (Tomi), Schadt, E.E. (Eric), Koplev, S. (Simon), Codoni, V. (Veronica), Civelek, M. (Mete), Smith, N.L. (Nicholas), Tregouet, D.-A. (David-Alexandre), Christophersen, I.E. (Ingrid E.), Roselli, C. (Carolina), Lubitz, S.A. (Steven A.), Ellinor, P.T. (Patrick), Tai, E.S. (E. Shyong), Kooner, J.S. (Jaspal S.), Kato, N. (Norihiro), He, J. (Jiang), Harst, P. (Pim) van der, Elliott, P. (Paul), Chambers, J.C. (John C.), Takeuchi, F. (Fumihiko), Johnson, A.D. (Andrew), Sanghera, D.K. (Dharambir K.), Jern, C. (Christina), Strbian, D. (Daniel), Fernandez-Cadenas, I. (Israel), Longstreth Jr, W.T., Rolfs, A. (Arndt), Hata, J. (Jun), Woo, D. (Daniel), Rosand, J. (Jonathan), Pare, G. (Guillame), Saleheen, D. (Danish), Zwart, J-A. (John-Anker), Worrall, B.B. (Bradford B.), Kittner, T. (Thomas), Howson, J.M.M. (Joanna M. M.), Kamatani, Y. (Yoichiro), Dehghan, A. (Abbas), Seldenrijk, K.A. (Kees), Morrison, A.C. (Alanna), Hamsten, A. (Anders), Psaty, B.M. (Bruce), Duijn, C.M. (Cornelia) van, Lawlor, D.A. (Debbie), Mook-Kanamori, D.O. (Dennis O.), Bowden, D.W. (Donald), Schmidt, H. (Helena), Wilson, J.F. (James F.), Wilson, J.F. (James), Rotter, J.I. (Jerome I.), Wardlaw, J.M. (J.), Deanfield, J. (John), Halcox, J. (Julian), Lyytikäinen, L.-P. (Leo-Pekka), Loeffler, M. (Markus), Evans, M.K. (Michele), Debette, S. (Stéphanie), Humphries, S.E. (Steve), Völker, U. (Uwe), Gudnason, V. (Vilmundur), Hingorani, A. (Aroon), Björkegren, J.L.M. (Johan L.M.), Casas, J.P. (Juan), Ódonnell, C.J. (Christopher), Morris, R.W. (Richard), Franceschini, N. (Nora), Giambartolomei, C. (Claudia), Vries, P.S. (Paul) de, Finan, C. (Chris), Bis, J.C. (Joshua), Huntley, R.P. (Rachael P.), Lovering, R.C. (Ruth C.), Tajuddin, S.M. (Salman M.), Winkler, T.W. (Thomas W.), Graff, M. (Misa), Kavousi, M. (Maryam), Dale, C. (Caroline), Smith, A.V. (Albert), Hofer, E. (Edith), Leeuwen, E.M. (Elisa) van, Nolte, I.M. (Ilja), Lu, L. (Lingyi), Scholz, M. (Markus), Sargurupremraj, M. (Muralidharan), Pitkanen, N. (Niina), Franzén, O. (Oscar), Joshi, P.K. (Peter), Noordam, R. (Raymond), Marioni, R.E. (Riccardo), Hwang, S.-J. (Shih-Jen), Musani, S.K. (Solomon K.), Schminke, U. (Ulf), Palmas, W. (Walter), Isaacs, A.J. (Aaron), Correa, D.D., Zonderman, A.B., Hofman, A. (Albert), Teumer, A. (Alexander), Cox, A.J. (Amanda J.), Uitterlinden, A.G. (André), Wong, A. (Andrew), Smit, A.J. (Andries), Newman, A.B. (Anne B.), Britton, A.R., Ruusalepp, A. (Arno), Sennblad, B. (Bengt), Hedblad, B. (Bo), Pasaniuc, B. (Bogdan), Penninx, B.W.J.H. (Brenda), Langefeld, C.D. (Carl D.), Wassel, C.L. (Christina), Tzourio, C. (Christophe), Fava, C. (Cristiano), Baldassarre, D. (Damiano), O’Leary, D.H. (Daniel H.), Teupser, D. (Daniel), Kuh, D. (Diana), Tremoli, E. (Elena), Mannarino, E. (Elmo), Grossi, E. (Enzo), Boerwinkle, E.A. (Eric), Schadt, E.E. (Eric E.), Ingelsson, E. (Erik), Veglia, F. (Fabrizio), Rivadeneira Ramirez, F. (Fernando), Beutner, F. (Frank), Chauhan, G. (Ganesh), Heiss, G. (Gerardo), Snieder, H. (Harold), Campbell, H. (Harry), Völzke, H. (Henry), Markus, H.S. (Hugh), Deary, I.J. (Ian), Jukema, J.W. (Jan Wouter), Graaf, J. (Jacqueline) de, Price, J. (Jacqueline), Pott, J. (Janne), Hopewell, J., Liang, J. (Jingjing), Thiery, J.P. (Joachim), Engmann, J. (Jorgen), Gertow, K. (Karl), Rice, K.M. (Kenneth), Taylor, K.D. (Kent), Dhana, K. (Klodian), Kiemeney, L.A.L.M. (Lambertus A. L. M.), Kao, W.H.L. (Wen), Raffield, L.M. (Laura M.), Launer, L.J. (Lenore), Holdt, L.M. (Lesca), Dörr, M. (Marcus), Kubisch, C. (Christian), Traylor, M. (Matthew), Sitzer, M. (Matthias), Kumari, M. (Meena), Kivimaki, M. (Mika), Nalls, M.A. (Michael), Melander, O. (Olle), Raitakari, O. (Olli), Franco, O.H. (Oscar), Rueda-Ochoa, O.L. (Oscar), Roussos, A. (Alexandra), Whincup, P.H. (Peter), Amouyel, P. (Philippe), Giral, P. (Philippe), Anugu, P. (Pramod), Wong, Q. (Quenna), Malik, R. (Rainer), Rauramaa, R. (Rainer), Burkhardt, R. (Ralph), Hardy, R. (Rebecca), Schmidt, R. (Reinhold), Mutsert, R. (Reneé) de, Strawbridge, R.J. (Rona), Wannamethee, S.G. (Goya), Hägg, S. (Sara), Shah, S. (Sonia), McLachlan, S. (Stela), Trompet, S. (Stella), Seshadri, S. (Sudha), Kurl, S. (Sudhir), Heckbert, S.R. (Susan), Ring, S.M. (Susan), Harris, T.B. (Tamara B.), Lehtimäki, T. (Terho), Galesloot, T.E. (Tessel), Shah, T. (Tina), Faire, U. (Ulf) de, Plagnol, V. (Vincent), Rosamond, W.D. (Wayne), Post, W.S. (Wendy S.), Zhu, X. (Xiaofeng), Zhang, X. (Xiaoling), Guo, X. (Xiuqing), Saba, Y. (Yasaman), Okada, Y. (Yukinori), Mishra, A. (Aniket), Rutten-Jacobs, L. (Loes), Giese, A.-K. (Anne-Katrin), van der Laan, S.W. (Sander W.), Gretarsdottir, S. (Solveig), Anderson, C.D. (Christopher D.), Chong, M. (Michael), Adams, H.H.H. (Hieab), Ago, T. (Tetsuro), Almgren, P. (Peter), Ay, H. (Hakan), Bartz, T.M. (Traci M.), Benavente, O.R. (Oscar R.), Bevan, S. (Steve), Boncoraglio, G. (Giorgio Battista), Brown, R.D. (Robert D.), Butterworth, A.S. (Adam S.), Carrera, C. (Caty), Carty, C.L. (Cara L.), Chasman, D.I. (Daniel), Chen, W-M., Cole, J.W. (John W.), Cotlarciuc, I. (Ioana), Cruchaga, C. (Carlos), Danesh, J. (John), Bakker, P.I.W. (Paul) de, DeStefano, A.L. (Anita), Hoed, M. (Marcel) den, Duan, Q. (Qing), Engelter, S.T. (Stefan), Falcone, G.J. (Guido J.), Gottesman, R.F. (Rebecca), Grewal, R.P. (Raji P.), Gustafsson, S. (Stefan), Haessler, J. (Jeff), Harris, T.B. (Tamara), Hassan, A. (Ahamad), Havulinna, A.S. (Aki), Holliday, E.G. (Elizabeth), Howard, G. (George), Hsu, F.-C. (Fang-Chi), Hyacinth, H.I. (Hyacinth I.), Ikram, M.A. (Arfan), Irvin, M.R. (Marguerite R.), Jian, X. (Xueqiu), Jimenez-Conde, J. (Jordi), Johnson, J.A. (Julie A.), Jukema, J.W. (J. Wouter), Kanai, M. (Masahiro), Keene, K.L. (Keith), Kissela, B.M. (Brett M.), Kleindorfer, D.O. (Dawn O.), Kooperberg, C. (Charles), Kubo, M. (Michiaki), Lange, L.A. (Leslie), Langefeld, C.D. (Carl), Langenberg, C. (Claudia), Lee, J.-M. (Jin-Moo), Lemmens, R. (Robin), Leys, D. (Didier), Lewis, C.M. (Cathryn), Lin, W.-Y. (Wei-Yu), Lindgren, A.G. (Arne G.), Lorentzen, E. (Erik), Magnusson, P.K. (Patrik), Maguire, J.M. (Jane), Manichaikul, A. (Ani), McArdle, P.F. (Patrick), Meschia, J.F. (James F.), Mosley, T.H. (Thomas H.), Ninomiya, T. (Toshiharu), O’Donnell, M.J. (Martin J.), Pulit, S.L. (Sara), Rannikmäe, K. (Kristiina), Reiner, A.P. (Alexander P.), Rexrode, K. (Kathryn), Rich, S.S. (Stephen), Ridker, P.M. (Paul), Rost, N.S. (Natalia), Rothwell, P.M. (Peter), Rundek, T. (Tatjana), Muir, K.W. (Keith), Sakaue, S. (Saori), Sale, M.M. (Michele M.), Salomaa, V. (Veikko), Sapkota, B.R. (Bishwa R.), Schmidt, C.O. (Carsten O.), Sharma, P. (Pankaj), Slowik, A. (Agnieszka), Sudlow, C. (Cathie), Tanislav, C. (Christian), Tatlisumak, T. (Turgut), Thijs, V. (Vincent), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnur), Tiedt, S. (Steffen), Walters, M. (Matthew), Wareham, N.J. (Nick), Wassertheil-Smoller, S. (Sylvia), Wiggins, K.L. (Kerri), Yang, Q. (Qiong Fang), Yusuf, S. (Salim), Pastinen, T. (Tomi), Schadt, E.E. (Eric), Koplev, S. (Simon), Codoni, V. (Veronica), Civelek, M. (Mete), Smith, N.L. (Nicholas), Tregouet, D.-A. (David-Alexandre), Christophersen, I.E. (Ingrid E.), Roselli, C. (Carolina), Lubitz, S.A. (Steven A.), Ellinor, P.T. (Patrick), Tai, E.S. (E. Shyong), Kooner, J.S. (Jaspal S.), Kato, N. (Norihiro), He, J. (Jiang), Harst, P. (Pim) van der, Elliott, P. (Paul), Chambers, J.C. (John C.), Takeuchi, F. (Fumihiko), Johnson, A.D. (Andrew), Sanghera, D.K. (Dharambir K.), Jern, C. (Christina), Strbian, D. (Daniel), Fernandez-Cadenas, I. (Israel), Longstreth Jr, W.T., Rolfs, A. (Arndt), Hata, J. (Jun), Woo, D. (Daniel), Rosand, J. (Jonathan), Pare, G. (Guillame), Saleheen, D. (Danish), Zwart, J-A. (John-Anker), Worrall, B.B. (Bradford B.), Kittner, T. (Thomas), Howson, J.M.M. (Joanna M. M.), Kamatani, Y. (Yoichiro), Dehghan, A. (Abbas), Seldenrijk, K.A. (Kees), Morrison, A.C. (Alanna), Hamsten, A. (Anders), Psaty, B.M. (Bruce), Duijn, C.M. (Cornelia) van, Lawlor, D.A. (Debbie), Mook-Kanamori, D.O. (Dennis O.), Bowden, D.W. (Donald), Schmidt, H. (Helena), Wilson, J.F. (James F.), Wilson, J.F. (James), Rotter, J.I. (Jerome I.), Wardlaw, J.M. (J.), Deanfield, J. (John), Halcox, J. (Julian), Lyytikäinen, L.-P. (Leo-Pekka), Loeffler, M. (Markus), Evans, M.K. (Michele), Debette, S. (Stéphanie), Humphries, S.E. (Steve), Völker, U. (Uwe), Gudnason, V. (Vilmundur), Hingorani, A. (Aroon), Björkegren, J.L.M. (Johan L.M.), Casas, J.P. (Juan), Ódonnell, C.J. (Christopher), and Morris, R.W. (Richard)

Abstract

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.

Published
2018
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25. Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease

Author

Webb, T.R., Erdmann, J., Stirrups, K.E., Stitziel, N.O., Masca, N.G.D., Jansen, H., Kanoni, S., Nelson, C.P., Ferrario, P.G., Konig, I.R., Eicher, J.D., Johnson, A.D., Hamby, S.E., Betsholtz, C., Ruusalepp, A., Franzen, O., Schadt, E.E., Bjorkegren, J.L.M., Weeke, P.E., Auer, P.L., Schick, U.M., Lu, Y.C., Zhang, H., Dube, M.P., Goel, A., Farrall, M., Peloso, G.M., Won, H.H., R. do, Iperen, E. van, Kruppa, J., Mahajan, A., Scott, R.A., Willenborg, C., Braund, P.S., Capelleveen, J.C. van, Doney, A.S.F., Donnelly, L.A., Asselta, R., Merlini, P.A., Duga, S., Marziliano, N., Denny, J.C., Shaffer, C., El-Mokhtari, N.E., Franke, A., Heilmann, S., Hengstenberg, C., Hoffmann, P., Holmen, O.L., Hveem, K., Jansson, J.H., Jockel, K.H., Kessler, T., Kriebel, J., Laugwitz, K.L., Marouli, E., Martinelli, N., McCarthy, M.I., Zuydam, N.R. van, Meisinger, C., Esko, T., Mihailov, E., Escher, S.A., Alver, M., Moebus, S., Morris, A.D., Virtamo, J., Nikpay, M., Olivieri, O., Provost, S., AlQarawi, A., Robertson, N.R., Akinsansya, K.O., Reilly, D.F., Vogt, T.F., Yin, W., Asselbergs, F.W., Kooperberg, C., Jackson, R.D., Stahl, E., Muller-Nurasyid, M., Strauch, K., Varga, T.V., Waldenberger, M., Zeng, L.Y., Chowdhury, R., Salomaa, V., Ford, I., Jukema, J.W., Amouyel, P., Kontto, J., Nordestgaard, B.G., Ferrieres, J., Saleheen, D., Sattar, N., Surendran, P., Wagner, A., Young, R., Howson, J.M.M., Butterworth, A.S., Danesh, J., Ardissino, D., Bottinger, E.P., Erbel, R., Franks, P.W., Girelli, D., Hall, A.S., Hovingh, G.K., Kastrati, A., Lieb, W., Meitinger, T., Kraus, W.E., Shah, S.H., McPherson, R., Orho-Melander, M., Melander, O., Metspalu, A., Palmer, C.N.A., Peters, A., Rader, D.J., Reilly, M.P., Loos, R.J.F., Reiner, A.P., Roden, D.M., Tardif, J.C., Thompson, J.R., Wareham, N.J., Watkins, H., Willer, C.J., Samani, N.J., Schunkert, H., Deloukas, P., Kathiresan, S., Wellcome Trust Case Control, MORGAM Investigators, and Myocardial Infarction Genetics

Subjects
expression quantitative trait loci, single nucleotide polymorphism, cholesteryl ester transfer protein, genome-wide association, genetics
Abstract

BACKGROUND: Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits. OBJECTIVES: This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci. METHODS: In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs. RESULTS: We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 × 10(-4) with a range of other diseases/traits. CONCLUSIONS: We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk.

Published
2017

26. A powerful statistical framework for generalization testing in GWAS, with application to the HCHS/SOL

Author

Graff, M., Heller, R., Reiner, A.P., North, K.E., Bogomolov, M., Benjamini, Y., Thornton, T.A., Laurie, C.C., Rice, K., Avery, C.L., Kerr, K.F., and Sofer, T.

Abstract

In genome-wide association studies (GWAS), “generalization” is the replication of genotype-phenotype association in a population with different ancestry than the population in which it was first identified. Current practices for declaring generalizations rely on testing associations while controlling the family-wise error rate (FWER) in the discovery study, then separately controlling error measures in the follow-up study. This approach does not guarantee control over the FWER or false discovery rate (FDR) of the generalization null hypotheses. It also fails to leverage the two-stage design to increase power for detecting generalized associations. We provide a formal statistical framework for quantifying the evidence of generalization that accounts for the (in)consistency between the directions of associations in the discovery and follow-up studies. We develop the directional generalization FWER (FWERg) and FDR (FDRg) controlling r-values, which are used to declare associations as generalized. This framework extends to generalization testing when applied to a published list of Single Nucleotide Polymorphism-(SNP)-trait associations. Our methods control FWERg or FDRg under various SNP selection rules based on P-values in the discovery study. We find that it is often beneficial to use a more lenient P-value threshold than the genome-wide significance threshold. In a GWAS of total cholesterol in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), when testing all SNPs with P-values < 5 × 10-8 (15 genomic regions) for generalization in a large GWAS of whites, we generalized SNPs from 15 regions. But when testing all SNPs with P-values < 6.6 × 10-5 (89 regions), we generalized SNPs from 27 regions.

Published
2017
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27. Genome-wide association study of heart rate and its variability in Hispanic/Latino cohorts

Author

Laurie, C.C., Raffield, L.M., Soliman, E.Z., Jain, D., Guo, X., Lange, L.A., Reiner, A.P., Peters, U., Rotter, J.I., Jackson, R.D., Browning, S.R., Kooperberg, C., Perez, M.V., Sotoodehnia, N., Lin, H.J., Browning, B.L., Sofer, T., Hohensee, C., Li, Y., Méndez-Giráldez, R., Yao, J., Conomos, M.P., Kerr, K.F., Wilson, J.G., Whitsel, E.A., Zhang, Z.-M., Taylor, K.D., Thornton, T.A., Zhang, Q.S., Heckbert, S.R., Gogarten, S.M., and Avery, C.L.

Abstract

Background Although time–domain measures of heart rate variability (HRV) are used to estimate cardiac autonomic tone and disease risk in multiethnic populations, the genetic epidemiology of HRV in Hispanics/Latinos has not been characterized. Objective The purpose of this study was to conduct a genome-wide association study of heart rate (HR) and its variability in the Hispanic Community Health Study/Study of Latinos, Multi-Ethnic Study of Atherosclerosis, and Women's Health Initiative Hispanic SNP-Health Association Resource project (n = 13,767). Methods We estimated HR (bpm), standard deviation of normal-to-normal interbeat intervals (SDNN, ms), and root mean squared difference in successive, normal-to-normal interbeat intervals (RMSSD, ms) from resting, standard 12-lead ECGs. We estimated associations between each phenotype and 17 million genotyped or imputed single nucleotide polymorphisms (SNPs), accounting for relatedness and adjusting for age, sex, study site, and ancestry. Cohort-specific estimates were combined using fixed-effects, inverse-variance meta-analysis. We investigated replication for select SNPs exceeding genome-wide (P

Published
2017
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28. Genome-wide Trans-ethnic Meta-analysis Identifies Seven Genetic Loci Influencing Erythrocyte Traits and a Role for RBPMS in Erythropoiesis

Author

Rooij, F.J.A. (Frank) van, Qayyum, Q. (Rehan), Smith, A.V. (Albert Vernon), Zhou, Y. (Yi), Trompet, S. (Stella), Tanaka, T. (Toshiko), Keller, M.F. (Margaux), Chang, L.-C. (Li-Ching), Schmidt, H. (Helena), Yang, M.-L. (Min-Lee), Chen, M.-H. (Ming-Huei), Hayes, J. (James), Johnson, A.D. (Andrew), Yanek, L.R. (Lisa), Mueller, C. (Christian), Lange, L.A. (Leslie), Floyd, J. (James), Ghanbari, M. (Mohsen), Zonderman, A.B., Jukema, J.W., Hofman, A. (Albert), Duijn, C.M. (Cornelia) van, Desch, K.C. (Karl C.), Saba, Y. (Yasaman), Ozel, A.B. (Ayse), Snively, B.M. (Beverly M.), Wu, J.-Y. (Jer-Yuarn), Schmidt, R. (Reinhold), Fornage, M. (Myriam), Klein, R.J. (Robert J.), Fox, C.S. (Caroline), Matsuda, K. (Koichi), Kamatani, N. (Naoyuki), Wild, P.S. (Philipp S.), Stott, D.J. (David J.), Ford, I., Slagboom, P.E. (Eline), Yang, J. (Jaden), Chu, A.Y. (Audrey Y), Lambert, A.J. (Amy J.), Uitterlinden, A.G. (André), Franco, O.H. (Oscar), Hofer, E. (Edith), Ginsburg, D. (David), Hu, B. (Bella), Keating, J. (John), Schick, U.M. (Ursula), Brody, J.A. (Jennifer A.), Li, J.Z. (Jun Z.), Chen, Z. (Zhao), Zeller, T. (Tanja), Guralnik, J.M. (Jack M.), Chasman, D.I. (Daniel), Peters, L.L. (Luanne L.), Kubo, M. (Michiaki), Becker, D.M. (Diane M.), Li, J. (Jin), Eiriksdottir, G. (Gudny), Rotter, J.I. (Jerome I.), Levy, D. (Daniel), Grossmann, V. (Vera), Patel, K.V. (Kushang V.), Chen, C.-H., Ridker, P.M. (Paul M.), Tang, H. (Hua), Launer, L.J. (Lenore), Rice, K.M. (Kenneth M.), Li-Gao, R. (Ruifang), Ferrucci, L. (Luigi), Evans, M.K. (Michelle K.), Choudhuri, A. (Avik), Trompouki, E. (Eirini), Abraham, B.J. (Brian J.), Yang, S. (Song), Takahashi, A. (Atsushi), Kamatani, Y. (Yoichiro), Kooperberg, C. (Charles), Harris, T.B. (Tamara), Jee, S.H. (Sun Ha), Coresh, J. (Josef), Tsai, F.-J. (Fuu-Jen), Longo, D.L. (Dan L.), Chen, Y.-T. (Yuan-Tsong), Felix, J.F. (Janine), Yang, Q. (Qiong), Psaty, B.M. (Bruce), Boerwinkle, E.A. (Eric), Becker, L.C. (Lewis C.), Mook-Kanamori, D.O. (Dennis), Wilson, J.F. (James), Gudnason, V. (Vilmundur), O'Donnell, C.J. (Christopher J.), Dehghan, A. (Abbas), Cupples, L.A. (Adrienne), Nalls, M.A. (Michael), Morris, A.P. (Andrew), Okada, Y. (Yukinori), Reiner, A.P. (Alexander P.), Zon, L.I. (Leonard), Ganesh, S.K. (Santhi), Rooij, F.J.A. (Frank) van, Qayyum, Q. (Rehan), Smith, A.V. (Albert Vernon), Zhou, Y. (Yi), Trompet, S. (Stella), Tanaka, T. (Toshiko), Keller, M.F. (Margaux), Chang, L.-C. (Li-Ching), Schmidt, H. (Helena), Yang, M.-L. (Min-Lee), Chen, M.-H. (Ming-Huei), Hayes, J. (James), Johnson, A.D. (Andrew), Yanek, L.R. (Lisa), Mueller, C. (Christian), Lange, L.A. (Leslie), Floyd, J. (James), Ghanbari, M. (Mohsen), Zonderman, A.B., Jukema, J.W., Hofman, A. (Albert), Duijn, C.M. (Cornelia) van, Desch, K.C. (Karl C.), Saba, Y. (Yasaman), Ozel, A.B. (Ayse), Snively, B.M. (Beverly M.), Wu, J.-Y. (Jer-Yuarn), Schmidt, R. (Reinhold), Fornage, M. (Myriam), Klein, R.J. (Robert J.), Fox, C.S. (Caroline), Matsuda, K. (Koichi), Kamatani, N. (Naoyuki), Wild, P.S. (Philipp S.), Stott, D.J. (David J.), Ford, I., Slagboom, P.E. (Eline), Yang, J. (Jaden), Chu, A.Y. (Audrey Y), Lambert, A.J. (Amy J.), Uitterlinden, A.G. (André), Franco, O.H. (Oscar), Hofer, E. (Edith), Ginsburg, D. (David), Hu, B. (Bella), Keating, J. (John), Schick, U.M. (Ursula), Brody, J.A. (Jennifer A.), Li, J.Z. (Jun Z.), Chen, Z. (Zhao), Zeller, T. (Tanja), Guralnik, J.M. (Jack M.), Chasman, D.I. (Daniel), Peters, L.L. (Luanne L.), Kubo, M. (Michiaki), Becker, D.M. (Diane M.), Li, J. (Jin), Eiriksdottir, G. (Gudny), Rotter, J.I. (Jerome I.), Levy, D. (Daniel), Grossmann, V. (Vera), Patel, K.V. (Kushang V.), Chen, C.-H., Ridker, P.M. (Paul M.), Tang, H. (Hua), Launer, L.J. (Lenore), Rice, K.M. (Kenneth M.), Li-Gao, R. (Ruifang), Ferrucci, L. (Luigi), Evans, M.K. (Michelle K.), Choudhuri, A. (Avik), Trompouki, E. (Eirini), Abraham, B.J. (Brian J.), Yang, S. (Song), Takahashi, A. (Atsushi), Kamatani, Y. (Yoichiro), Kooperberg, C. (Charles), Harris, T.B. (Tamara), Jee, S.H. (Sun Ha), Coresh, J. (Josef), Tsai, F.-J. (Fuu-Jen), Longo, D.L. (Dan L.), Chen, Y.-T. (Yuan-Tsong), Felix, J.F. (Janine), Yang, Q. (Qiong), Psaty, B.M. (Bruce), Boerwinkle, E.A. (Eric), Becker, L.C. (Lewis C.), Mook-Kanamori, D.O. (Dennis), Wilson, J.F. (James), Gudnason, V. (Vilmundur), O'Donnell, C.J. (Christopher J.), Dehghan, A. (Abbas), Cupples, L.A. (Adrienne), Nalls, M.A. (Michael), Morris, A.P. (Andrew), Okada, Y. (Yukinori), Reiner, A.P. (Alexander P.), Zon, L.I. (Leonard), and Ganesh, S.K. (Santhi)

Abstract

Genome-wide association studies (GWASs) have identified loci for erythrocyte traits in primarily European ancestry populations. We conducted GWAS meta-analyses of six erythrocyte traits in 71,638 individuals from European, East Asian, and African ancestries using a Bayesian approach to account for heterogeneity in allelic effects and variation in the structure of linkage disequilibrium between ethnicities. We identified seven loci for erythrocyte traits including a locus (RBPM

Published
2017
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29. Adult height, coronary heart disease and stroke: a multi-locus Mendelian randomization meta-analysis

Author

Nuesch, E., Dale, C., Palmer, T.M., White, J., Keating, B.J., van Iperen, E.P., Goel, A., Padmanabhan, S., Asselbergs, F.W., Verschuren, W., Wijmenga, C., Van der Schouw, Y., Onland-Moret, N., Lange, L.A., Hovingh, G., Sivapalaratnam, S., Morris, R.W., Whincup, P.H., Wannamethe, G.S., Gaunt, T.R., Ebrahim, S., Steel, L., Nair, N., Reiner, A.P., Kooperberg, C., Wilson, J.F., Bolton, J.L., McLachlan, S., Price, J.F., Strachan, M.W., Robertson, C.M., Kleber, M.E., Delgado, G., Marz, W., Melander, O., Dominiczak, A.F., Farrall, M., Watkins, H., Leusink, M., Maitland-van der Zee, A.H., de Groot, M.C., Dudbridge, F., Hingorani, A., Ben-Shlomo, Y., Lawlor, D.A., Amuzu, A., Caufield, M., Cavadino, A., Cooper, J., Davies, T., Drenos, F., Engmann, J., Finan, C., Giambartolomei, C., Hardy, R., Humphries, S., Hypponen, E., Kivimaki, M., Kuh, D., Kumari, M., Ong, K., Plagnol, V., Power, C., Richards, M., Shah, S., Shah, T., Sofat, R., Talmud, P., Wareham, N., Warren, H., Whittaker, J., Wong, A., Zabaneh, D., Davey Smith, G., Wells, J.C., Leon, D.A., Holmes, M.V., and Casas, J.P.

Subjects
Blood Pressure, Coronary Disease, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, Body Height, Body Mass Index, Respiratory Function Tests, Stroke, Observational Studies as Topic, Cholesterol, Logistic Models, Risk Factors, Humans, Mendelian Randomisation and Instrumental Variable Analysis, Genetic Predisposition to Disease, Triglycerides
Abstract

Background: We investigated causal effect of completed growth, measured by adult height, on coronary heart disease (CHD), stroke and cardiovascular traits, using instrumental variable (IV) Mendelian randomization meta-analysis.\ud \ud Methods: We developed an allele score based on 69 single nucleotide polymorphisms (SNPs) associated with adult height, identified by the IBCCardioChip, and used it for IV analysis against cardiovascular risk factors and events in 21 studies and 60 028 participants. IV analysis on CHD was supplemented by summary data from 180 height-SNPs from the GIANT consortium and their corresponding CHD estimates derived from CARDIoGRAMplusC4D.\ud \ud Results: IV estimates from IBCCardioChip and GIANT-CARDIoGRAMplusC4D showed that a 6.5-cm increase in height reduced the odds of CHD by 10% [odds ratios 0.90; 95% confidence intervals (CIs): 0.78 to 1.03 and 0.85 to 0.95, respectively],which agrees with the estimate from the Emerging Risk Factors Collaboration (hazard ratio 0.93; 95% CI: 0.91 to 0.94). IV analysis revealed no association with stroke (odds ratio 0.97; 95% CI: 0.79 to 1.19). IV analysis showed that a 6.5-cm increase in height resulted in lower levels of body mass index (P

Published
2016

30. PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study

Author

Schmidt, A.F., Swerdlow, D.I., Holmes, M.V., Patel, R.S., Fairhurst-Hunter, Z., Lyall, D.M., Hartwig, F.P., Horta, B.L., Hypponen, E., Power, C., Moldovan, M., Iperen, E. van, Hovingh, G.K., Demuth, I., Norman, K., Steinhagen-Thiessen, E., Demuth, J., Bertram, L., Liu, T., Coassin, S., Willeit, J., Kiechl, S., Willeit, K., Mason, D., Wright, J., Morris, R., Wanamethee, G., Whincup, P., Ben-Shlomo, Y., McLachlan, S., Price, J.F., Kivimaki, M., Welch, C., Sanchez-Galvez, A., Marques-Vidal, P., Nicolaides, A., Panayiotou, A.G., Onland-Moret, N.C., Schouw, Y.T. van der, Matullo, G., Fiorito, G., Guarrera, S., Sacerdote, C., Wareham, N.J., Langenberg, C., Scott, R., Luan, J.A., Bobak, M., Malyutina, S.A., Pajak, A., Kubinova, R., Tamosiunas, A., Pikhart, H., Husemoen, L.L.N., Grarup, N., Pedersen, O., Hansen, T., Linneberg, A., Simonsen, K.S., Cooper, J., Humphries, S.E., Brilliant, M., Kitchner, T., Hakonarson, H., Carrell, D.S., McCarty, C.A., Kirchner, H.L., Larson, E.B., Crosslin, D.R., Andrade, M. de, Roden, D.M., Denny, J.C., Carty, C., Hancock, S., Attia, J., Holliday, E., Donnell, M.O., Yusuf, S., Chong, M., Pare, G., Harst, P. van der, Said, M.A., Eppinga, R.N., Verweij, N., Snieder, H., Christen, T., Mook-Kanamori, D.O., Gustafsson, S., Lind, L., Ingelsson, E., Pazoki, R., Franco, O., Hofman, A., Uitterlinden, A., Dehghan, A., Teumer, A., Baumeister, S., Dorr, M., Lerch, M.M., Volker, U., Volzke, H., Ward, J., Pell, J.P., Smith, D.J., Meade, T., Maitland-van der Zee, A.H., Baranova, E.V., Young, R., Ford, I., Campbell, A., Padmanabhan, S., Bots, M.L., Grobbee, D.E., Froguel, P., Thuillier, D., Balkau, B., Bonnefond, A., Cariou, B., Smart, M., Bao, Y., Kumari, M., Mahajan, A., Ridker, P.M., Chasman, D.I., Reiner, A.P., Lange, L.A., Ritchie, M.D., Asselbergs, F.W., Casas, J.P., Keating, B.J., Preiss, D., Hingorani, A.D., Sattar, N., LifeLines Cohort Study Grp, UCLEB Consortium, Centre for Paediatric Epidemiology and Biostatistics, University College of London [London] (UCL), MRC Centre for Epidemiology of Child Health, UCL Institute of Child Health, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Dept. of Gastroenterology, Hepatology and Endocrinology, Neuroepidemiology of Ageing Research Unit, Imperial College London, Institut des Sciences Moléculaires (ISM), Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Université Sciences et Technologies - Bordeaux 1-Université Montesquieu - Bordeaux 4-Institut de Chimie du CNRS (INC), Division of Community Health Sciences, St George's University of London, Department of Social Medicine, University of Bristol [Bristol], Finnish Institute of Occupational Health of Helsinki, Department of Epidemiology and Public Health, Institute of Social and Preventive Medicine, Lausanne university hospital, Computer Science Department, University of Cyprus, Cyprus Institute of Neurology and Genetics, University Medical Center [Utrecht], Department of Genetics, Biology and Biochemistry, University of Turin, Institute for Scientific Interchange Foundation, Center for Cancer Prevention, CPO-Piemonte, Unità di epidemiologia dei tumori, Università degli studi di Torino (UNITO)-HuGeF Foundation, Medical Research Council Epidemiology Unit, University of Cambridge [UK] (CAM), Serono Genetics Institute S.A.[Evry], Serono Genetics Institute, Institute of Internal and Preventive Medicine Sibe rian Branch, Russian Academy of Medical Sciences, Institute of Internal Medicine, Novosibirsk State Medical University, Centre for Environmental Health, National Institute of Public Health [Prague], Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR), Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), University of Copenhagen = Københavns Universitet (KU), Research Centre for Prevention and Health (RCPH), Department of Public Health [Copenhagen], University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU)-Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU)-Capital Region of Denmark, Rigshospitalet [Copenhagen], Copenhagen University Hospital, BHF Laboratories, Rayne building, Department of Medicine, 5 University Street, The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia]-Children’s Hospital of Philadelphia (CHOP ), Population Health Research Institute, Institut de Physique et Chimie des Matériaux de Strasbourg (IPCMS), Université de Strasbourg (UNISTRA)-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Unit of Genetic Epidemiology and Bioinformatics, Department of Epidemiology, University Medical Center Groningen, University of Groningen [Groningen], Augusta University - Medical College of Georgia, University System of Georgia (USG)-University System of Georgia (USG), Limnology, Ecology, Uppsala Universitet [Uppsala], Metacohorts Consortium, Erasmus University Medical Center [Rotterdam] (Erasmus MC), King‘s College London, Interfaculty Institute for Genetics and Functional Genomics, Universität Greifswald - University of Greifswald, Institute for Community Medicine, Department of Oncology and Metabolism [Sheffield, UK], The University of Sheffield [Sheffield, U.K.], European Associated Laboratory [Sheffield, UK] (Sarcoma Research Unit), Robertson Centre for Biostatistics, University of Glasgow, Faculty of Medicine, University of Glasgow, Julius Center for Health Sciences and Primary Care, Génétique des maladies multifactorielles (GMM), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), INSERM UMRS 1178, Institut de recherche en biothérapie (IRB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Physics, Indian Institute of Technology Kanpur (IIT Kanpur), Department of Pathological Biochemistry, Royal Infirmary, Wareham, Nicholas [0000-0003-1422-2993], Langenberg, Claudia [0000-0002-5017-7344], Luan, Jian'an [0000-0003-3137-6337], and Apollo - University of Cambridge Repository

Subjects
Blood Glucose, Cohort Studies, Diabetes Mellitus, Type 2, Case-Control Studies, [SDV]Life Sciences [q-bio], Genetic Variation, Humans, Genetic Predisposition to Disease, Cholesterol, LDL, Mendelian Randomization Analysis, Proprotein Convertase 9, Randomized Controlled Trials as Topic
Abstract

BACKGROUND:Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way offsets their substantial benefits. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk.METHODS:In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores.FINDINGS:Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL cholesterol showed associations with increased fasting glucose (0·09 mmol/L, 95% CI 0·02 to 0·15), bodyweight (1·03 kg, 0·24 to 1·82), waist-to-hip ratio (0·006, 0·003 to 0·010), and an odds ratio for type diabetes of 1·29 (1·11 to 1·50). Based on the collected data, we did not identify associations with HbA1c (0·03%, -0·01 to 0·08), fasting insulin (0·00%, -0·06 to 0·07), and BMI (0·11 kg/m2, -0·09 to 0·30).INTERPRETATION:PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefits of PCSK9 inhibitor treatment, as was previously done for statins.FUNDING:British Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre.

Published
2016

31. Low-frequency and common genetic variation in ischemic stroke : the METASTROKE collaboration

Author

Malik, R., Traylor, M., Pulit, S.L., Bevan, S., Hopewell, J.C., Holliday, E.G., Zhao, W., Abrantes, P., Amouyel, P., Attia, J.R., Battey, T.W., Berger, K., Boncoraglio, G.B., Chauhan, G., Cheng, Y.C., Chen, W.M., Clarke, R., Cotlarciuc, I., Debette, S., Falcone, G.J., Ferro, J.M., Gamble, D.M., Ilinca, A., Kittner, S.J., Kourkoulis, C.E., Lemmens, R., Levi, C.R., Lichtner, P., Lindgren, A., Liu, J., Meschia, J.F., Mitchell, B.D., Oliveira, S.A., Pera, J., Reiner, A.P., Rothwell, P.M., Sharma, P., Slowik, A., Sudlow, C.L., Tatlisumak, T., Thijs, V., Vicente, A.M., Woo, D., Seshadri, S., Saleheen, D., Rosand, J., Markus, H.S., Worrall, B.B., Dichgans, M., ISGC Analysis Group, METASTROKE collaboration, Wellcome Trust Case Control Consortium 2 (WTCCC2), and NINDS Stroke Genetics Network (SiGN)

Subjects
0301 basic medicine, medicine.medical_specialty, Genome-wide association study, Polymorphism, Single Nucleotide, Gastroenterology, Article, Brain Ischemia, Doenças Cardio e Cérebro-vasculares, 03 medical and health sciences, 0302 clinical medicine, Missing heritability problem, Internal medicine, ABO blood group system, Genetic variation, Humans, Medicine, Cooperative Behavior, 1000 Genomes Project, Allele frequency, Stroke, Ischemic Stroke, Genetic association, Genetics, business.industry, Genetic Variation, Correction, medicine.disease, 030104 developmental biology, Case-Control Studies, Ischemic stroke, Cardiology, Neurology (clinical), business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Erratum in: Low-frequency and common genetic variation in ischemic stroke: The METASTROKE collaboration. [Neurology. 2016] Objective: To investigate the influence of common and low-frequency genetic variants on the risk of ischemic stroke (all IS) and etiologic stroke subtypes. Methods: We meta-analyzed 12 individual genome-wide association studies comprising 10,307 cases and 19,326 controls imputed to the 1000 Genomes (1 KG) phase I reference panel. We selected variants showing the highest degree of association (p , 1E-5) in the discovery phase for replication in Caucasian (13,435 cases and 29,269 controls) and South Asian (2,385 cases and 5,193 controls) samples followed by a transethnic meta-analysis. We further investigated the p value distribution for different bins of allele frequencies for all IS and stroke subtypes. Results: We showed genome-wide significance for 4 loci: ABO for all IS, HDAC9 for large vessel disease (LVD), and both PITX2 and ZFHX3 for cardioembolic stroke (CE). We further refined the association peaks for ABO and PITX2. Analyzing different allele frequency bins, we showed significant enrichment in low-frequency variants (allele frequency ,5%) for both LVD and small vessel disease, and an enrichment of higher frequency variants (allele frequency 10% and 30%) for CE (all p , 1E-5). Conclusions: Our findings suggest that the missing heritability in IS subtypes can in part be attributed to low-frequency and rare variants. Larger sample sizes are needed to identify the variants associated with all IS and stroke subtypes.

Published
2016

32. Corrigendum: Rare coding variants and X-linked loci associated with age at menarche

Author

Lunetta, K.L., Day, F.R., Sulem, P., Ruth, K.S., Tung, J.Y., Hinds, D.A., Esko, T., Elks, C.E., Altmaier, E., He, C., Huffman, J.E., Mihailov, E., Porcu, E., Robino, A., Rose, L.M., Schick, U.M., Stolk, L., Teumer, A., Thompson, D.J., Traglia, M., Wang, C.A., Yerges-Armstrong, L.M., Antoniou, A.C., Barbieri, C., Coviello, A.D., Cucca, F., Demerath, E.W., Dunning, A.M., Gandin, I., Grove, M.L., Gudbjartsson, D.F., Hocking, L.J., Hofman, A., Huang, J., Jackson, R.D., Karasik, D., Kriebel, J., Lange, E.M., Lange, L.A., Langenberg, C., Li, X., Luan, J., Mägi, R., Morrison, A.C., Padmanabhan, S., Pirie, A., Polasek, O., Porteous, D.J., Reiner, A.P., Rivadeneira, F., Rudan, I., Sala, C.F., Schlessinger, D., Scott, R.A., Stöckl, D., Visser, J.A., Völker, U., Vozzi, D., Wilson, J.G., Zygmunt, M., EPIC-Interact Consortium (), Generation Scotland Consortium (), Boerwinkle, E., Buring, J.E., Crisponi, L., Easton, D.F., Hayward, C., Hu, F.B., Liu, S., Metspalu, A., Pennell, C.E., Ridker, P.M., Strauch, K., Streeten, E.A., Toniolo, D., Uitterlinden, A.G., Ulivi, S., Völzke, H., Wareham, N.J., Wellons, M., Franceschini, N., Chasman, D.I., Thorsteinsdottir, U., Murray, A., Stefansson, K., Murabito, J.M., Ong, K.K., and Perry, J.R.

Subjects
Adult, Adolescent, Genotype, Mutation, Missense, Immunoglobulins, Cell Cycle Proteins, Penetrance, AMP-Activated Protein Kinases, Autoantigens, White People, Young Adult, Gene Frequency, Genes, X-Linked, Humans, Aged, Menarche, Chromosomes, Human, X, Hypogonadism, Fatty Acids, Age Factors, Genetic Variation, Membrane Proteins, Proteins, RNA-Binding Proteins, Receptors, Neurokinin-3, Middle Aged, Corrigenda, Amides, Phenotype, Codon, Nonsense, Female, RNA Interference, Laminin, Energy Metabolism, Signal Transduction
Abstract

More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only ∼3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; P5 × 10(-8)). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P=9.4 × 10(-13)) and FAAH2 (rs5914101, P=4.9 × 10(-10)). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P=2.8 × 10(-11)), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain ∼0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait.

Published
2015

33. Cystatin C and Cardiovascular Disease: A Mendelian Randomization Study

Author

Laan, S.W. van der, Fall, T., Soumare, A., Teumer, A., Sedaghat, S., Baumert, J., Zabaneh, D., Setten, J. van, Isgum, I., Galesloot, T.E., Arpegard, J., Amouyel, P., Trompet, S., Waldenberger, M., Dorr, M., Magnusson, P.K., Giedraitis, V., Larsson, A., Morris, A.P., Felix, J.F., Morrison, A.C., Franceschini, N., Bis, J.C., Kavousi, M., O'Donnell, C., Drenos, F., Tragante, V., Munroe, P.B., Malik, R., Dichgans, M., Worrall, B.B., Erdmann, J., Nelson, C.P., Samani, N.J., Schunkert, H., Marchini, J., Patel, R.S., Hingorani, A.D., Lind, L., Pedersen, N.L., Graaf, J. de, Kiemeney, L.A.L.M., Baumeister, S.E., Franco, O.H., Hofman, A., Uitterlinden, A.G., Koenig, W., Meisinger, C., Peters, A., Thorand, B., Jukema, J.W., Eriksen, B.O., Toft, I., Wilsgaard, T., Onland-Moret, N.C., Schouw, Y.T. van der, Debette, S., Kumari, M., Svensson, P., Harst, P. van der, Kivimäki, M., Keating, B.J., Sattar, N., Dehghan, A., Reiner, A.P., Ingelsson, E., Ruijter, H.M. Den, Bakker, P.I. de, Pasterkamp, G., Arnlov, J., Holmes, M.V., Asselbergs, F.W., Laan, S.W. van der, Fall, T., Soumare, A., Teumer, A., Sedaghat, S., Baumert, J., Zabaneh, D., Setten, J. van, Isgum, I., Galesloot, T.E., Arpegard, J., Amouyel, P., Trompet, S., Waldenberger, M., Dorr, M., Magnusson, P.K., Giedraitis, V., Larsson, A., Morris, A.P., Felix, J.F., Morrison, A.C., Franceschini, N., Bis, J.C., Kavousi, M., O'Donnell, C., Drenos, F., Tragante, V., Munroe, P.B., Malik, R., Dichgans, M., Worrall, B.B., Erdmann, J., Nelson, C.P., Samani, N.J., Schunkert, H., Marchini, J., Patel, R.S., Hingorani, A.D., Lind, L., Pedersen, N.L., Graaf, J. de, Kiemeney, L.A.L.M., Baumeister, S.E., Franco, O.H., Hofman, A., Uitterlinden, A.G., Koenig, W., Meisinger, C., Peters, A., Thorand, B., Jukema, J.W., Eriksen, B.O., Toft, I., Wilsgaard, T., Onland-Moret, N.C., Schouw, Y.T. van der, Debette, S., Kumari, M., Svensson, P., Harst, P. van der, Kivimäki, M., Keating, B.J., Sattar, N., Dehghan, A., Reiner, A.P., Ingelsson, E., Ruijter, H.M. Den, Bakker, P.I. de, Pasterkamp, G., Arnlov, J., Holmes, M.V., and Asselbergs, F.W.

Abstract

Contains fulltext : 172252.pdf (Publisher’s version ) (Open Access), BACKGROUND: Epidemiological studies show that high circulating cystatin C is associated with risk of cardiovascular disease (CVD), independent of creatinine-based renal function measurements. It is unclear whether this relationship is causal, arises from residual confounding, and/or is a consequence of reverse causation. OBJECTIVES: The aim of this study was to use Mendelian randomization to investigate whether cystatin C is causally related to CVD in the general population. METHODS: We incorporated participant data from 16 prospective cohorts (n = 76,481) with 37,126 measures of cystatin C and added genetic data from 43 studies (n = 252,216) with 63,292 CVD events. We used the common variant rs911119 in CST3 as an instrumental variable to investigate the causal role of cystatin C in CVD, including coronary heart disease, ischemic stroke, and heart failure. RESULTS: Cystatin C concentrations were associated with CVD risk after adjusting for age, sex, and traditional risk factors (relative risk: 1.82 per doubling of cystatin C; 95% confidence interval [CI]: 1.56 to 2.13; p = 2.12 x 10(-14)). The minor allele of rs911119 was associated with decreased serum cystatin C (6.13% per allele; 95% CI: 5.75 to 6.50; p = 5.95 x 10(-211)), explaining 2.8% of the observed variation in cystatin C. Mendelian randomization analysis did not provide evidence for a causal role of cystatin C, with a causal relative risk for CVD of 1.00 per doubling cystatin C (95% CI: 0.82 to 1.22; p = 0.994), which was statistically different from the observational estimate (p = 1.6 x 10(-5)). A causal effect of cystatin C was not detected for any individual component of CVD. CONCLUSIONS: Mendelian randomization analyses did not support a causal role of cystatin C in the etiology of CVD. As such, therapeutics targeted at lowering circulating cystatin C are unlikely to be effective in preventing CVD.

Published
2016

34. Meta-analysis of rare and common exome chip variants identifies S1PR4 and other loci influencing blood cell traits

Author

Pankratz, V.S. (Shane), Schick, U.M. (Ursula), Zhou, Y. (Yi), Zhou, W. (Wei), Ahluwalia, T.S. (Tarunveer Singh), Allende, M.L. (Maria Laura), Auer, P. (Paul), Bork-Jensen, J. (Jette), Brody, J.A. (Jennifer A.), Chen, M.-H. (Ming-Huei), Clavo, V. (Vinna), Eicher, J.D. (John D.), Grarup, N. (Niels), Hagedorn, E.J. (Elliott J.), Hu, B. (Bella), Hunker, K. (Kristina), Johnson, A.D. (Andrew), Leusink, M. (Maarten), Lu, Y. (Yingchang), Lyytikäinen, L.-P. (Leo-Pekka), Manichaikul, A. (Ani), Marioni, R.E. (Riccardo), Nalls, M.A. (Michael), Pazoki, R. (Raha), Smith, A.V. (Albert Vernon), Rooij, F.J.A. (Frank) van, Yang, M.-L. (Min-Lee), Zhang, X. (Xiaoling), Zhang, Y. (Yan), Asselbergs, F.W. (Folkert), Boerwinkle, E.A. (Eric), Borecki, I.B. (Ingrid), Bottinger, E.P. (Erwin), Cushman, M. (Mary Ann), Bakker, P.I.W. (Paul) de, Deary, I.J. (Ian), Dong, L. (Liguang), Feitosa, M.F. (Mary Furlan), Floyd, J. (James), Franceschini, N. (Nora), Franco, O.H. (Oscar), Garcia, M. (Melissa), Grove, M.L. (Megan), Gudnason, V. (Vilmundur), Hansen, T. (T.), Harris, T.B. (Tamara), Hofman, A. (Albert), Jackson, R.D. (Rebecca), Jia, J. (Jia), Kähönen, M. (Mika), Launer, L.J. (Lenore J.), Lehtimäki, T. (Terho), Liewald, D.C.M. (David), Linneberg, A. (Allan), Liu, Y. (YongMei), Loos, R.J.F. (Ruth), Nguyen, V.M. (Vy M.), Numans, M.E. (Mattijs), Pedersen, O. (Oluf), Psaty, B.M. (Bruce M.), Raitakari, O.T. (Olli T.), Rich, S.S. (Stephen), Rivadeneira Ramirez, F. (Fernando), Di Sant, A.M.R. (Amanda M. Rosa), Rotter, J.I. (Jerome I.), Starr, J.M. (John), Taylor, K.D. (Kent), Thuesen, B.H. (Betina Heinsbek), Tracy, R.P. (Russell), Uitterlinden, A.G. (André), Wang, J. (Jiansong), Wang, J. (Judy), Dehghan, A. (Abbas), Huo, Y. (Yong), Cupples, L.A. (Adrienne), Wilson, J.F. (James), Proia, R.L. (Richard L.), Zon, L.I. (Leonard), O'Donnell, C.J. (Christopher), Reiner, A.P. (Alex P.), Ganesh, S.K. (Santhi), Pankratz, V.S. (Shane), Schick, U.M. (Ursula), Zhou, Y. (Yi), Zhou, W. (Wei), Ahluwalia, T.S. (Tarunveer Singh), Allende, M.L. (Maria Laura), Auer, P. (Paul), Bork-Jensen, J. (Jette), Brody, J.A. (Jennifer A.), Chen, M.-H. (Ming-Huei), Clavo, V. (Vinna), Eicher, J.D. (John D.), Grarup, N. (Niels), Hagedorn, E.J. (Elliott J.), Hu, B. (Bella), Hunker, K. (Kristina), Johnson, A.D. (Andrew), Leusink, M. (Maarten), Lu, Y. (Yingchang), Lyytikäinen, L.-P. (Leo-Pekka), Manichaikul, A. (Ani), Marioni, R.E. (Riccardo), Nalls, M.A. (Michael), Pazoki, R. (Raha), Smith, A.V. (Albert Vernon), Rooij, F.J.A. (Frank) van, Yang, M.-L. (Min-Lee), Zhang, X. (Xiaoling), Zhang, Y. (Yan), Asselbergs, F.W. (Folkert), Boerwinkle, E.A. (Eric), Borecki, I.B. (Ingrid), Bottinger, E.P. (Erwin), Cushman, M. (Mary Ann), Bakker, P.I.W. (Paul) de, Deary, I.J. (Ian), Dong, L. (Liguang), Feitosa, M.F. (Mary Furlan), Floyd, J. (James), Franceschini, N. (Nora), Franco, O.H. (Oscar), Garcia, M. (Melissa), Grove, M.L. (Megan), Gudnason, V. (Vilmundur), Hansen, T. (T.), Harris, T.B. (Tamara), Hofman, A. (Albert), Jackson, R.D. (Rebecca), Jia, J. (Jia), Kähönen, M. (Mika), Launer, L.J. (Lenore J.), Lehtimäki, T. (Terho), Liewald, D.C.M. (David), Linneberg, A. (Allan), Liu, Y. (YongMei), Loos, R.J.F. (Ruth), Nguyen, V.M. (Vy M.), Numans, M.E. (Mattijs), Pedersen, O. (Oluf), Psaty, B.M. (Bruce M.), Raitakari, O.T. (Olli T.), Rich, S.S. (Stephen), Rivadeneira Ramirez, F. (Fernando), Di Sant, A.M.R. (Amanda M. Rosa), Rotter, J.I. (Jerome I.), Starr, J.M. (John), Taylor, K.D. (Kent), Thuesen, B.H. (Betina Heinsbek), Tracy, R.P. (Russell), Uitterlinden, A.G. (André), Wang, J. (Jiansong), Wang, J. (Judy), Dehghan, A. (Abbas), Huo, Y. (Yong), Cupples, L.A. (Adrienne), Wilson, J.F. (James), Proia, R.L. (Richard L.), Zon, L.I. (Leonard), O'Donnell, C.J. (Christopher), Reiner, A.P. (Alex P.), and Ganesh, S.K. (Santhi)

Abstract

Hematologic measures such as hematocrit and white blood cell (WBC) count are heritable and clinically relevant. We analyzed erythrocyte and WBC phenotypes in 52,531 individuals (37,775 of European ancestry, 11,589 African Americans, and 3,167 Hispanic Americans) from 16 population-based cohorts with Illumina HumanExome BeadChip genotypes. We then performed replication analyses of new discoveries in 18,018 European-American women and 5,261 Han Chinese. We identified and replicated four new erythrocyte trait-locus associations (CEP89, SHROOM3, FADS2, and APOE) and six new WBC loci for neutrophil count (S1PR4), monocyte count (BTBD8, NLRP12, and IL17RA), eosinophil count (IRF1), and total WBC count (MYB). The association of a rare missense variant in S1PR4 supports the role of sphingosine-1-phosphate signaling in leukocyte trafficking and circulating neutrophil counts. Loss-of-function experiments for S1pr4 in mouse and s1pr4 in zebrafish demonstrated phenotypes consistent with the association observed in humans and altered kinetics of neutrophil recruitment and resolution in response to tissue injury.

Published
2016
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35. A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration

Author

Vries, P.S. (Paul) de, Chasman, D.I. (Daniel), Sabater-Lleal, M. (Maria), Chen, M.-H. (Ming-Huei), Huffman, J.E. (Jennifer E.), Steri, M. (Maristella), Tang, W. (Weihong), Teumer, A. (Alexander), Marioni, R.E. (Riccardo), Grossmann, V. (Vera), Hottenga, J.J. (Jouke Jan), Trompet, S. (Stella), Müller-Nurasyid, M. (Martina), Zhao, J.H. (Jing Hua), Brody, J.A. (Jennifer A.), Kleber, M.E. (Marcus), Guo, X. (Xiuqing), Wang, J.J. (Jie Jin), Auer, P. (Paul), Attia, J. (John), Yanek, L.R. (Lisa), Ahluwalia, T.S. (Tarunveer Singh), Lahti, J. (Jari), Venturini, C. (Cristina), Tanaka, T. (Toshiko), Bielak, L.F. (Lawrence F.), Joshi, P.K. (Peter), Rocanin-Arjo, A. (Ares), Kolcic, I. (Ivana), Navarro, P. (Pau), Rose, L.M. (Lynda), Oldmeadow, C. (Christopher), Riess, H. (Helene), Mazur, J. (Johanna), Basu, S. (Saonli), Goel, A. (Anuj), Yang, Q. (Qiong), Ghanbari, M. (Mohsen), Willemsen, G. (Gonneke), Rumley, A. (Ann), Fiorillo, E. (Edoardo), Craen, A.J. (Anton) de, Grotevendt, A. (Anne), Scott, R.A. (Robert), Taylor, K.D. (Kent D.), Delgado, G.E. (Graciela E.), Yao, J. (Jie), Kifley, A. (Annette), Kooperberg, C. (Charles), Qayyum, Q. (Rehan), Lopez, L. (Lornam), Berentzen, T.L. (Tina L.), Räikkönen, K. (Katri), Mangino, M. (Massimo), Bandinelli, S. (Stefania), Peyser, P.A. (Patricia A.), Wild, S. (Sarah), Tregouet, D.-A. (David-Alexandre), Wright, A.F. (Alan), Marten, J. (Jonathan), Zemunik, T. (Tatijana), Morrison, A.C. (Alanna), Sennblad, B. (Bengt), Tofler, G.H. (Geoffrey), Maat, M.P.M. (Moniek) de, Geus, E.J.C. (Eco) de, Lowe, G.D. (Gordon D.), Zoledziewska, M. (Magdalena), Sattar, N. (Naveed), Binder, H. (Harald), Völker, U. (Uwe), Waldenberger, M. (Melanie), Khaw, K.-T. (Kay-Tee), McKnight, B. (Barbara), Huang, J. (Jian), Jenny, N.S. (Nancy), Holliday, E.G. (Elizabeth), Qi, L. (Lihong), Mcevoy, M.G. (Mark G.), Becker, D.M. (Diane), Starr, J.M. (John), Sarin, A.-P., Hysi, P.G. (Pirro), Hernandez, D.G. (Dena), Jhun, M.A. (Min A.), Campbell, H. (Harry), Hamsten, A. (Anders), Sarin, F. (Fernando), McArdle, W.L. (Wendy), Slagboom, P.E. (Eline), Zeller, T. (Tanja), Koenig, W. (Wolfgang), Psaty, B. (Brucem), Haritunians, T. (Talin), Liu, J. (Jingmin), Palotie, A. (Aarno), Uitterlinden, A.G. (André), Stott, D.J. (David J.), Hofman, A. (Albert), Franco, O.H. (Oscar), Polasek, O. (Ozren), Rudan, I. (Igor), Morange, P.-E. (P.), Wilson, J.F. (James F.), Kardia, S.L. (Sharon L.r), Ferrucci, L. (Luigi), Spector, T.D. (Timothy), Eriksson, J.G. (Johan G.), Hansen, T. (Torben), Deary, I.J. (Ian), Becker, L.C. (Lewis), Scott, R.J. (Rodney), Mitchell, P. (Paul), März, W. (Winfried), Wareham, N.J. (Nick J.), Peters, A. (Annette), Greinacher, A. (Andreas), Wild, P.S. (Philipp S.), Jukema, J.W. (Jan Wouter), Boomsma, D.I. (Dorret), Hayward, C. (Caroline), Cucca, F. (Francesco), Tracy, R.P. (Russell), Watkins, H. (Hugh), Reiner, A.P. (Alex P.), Folsom, A.R. (Aaron), Ridker, P.M. (Paul), O'Donnell, C.J. (Christopher J.), Smith, N.L. (Nicholas L.), Strachan, D.P. (David P.), Dehghan, A. (Abbas), Vries, P.S. (Paul) de, Chasman, D.I. (Daniel), Sabater-Lleal, M. (Maria), Chen, M.-H. (Ming-Huei), Huffman, J.E. (Jennifer E.), Steri, M. (Maristella), Tang, W. (Weihong), Teumer, A. (Alexander), Marioni, R.E. (Riccardo), Grossmann, V. (Vera), Hottenga, J.J. (Jouke Jan), Trompet, S. (Stella), Müller-Nurasyid, M. (Martina), Zhao, J.H. (Jing Hua), Brody, J.A. (Jennifer A.), Kleber, M.E. (Marcus), Guo, X. (Xiuqing), Wang, J.J. (Jie Jin), Auer, P. (Paul), Attia, J. (John), Yanek, L.R. (Lisa), Ahluwalia, T.S. (Tarunveer Singh), Lahti, J. (Jari), Venturini, C. (Cristina), Tanaka, T. (Toshiko), Bielak, L.F. (Lawrence F.), Joshi, P.K. (Peter), Rocanin-Arjo, A. (Ares), Kolcic, I. (Ivana), Navarro, P. (Pau), Rose, L.M. (Lynda), Oldmeadow, C. (Christopher), Riess, H. (Helene), Mazur, J. (Johanna), Basu, S. (Saonli), Goel, A. (Anuj), Yang, Q. (Qiong), Ghanbari, M. (Mohsen), Willemsen, G. (Gonneke), Rumley, A. (Ann), Fiorillo, E. (Edoardo), Craen, A.J. (Anton) de, Grotevendt, A. (Anne), Scott, R.A. (Robert), Taylor, K.D. (Kent D.), Delgado, G.E. (Graciela E.), Yao, J. (Jie), Kifley, A. (Annette), Kooperberg, C. (Charles), Qayyum, Q. (Rehan), Lopez, L. (Lornam), Berentzen, T.L. (Tina L.), Räikkönen, K. (Katri), Mangino, M. (Massimo), Bandinelli, S. (Stefania), Peyser, P.A. (Patricia A.), Wild, S. (Sarah), Tregouet, D.-A. (David-Alexandre), Wright, A.F. (Alan), Marten, J. (Jonathan), Zemunik, T. (Tatijana), Morrison, A.C. (Alanna), Sennblad, B. (Bengt), Tofler, G.H. (Geoffrey), Maat, M.P.M. (Moniek) de, Geus, E.J.C. (Eco) de, Lowe, G.D. (Gordon D.), Zoledziewska, M. (Magdalena), Sattar, N. (Naveed), Binder, H. (Harald), Völker, U. (Uwe), Waldenberger, M. (Melanie), Khaw, K.-T. (Kay-Tee), McKnight, B. (Barbara), Huang, J. (Jian), Jenny, N.S. (Nancy), Holliday, E.G. (Elizabeth), Qi, L. (Lihong), Mcevoy, M.G. (Mark G.), Becker, D.M. (Diane), Starr, J.M. (John), Sarin, A.-P., Hysi, P.G. (Pirro), Hernandez, D.G. (Dena), Jhun, M.A. (Min A.), Campbell, H. (Harry), Hamsten, A. (Anders), Sarin, F. (Fernando), McArdle, W.L. (Wendy), Slagboom, P.E. (Eline), Zeller, T. (Tanja), Koenig, W. (Wolfgang), Psaty, B. (Brucem), Haritunians, T. (Talin), Liu, J. (Jingmin), Palotie, A. (Aarno), Uitterlinden, A.G. (André), Stott, D.J. (David J.), Hofman, A. (Albert), Franco, O.H. (Oscar), Polasek, O. (Ozren), Rudan, I. (Igor), Morange, P.-E. (P.), Wilson, J.F. (James F.), Kardia, S.L. (Sharon L.r), Ferrucci, L. (Luigi), Spector, T.D. (Timothy), Eriksson, J.G. (Johan G.), Hansen, T. (Torben), Deary, I.J. (Ian), Becker, L.C. (Lewis), Scott, R.J. (Rodney), Mitchell, P. (Paul), März, W. (Winfried), Wareham, N.J. (Nick J.), Peters, A. (Annette), Greinacher, A. (Andreas), Wild, P.S. (Philipp S.), Jukema, J.W. (Jan Wouter), Boomsma, D.I. (Dorret), Hayward, C. (Caroline), Cucca, F. (Francesco), Tracy, R.P. (Russell), Watkins, H. (Hugh), Reiner, A.P. (Alex P.), Folsom, A.R. (Aaron), Ridker, P.M. (Paul), O'Donnell, C.J. (Christopher J.), Smith, N.L. (Nicholas L.), Strachan, D.P. (David P.), and Dehghan, A. (Abbas)

Abstract

Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels.We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ~120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indelswere examined.We identified 41 genome-wide significant fibrinogen loci; of which, 18were newly identified. Therewere no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.

Published
2016
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36. Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease

Author

Sabater-Lleal, M., Huang, J., Chasman, D., Naitza, S., Dehghan, A., Johnson, A.D., Teumer, A., Reiner, A.P., Folkersen, L., Basu, S., Rudnicka, A.R., Trompet, S., Malarstig, A., Baumert, J., Bis, J.C., Guo, X.Q., Hottenga, J.J., Shin, S.Y., Lopez, L.M., Lahti, J., Tanaka, T., Yanek, L.R., Oudot-Mellakh, T., Wilson, J.F., Navarro, P., Huffman, J.E., Zemunik, T., Redline, S., Mehra, R., Pulanic, D., Rudan, I., Wright, A.F., Kolcic, I., Polasek, O., Wild, S.H., Campbell, H., Curb, J.D., Wallace, R., Liu, S.M., Eaton, C.B., Becker, D.M., Becker, L.C., Bandinelli, S., Raikkonen, K., Widen, E., Palotie, A., Fornage, M., Green, D., Gross, M., Davies, G., Harris, S.E., Liewald, D.C., Starr, J.M., Williams, F.M.K., Grant, P.J., Spector, T.D., Strawbridge, R.J., Silveira, A., Sennblad, B., Rivadeneira, F., Uitterlinden, A.G., Franco, O.H., Hofman, A., Dongen, J. van, Willemsen, G., Boomsma, D.I., Yao, J., Jenny, N.S., Haritunians, T., McKnight, B., Lumley, T., Taylor, K.D., Rotter, J.I., Psaty, B.M., Peters, A., Gieger, C., Illig, T., Grotevendt, A., Homuth, G., Volzke, H., Kocher, T., Goel, A., Franzosi, M.G., Seedorf, U., Clarke, R., Steri, M., Tarasov, K.V., Sanna, S., Schlessinger, D., Stott, D.J., Sattar, N., Buckley, B.M., Rumley, A., Lowe, G.D., McArdle, W.L., Chen, M.H., Tofler, G.H., Song, J., Boerwinkle, E., Folsom, A.R., Rose, L.M., Franco-Cereceda, A., Teichert, M., Ikram, M.A., Mosley, T.H., Bevan, S., Dichgans, M., Rothwell, P.M., Sudlow, C.L.M., Hopewell, J.C., Chambers, J.C., Saleheen, D., Kooner, J.S., Danesh, J., Nelson, C.P., Erdmann, J., Reilly, M.P., Kathiresan, S., Schunkert, H., Morange, P.E., Ferrucci, L., Eriksson, J.G., Jacobs, D., Deary, I.J., Soranzo, N., Witteman, J.C.M., Geus, E.J.C. de, Tracy, R.P., Hayward, C., Koenig, W., Cucca, F., Jukema, J.W., Eriksson, P., Seshadri, S., Markus, H.S., Watkins, H., Samani, N.J., Wallaschofski, H., Smith, N.L., Tregouet, D., Ridker, P.M., Tang, W.H., Strachan, D.P., Hamsten, A., O'Donnell, C.J., VTE Consortium, STROKE Consortium, WTCCC2, CD4 Consortium, CARDIoGRAM Consortium, Epidemiology, Cell biology, Urology, Internal Medicine, Immunology, Radiology & Nuclear Medicine, Biological Psychology, and EMGO+ - Lifestyle, Overweight and Diabetes

Subjects
Male, Netherlands Twin Register (NTR), Pathology, Myocardial Infarction, Genome-wide association study, Coronary Artery Disease, Disease, VARIANTS, 030204 cardiovascular system & hematology, Fibrinogen, Genome, 0302 clinical medicine, Risk Factors, Genotype, ARTERY-DISEASE, GENE-EXPRESSION, Aged, 80 and over, Genetics, INDIVIDUAL PARTICIPANT METAANALYSIS, 0303 health sciences, Hispanic or Latino, Venous Thromboembolism, Middle Aged, 3. Good health, Stroke, Meta-analysis, Medical genetics, Female, HEALTH, Cardiology and Cardiovascular Medicine, medicine.drug, Adult, medicine.medical_specialty, cardiovascular diseases, fibrinogen, gene expression, genome-wide association study, Adolescent, Implementation Science [NCEBP 3], Black People, Polymorphism, Single Nucleotide, White People, Young Adult, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Physiology (medical), medicine, Humans, CORONARY-HEART-DISEASE, HEMOSTASIS, Genetic Predisposition to Disease, Aged, 030304 developmental biology, business.industry, Heritability, GENOTYPES, MYOCARDIAL-INFARCTION, Genetic Loci, RISK-FACTORS, business
Abstract

Background— Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants so far identified by genome-wide association studies explain only a small proportion ( Methods and Results— We conducted a meta-analysis of 28 genome-wide association studies including >90 000 subjects of European ancestry, the first genome-wide association meta-analysis of fibrinogen levels in 7 studies in blacks totaling 8289 samples, and a genome-wide association study in Hispanics totaling 1366 samples. Evaluation for association of single-nucleotide polymorphisms with clinical outcomes included a total of 40 695 cases and 85 582 controls for coronary artery disease, 4752 cases and 24 030 controls for stroke, and 3208 cases and 46 167 controls for venous thromboembolism. Overall, we identified 24 genome-wide significant ( P −8 ) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the 3 structural fibrinogen genes and pathways related to inflammation, adipocytokines, and thyrotrophin-releasing hormone signaling. Whereas lead single-nucleotide polymorphisms in a few loci were significantly associated with coronary artery disease, the combined effect of all 24 fibrinogen-associated lead single-nucleotide polymorphisms was not significant for coronary artery disease, stroke, or venous thromboembolism. Conclusions— We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and coronary artery disease, stroke, or venous thromboembolism.

Published
2013

37. The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis

Author

Swerdlow, D.I., Holmes, M.V., Kuchenbaecker, K.B., Engmann, J.E.L., Shah, T., Sofat, R., Guo, Y.R., Chung, C., Peasey, A., Ster, R.P., Mooijaart, S.P., Ireland, H.A., Leusink, M., Langenberg, C., Li, K., Palmen, J., Howard, P., Cooper, J.A., Drenos, F., Hardy, J., Nalls, M.A., Li, Y.R., Lowe, G., Stewart, M., Bielinski, S.J., Peto, J., Timpson, N.J., Gallacher, J., Dunlop, M., Houlston, R., Tomlinson, I., Tzoulaki, I., Luan, J., Boer, J.M.A., Forouhi, N.G., Onland-Moret, N.C., Schouw, Y.T. van der, Schnabel, R.B., Hubacek, J.A., Kubinova, R., Baceviciene, M., Tamosiunas, A., Pajak, A., Topor-Madry, R., Malyutina, S.A., Baldassarre, D., Sennblad, B., Tremoli, E., Faire, U. de, Ferrucci, L., Bandenelli, S., Tanaka, T., Meschia, J.F., Singleton, A., Navis, G., Leach, I.M., Bakker, S.J.L., Gansevoort, R.T., Ford, I., Epstein, S.E., Burnett, M.S., Devaney, J.M., Jukema, J.W., Westendorp, R.G.J., Borst, G.J. de, Graaf, Y. van der, Jong, P.A. de, Maitland-van der Zee, A.H., Klungel, O.H., Boer, A. de, Doevendans, P.A., Stephens, J.W., Eaton, C.B., Robinson, J.G., Manson, J.E., Fowkes, F.G.R., Frayling, T.M., Price, J.F., Whincup, P.H., Morris, R.W., Lawlor, D.A., Smith, G.D., Ben-Shlomo, Y., Redline, S., Lange, L.A., Kumari, M., Wareham, N.J., Verschuren, W.M.M., Benjamin, E.J., Whittaker, J.C., Hamsten, A., Dudbridge, F., Delaney, J.A.C., Wong, A., Kuh, D., Hardy, R., Castillo, B.A., Connolly, J.J., Harst, P. van der, Brunner, E.J., Marmot, M.G., Wassel, C.L., Humphries, S.E., Talmud, P.J., Kivimaki, M., Asselbergs, F.W., Voevoda, M., Bobak, M., Pikhart, H., Wilson, J.G., Hakonarson, H., Reiner, A.P., Keating, B.J., Sattar, N., Hingorani, A.D., Casas, J.P., and Interleukin-6 Receptor Mendelian R

Abstract

BACKGROUND: A high circulating concentration of interleukin 6 is associated with increased risk of coronary heart disease. Blockade of the interleukin-6 receptor (IL6R) with a monoclonal antibody (tocilizumab) licensed for treatment of rheumatoid arthritis reduces systemic and articular inflammation. However, whether IL6R blockade also reduces risk of coronary heart disease is unknown. METHODS: Applying the mendelian randomisation principle, we used single nucleotide polymorphisms (SNPs) in the gene IL6R to evaluate the likely efficacy and safety of IL6R inhibition for primary prevention of coronary heart disease. We compared genetic findings with the effects of tocilizumab reported in randomised trials in patients with rheumatoid arthritis. FINDINGS: In 40 studies including up to 133,449 individuals, an IL6R SNP (rs7529229) marking a non-synonymous IL6R variant (rs8192284; p.Asp358Ala) was associated with increased circulating log interleukin-6 concentration (increase per allele 9·45%, 95% CI 8·34-10·57) as well as reduced C-reactive protein (decrease per allele 8·35%, 95% CI 7·31-9·38) and fibrinogen concentrations (decrease per allele 0·85%, 95% CI 0·60-1·10). This pattern of effects was consistent with IL6R blockade from infusions of tocilizumab (4-8 mg/kg every 4 weeks) in patients with rheumatoid arthritis studied in randomised trials. In 25,458 coronary heart disease cases and 100,740 controls, the IL6R rs7529229 SNP was associated with a decreased odds of coronary heart disease events (per allele odds ratio 0·95, 95% CI 0·93-0·97, p=1·53×10(-5)). INTERPRETATION: On the basis of genetic evidence in human beings, IL6R signalling seems to have a causal role in development of coronary heart disease. IL6R blockade could provide a novel therapeutic approach to prevention of coronary heart disease that warrants testing in suitably powered randomised trials. Genetic studies in populations could be used more widely to help to validate and prioritise novel drug targets or to repurpose existing agents and targets for new therapeutic uses. FUNDING: UK Medical Research Council; British Heart Foundation; Rosetrees Trust; US National Heart, Lung, and Blood Institute; Du Pont Pharma; Chest, Heart and Stroke Scotland; Wellcome Trust; Coronary Thrombosis Trust; Northwick Park Institute for Medical Research; UCLH/UCL Comprehensive Medical Research Centre; US National Institute on Aging; Academy of Finland; Netherlands Organisation for Health Research and Development; SANCO; Dutch Ministry of Public Health, Welfare and Sports; World Cancer Research Fund; Agentschap NL; European Commission; Swedish Heart-Lung Foundation; Swedish Research Council; Strategic Cardiovascular Programme of the Karolinska Institutet; Stockholm County Council; US National Institute of Neurological Disorders and Stroke; MedStar Health Research Institute; GlaxoSmithKline; Dutch Kidney Foundation; US National Institutes of Health; Netherlands Interuniversity Cardiology Institute of the Netherlands; Diabetes UK; European Union Seventh Framework Programme; National Institute for Healthy Ageing; Cancer Research UK; MacArthur Foundation.

Published
2012

38. Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data

Author

Holmes, M.V. (Michael), Dale, C.E. (Caroline), Zuccolo, L. (Luisa), Silverwood, R.J. (Richard), Guo, Y. (Yongli), Ye, Z. (Zheng), Prieto-Merino, D. (David), Dehghan, A. (Abbas), Trompet, S. (Stella), Wong, A. (Andrew), Cavadino, A. (Alana), Drogan, D. (Dagmar), Padmanabhan, S. (Sandosh), Li, S. (Shanshan), Yesupriya, A. (Ajay), Leusink, M. (Maarten), Sundstrom, J. (Johan), Hubacek, J.A. (Jaroslav A.), Pikhart, H. (Hynek), Swerdlow, D.I. (Daniel), Panayiotou, A.G. (Andrie), Borinskaya, S.A. (Svetlana), Finan, C. (Chris), Shah, S. (Sonia), Kuchenbaecker, K.B. (Karoline), Shah, T. (Tina), Engmann, J. (Jorgen), Folkersen, L. (Lasse), Eriksson, P. (Per), Ricceri, F. (Fulvio), Melander, O. (Olle), Sacerdote, C. (Carlotta), Gamble, D.M. (Dale), Rayaprolu, S. (Sruti), Ross, O.A. (Owen), McLachlan, S. (Stela), Vikhireva, O. (Olga), Sluijs, I., Scott, R.A. (Robert), Adamkova, V. (Vera), Flicker, L. (Leon), Bockxmeer, F.M. (Frank) van, Power, C. (Christine), Marques-Vidal, P. (Pedro), Meade, T. (Tom), Marmot, M. (Michael), Ferro, M.T. (María), Paulos-Pinheiro, S. (Sofia), Humphries, S.E. (Steve), Talmud, P.J., Leach, I.M. (Irene Mateo), Verweij, N. (Niek), Linneberg, A. (Allan), Skaaby, T. (Tea), Doevendans, P.A. (Pieter), Cramer, M.-J. (Maarten-Jan), Harst, P. (Pim) van der, Klungel, O.H. (Olaf), Dowling, N. (Nicole), Dominiczak, A. (Anna), Kumari, M. (Meena), Nicolaides, A.N. (Andrew), Weikert, C. (Cornelia), Boeing, H. (Heiner), Ebrahim, S. (Shanil), Gaunt, T.R. (Tom), Price, J.F. (Jackie F.), Lannfelt, L. (Lars), Peasey, A. (Anne), Kubinova, R., Pajak, A. (Andrzej), Malyutina, S., Voevoda, M.I. (Mikhail), Tamosiunas, A. (Abdonas), Maitland-van der Zee, A-H. (Anke-Hilse), Norman, P.E. (Paul), Hankey, G.J. (Graeme), Bergmann, M.M. (Manuela), Hofman, A. (Albert), Franco, O.H. (Oscar), Cooper, J. (Jim), Palmen, J. (Jutta), Spiering, W. (Wilko), Jong, P.A. (Pim) de, Kuh, D. (Diana), Hardy, R., Uitterlinden, A.G. (André), Ikram, M.A. (Arfan), Ford, I. (Ian), Hyppönen, E. (Elina), Almeida, O.P. (Osvaldo), Wareham, N.J. (Nick), Khaw, K-T. (Kay-Tee), Hamsten, A. (Anders), Husemoen, L.L.N. (Lise Lotte), Tjønneland, A. (Anne), Tolstrup, J.S. (Janne), Rimm, E., Beulens, J.W.J. (Joline), Verschuren, W.M.M. (W. M. Monique), Onland-Moret, N.C. (Charlotte), Hofker, M.A. (Marten), Wannamethee, S.G. (Goya), Whincup, P.H. (Peter), Morris, R.W. (Richard), Vicente, A.M. (Astrid), Watkins, H. (Hugh), Farrall, M. (Martin), Jukema, J.W. (Jan Wouter), Meschia, J.F. (James F.), Cupples, L.A. (Adrienne), Sharp, S.J. (Stephen), Fornage, M. (Myriam), Kooperberg, C. (Charles), LaCroix, A.Z. (Andrea), Dai, J.Y. (James), Lanktree, M.B. (Matthew), Siscovick, D.S. (David), Jorgenson, E. (Eric), Spring, B. (Bonnie), Coresh, J. (Josef), Li, Y.R. (Yun), Buxbaum, S.G. (Sarah), Schreiner, P.J. (Pamela), Ellison, D.H. (David), Tsai, M.Y. (Michael), Patel, S.R. (Sanjay), Redline, S. (Susan), Johnson, A.D. (Andrew), Hoogeveen, R.C. (Ron), Hakonarson, H. (Hakon), Rotter, J.I. (Jerome), Boerwinkle, E.A. (Eric), Bakker, P.I.W. (Paul) de, Kivimaki, M. (Mika), Asselbergs, F.W. (Folkert), Sattar, N. (Naveed), Lawlor, D.A. (Debbie), Whittaker, J. (John), Smith, A.V. (Davey), Mukamal, K. (Kenneth), Psaty, B.M. (Bruce), Wilson, J.G. (James), Lange, L.A. (Leslie), Hamidovic, A. (Ajna), Nordestgaard, B.G. (Børge), Bobak, M. (Martin), Leon, D.A. (David), Langenberg, C. (Claudia), Palmer, T.M. (Tom), Reiner, A.P. (Alex), Keating, J. (John), Dudbridge, F. (Frank), Casas, J.P. (Juan), Holmes, M.V. (Michael), Dale, C.E. (Caroline), Zuccolo, L. (Luisa), Silverwood, R.J. (Richard), Guo, Y. (Yongli), Ye, Z. (Zheng), Prieto-Merino, D. (David), Dehghan, A. (Abbas), Trompet, S. (Stella), Wong, A. (Andrew), Cavadino, A. (Alana), Drogan, D. (Dagmar), Padmanabhan, S. (Sandosh), Li, S. (Shanshan), Yesupriya, A. (Ajay), Leusink, M. (Maarten), Sundstrom, J. (Johan), Hubacek, J.A. (Jaroslav A.), Pikhart, H. (Hynek), Swerdlow, D.I. (Daniel), Panayiotou, A.G. (Andrie), Borinskaya, S.A. (Svetlana), Finan, C. (Chris), Shah, S. (Sonia), Kuchenbaecker, K.B. (Karoline), Shah, T. (Tina), Engmann, J. (Jorgen), Folkersen, L. (Lasse), Eriksson, P. (Per), Ricceri, F. (Fulvio), Melander, O. (Olle), Sacerdote, C. (Carlotta), Gamble, D.M. (Dale), Rayaprolu, S. (Sruti), Ross, O.A. (Owen), McLachlan, S. (Stela), Vikhireva, O. (Olga), Sluijs, I., Scott, R.A. (Robert), Adamkova, V. (Vera), Flicker, L. (Leon), Bockxmeer, F.M. (Frank) van, Power, C. (Christine), Marques-Vidal, P. (Pedro), Meade, T. (Tom), Marmot, M. (Michael), Ferro, M.T. (María), Paulos-Pinheiro, S. (Sofia), Humphries, S.E. (Steve), Talmud, P.J., Leach, I.M. (Irene Mateo), Verweij, N. (Niek), Linneberg, A. (Allan), Skaaby, T. (Tea), Doevendans, P.A. (Pieter), Cramer, M.-J. (Maarten-Jan), Harst, P. (Pim) van der, Klungel, O.H. (Olaf), Dowling, N. (Nicole), Dominiczak, A. (Anna), Kumari, M. (Meena), Nicolaides, A.N. (Andrew), Weikert, C. (Cornelia), Boeing, H. (Heiner), Ebrahim, S. (Shanil), Gaunt, T.R. (Tom), Price, J.F. (Jackie F.), Lannfelt, L. (Lars), Peasey, A. (Anne), Kubinova, R., Pajak, A. (Andrzej), Malyutina, S., Voevoda, M.I. (Mikhail), Tamosiunas, A. (Abdonas), Maitland-van der Zee, A-H. (Anke-Hilse), Norman, P.E. (Paul), Hankey, G.J. (Graeme), Bergmann, M.M. (Manuela), Hofman, A. (Albert), Franco, O.H. (Oscar), Cooper, J. (Jim), Palmen, J. (Jutta), Spiering, W. (Wilko), Jong, P.A. (Pim) de, Kuh, D. (Diana), Hardy, R., Uitterlinden, A.G. (André), Ikram, M.A. (Arfan), Ford, I. (Ian), Hyppönen, E. (Elina), Almeida, O.P. (Osvaldo), Wareham, N.J. (Nick), Khaw, K-T. (Kay-Tee), Hamsten, A. (Anders), Husemoen, L.L.N. (Lise Lotte), Tjønneland, A. (Anne), Tolstrup, J.S. (Janne), Rimm, E., Beulens, J.W.J. (Joline), Verschuren, W.M.M. (W. M. Monique), Onland-Moret, N.C. (Charlotte), Hofker, M.A. (Marten), Wannamethee, S.G. (Goya), Whincup, P.H. (Peter), Morris, R.W. (Richard), Vicente, A.M. (Astrid), Watkins, H. (Hugh), Farrall, M. (Martin), Jukema, J.W. (Jan Wouter), Meschia, J.F. (James F.), Cupples, L.A. (Adrienne), Sharp, S.J. (Stephen), Fornage, M. (Myriam), Kooperberg, C. (Charles), LaCroix, A.Z. (Andrea), Dai, J.Y. (James), Lanktree, M.B. (Matthew), Siscovick, D.S. (David), Jorgenson, E. (Eric), Spring, B. (Bonnie), Coresh, J. (Josef), Li, Y.R. (Yun), Buxbaum, S.G. (Sarah), Schreiner, P.J. (Pamela), Ellison, D.H. (David), Tsai, M.Y. (Michael), Patel, S.R. (Sanjay), Redline, S. (Susan), Johnson, A.D. (Andrew), Hoogeveen, R.C. (Ron), Hakonarson, H. (Hakon), Rotter, J.I. (Jerome), Boerwinkle, E.A. (Eric), Bakker, P.I.W. (Paul) de, Kivimaki, M. (Mika), Asselbergs, F.W. (Folkert), Sattar, N. (Naveed), Lawlor, D.A. (Debbie), Whittaker, J. (John), Smith, A.V. (Davey), Mukamal, K. (Kenneth), Psaty, B.M. (Bruce), Wilson, J.G. (James), Lange, L.A. (Leslie), Hamidovic, A. (Ajna), Nordestgaard, B.G. (Børge), Bobak, M. (Martin), Leon, D.A. (David), Langenberg, C. (Claudia), Palmer, T.M. (Tom), Reiner, A.P. (Alex), Keating, J. (John), Dudbridge, F. (Frank), and Casas, J.P. (Juan)

Published
2014
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39. Gene-centric meta-analysis in 87,736 individuals of European ancestry identifies multiple blood-pressure-related loci

Author

Tragante, V. (Vinicius), Barnes, M.J. (Michael), Ganesh, S.K. (Santhi), Lanktree, M.B. (Matthew), Guo, W. (Weixiang), Franceschini, N. (Nora), Smith, A.V. (Davey), Johnson, T. (Toby), Holmes, M.V. (Michael), Padmanabhan, S. (Sandosh), Karczewski, K.J. (Konrad), Almoguera, B. (Berta), Barnard, J. (John), Baumert, J. (Jens), Chang, Y.-P.C. (Yen-Pei), Elbers, C.C. (Clara), Farrall, M. (Martin), Fischer, M.E. (Mary), Gaunt, T.R. (Tom), Gho, J.M.I.H. (Johannes), Gieger, C. (Christian), Goel, A. (Anuj), Gong, Y. (Yeming), Isaacs, A.J. (Aaron), Kleber, M.E. (Marcus), Leach, I.M. (Irene Mateo), McDonough, C.W. (Caitrin), Meijs, M.F.L. (Matthijs), Melander, O. (Olle), Nelson, C.P. (Christopher P.), Nolte, I.M. (Ilja), Pankratz, V.S. (Shane), Price, T.S. (Thomas), Shaffer, J. (Jonathan), Shah, S. (Sonia), Tomaszewski, M. (Maciej), Most, P.J. (Peter) van der, Iperen, E.P.A. (Erik) van, Vonk, J.M. (Judith), Witkowska, H.E. (Ewa), Wong, C.O.L. (Caroline), Zhang, L. (Lingling), Beitelshees, A.L. (Amber), Berenson, G. (Gerald), Bhatt, D.L. (Deepak), Brown, M.J. (Morris), Burt, A.D. (Alastair), Cooper-Dehoff, R.M. (Rhonda), Connell, J. (John), Cruickshanks, K.J. (Karen), Curtis, S.P. (Sean), Davey-Smith, G. (George), Delles, C. (Christian), Gansevoort, R.T. (Ron), Guo, X. (Xiuqing), Haiqing, S. (Shen), Hastie, C.E. (Claire), Hofker, M.A. (Marten), Hovingh, G.K. (Kees), Kim, D.S. (Daniel), Kirkland, S.A. (Susan), Klein, B.E.K. (Barbara), Li, Y.R. (Yun), Maiwald, R. (Robert), Newton-Cheh, C. (Christopher), O'Brien, E. (Eoin), Onland-Moret, N.C. (Charlotte), Palmas, W. (Walter), Parsa, A. (Afshin), Penninx, B.W.J.H. (Brenda), Pettinger, M. (Mary), Vasan, R.S. (Ramachandran Srini), Ranchalis, J.E. (Jane), Ridker, P.M. (Paul), Rose, L.M. (Lynda), Sever, P. (Peter), Shimbo, D. (Daichi), Steele, L. (Linda), Stolk, R.P. (Ronald), Thorand, B. (Barbara), Trip, M.D. (Mieke), Duijn, C.M. (Cornelia) van, Verschuren, W.M.M. (W. M. Monique), Wijmenga, C. (Cisca), Wyatt, S. (Sally), Young, J.C. (J. C.), Zwinderman, A.H. (Ailko), Bezzina, C.R. (Connie), Boerwinkle, E.A. (Eric), Casas, J.P. (Juan), Caulfield, M. (Mark), Chakravarti, A. (Aravinda), Chasman, D.I. (Daniel), Davidson, K.W. (Karina), Doevendans, P.A. (Pieter), Dominiczak, A. (Anna), Fitzgerald, G.A. (Garret), Gums, J.G. (John), Fornage, M. (Myriam), Hakonarson, H. (Hakon), Halder, H. (Han) van, Hillege, H.L. (Hans), Illig, T. (Thomas), Jarvik, G.P. (Gail), Johnson, J.A. (Jennifer ), Kastelein, J.J.P. (John), Koenig, W. (Wolfgang), Kumari, M. (Meena), März, W. (Winfried), Murray, S.S. (Sarah), O'Connell, J.R. (Jeffery), Oldehinkel, A.J. (Albertine), Pankow, J.S. (James), Rader, D.J. (Daniel), Redline, S. (Susan), Reilly, M.P. (Muredach), Schadt, E.E. (Eric), Kottke-Marchant, K. (Kandice), Snieder, H. (Harold), Snyder, M. (Michael), Stanton, A. (Alice), Tobin, M.D. (Martin), Uitterlinden, A.G. (André), Harst, P. (Pim) van der, Schouw, Y.T. (Yvonne) van der, Samani, N.J. (Nilesh), Watkins, H. (Hugh), Johnson, A.D. (Andrew), Reiner, A.P. (Alex), Zhu, X. (Xiaofeng), Bakker, P.I.W. (Paul) de, Levy, D. (Daniel), Asselbergs, F.W. (Folkert), Munroe, P. (Patricia), Keating, J. (John), Tragante, V. (Vinicius), Barnes, M.J. (Michael), Ganesh, S.K. (Santhi), Lanktree, M.B. (Matthew), Guo, W. (Weixiang), Franceschini, N. (Nora), Smith, A.V. (Davey), Johnson, T. (Toby), Holmes, M.V. (Michael), Padmanabhan, S. (Sandosh), Karczewski, K.J. (Konrad), Almoguera, B. (Berta), Barnard, J. (John), Baumert, J. (Jens), Chang, Y.-P.C. (Yen-Pei), Elbers, C.C. (Clara), Farrall, M. (Martin), Fischer, M.E. (Mary), Gaunt, T.R. (Tom), Gho, J.M.I.H. (Johannes), Gieger, C. (Christian), Goel, A. (Anuj), Gong, Y. (Yeming), Isaacs, A.J. (Aaron), Kleber, M.E. (Marcus), Leach, I.M. (Irene Mateo), McDonough, C.W. (Caitrin), Meijs, M.F.L. (Matthijs), Melander, O. (Olle), Nelson, C.P. (Christopher P.), Nolte, I.M. (Ilja), Pankratz, V.S. (Shane), Price, T.S. (Thomas), Shaffer, J. (Jonathan), Shah, S. (Sonia), Tomaszewski, M. (Maciej), Most, P.J. (Peter) van der, Iperen, E.P.A. (Erik) van, Vonk, J.M. (Judith), Witkowska, H.E. (Ewa), Wong, C.O.L. (Caroline), Zhang, L. (Lingling), Beitelshees, A.L. (Amber), Berenson, G. (Gerald), Bhatt, D.L. (Deepak), Brown, M.J. (Morris), Burt, A.D. (Alastair), Cooper-Dehoff, R.M. (Rhonda), Connell, J. (John), Cruickshanks, K.J. (Karen), Curtis, S.P. (Sean), Davey-Smith, G. (George), Delles, C. (Christian), Gansevoort, R.T. (Ron), Guo, X. (Xiuqing), Haiqing, S. (Shen), Hastie, C.E. (Claire), Hofker, M.A. (Marten), Hovingh, G.K. (Kees), Kim, D.S. (Daniel), Kirkland, S.A. (Susan), Klein, B.E.K. (Barbara), Li, Y.R. (Yun), Maiwald, R. (Robert), Newton-Cheh, C. (Christopher), O'Brien, E. (Eoin), Onland-Moret, N.C. (Charlotte), Palmas, W. (Walter), Parsa, A. (Afshin), Penninx, B.W.J.H. (Brenda), Pettinger, M. (Mary), Vasan, R.S. (Ramachandran Srini), Ranchalis, J.E. (Jane), Ridker, P.M. (Paul), Rose, L.M. (Lynda), Sever, P. (Peter), Shimbo, D. (Daichi), Steele, L. (Linda), Stolk, R.P. (Ronald), Thorand, B. (Barbara), Trip, M.D. (Mieke), Duijn, C.M. (Cornelia) van, Verschuren, W.M.M. (W. M. Monique), Wijmenga, C. (Cisca), Wyatt, S. (Sally), Young, J.C. (J. C.), Zwinderman, A.H. (Ailko), Bezzina, C.R. (Connie), Boerwinkle, E.A. (Eric), Casas, J.P. (Juan), Caulfield, M. (Mark), Chakravarti, A. (Aravinda), Chasman, D.I. (Daniel), Davidson, K.W. (Karina), Doevendans, P.A. (Pieter), Dominiczak, A. (Anna), Fitzgerald, G.A. (Garret), Gums, J.G. (John), Fornage, M. (Myriam), Hakonarson, H. (Hakon), Halder, H. (Han) van, Hillege, H.L. (Hans), Illig, T. (Thomas), Jarvik, G.P. (Gail), Johnson, J.A. (Jennifer ), Kastelein, J.J.P. (John), Koenig, W. (Wolfgang), Kumari, M. (Meena), März, W. (Winfried), Murray, S.S. (Sarah), O'Connell, J.R. (Jeffery), Oldehinkel, A.J. (Albertine), Pankow, J.S. (James), Rader, D.J. (Daniel), Redline, S. (Susan), Reilly, M.P. (Muredach), Schadt, E.E. (Eric), Kottke-Marchant, K. (Kandice), Snieder, H. (Harold), Snyder, M. (Michael), Stanton, A. (Alice), Tobin, M.D. (Martin), Uitterlinden, A.G. (André), Harst, P. (Pim) van der, Schouw, Y.T. (Yvonne) van der, Samani, N.J. (Nilesh), Watkins, H. (Hugh), Johnson, A.D. (Andrew), Reiner, A.P. (Alex), Zhu, X. (Xiaofeng), Bakker, P.I.W. (Paul) de, Levy, D. (Daniel), Asselbergs, F.W. (Folkert), Munroe, P. (Patricia), and Keating, J. (John)

Abstract

Blood pressure (BP) is a heritable risk factor for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ∼50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis. We replicated findings in an independent set of 68,368 individuals of European ancestry. Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 × 10-7) and confirmed 27 previously reported associations. Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2. Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules. In summary, we identified previously unknown loci associated with BP. Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification.

Published
2014
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41. A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple loci implicated in s

Author

Coviello, A.D. (Andrea), Haring, R. (Robin), Wellons, M. (Melissa), Vaidya, D. (Dhananjay), Lehtimäki, T. (Terho), Keildson, S. (Sarah), Lunetta, K.L. (Kathryn), He, C. (Chunyan), Fornage, M. (Myriam), Lagou, V. (Vasiliki), Mangino, M. (Massimo), Onland-Moret, N.C. (Charlotte), Chen, B.H. (Brian), Eriksson, J. (Joel), Garcia, M. (Melissa), Liu, Y. (YongMei), Koster, A. (Annemarie), Lohman, K. (Kurt), Lyytikäinen, L.-P. (Leo-Pekka), Petersen, A.K., Prescott, C.A.J., Stolk, L. (Lisette), Vandenput, L. (Liesbeth), Wood, A.R. (Andrew), Zhuang, W.V., Ruokonen, A. (Aimo), Hartikainen, A.L., Pouta, A. (Anneli), Bandinelli, S. (Stefania), Biffar, R. (Reiner), Brabant, G. (Georg), Cox, D.G. (David), Cummings, S., Ferrucci, L. (Luigi), Gunter, M.J. (Marc J.), Hankinson, S.E. (Susan), Martikainen, H. (Hannu), Hofman, A. (Albert), Homuth, G. (Georg), Illig, T. (Thomas), Jansson, J.O., Johnson, A.D. (Andrew), Karasik, D. (David), Karlsson, M. (Magnus), Kettunen, J. (Johannes), Kiel, D.P. (Douglas), Kraft, P. (Peter), Ljunggren, O. (Östen), Lorentzon, M. (Mattias), Maggio, M. (Marcello), Markus, M.R.P. (Marcello R. P.), Mellström, D. (Dan), Miljkovic, I. (Iva), Mirel, D. (Daniel), Nelson, S. (Sarah), Morin Papunen, L. (Laure), Peeters, P.H.M., Prokopenko, I. (Inga), Raffel, L.J. (Leslie), Reincke, M. (Martin), Reiner, A.P. (Alex), Rexrode, K. (Kathryn), Rivadeneira Ramirez, F. (Fernando), Schwartz, S.M. (Stephen), Siscovick, D.S. (David), Soranzo, N. (Nicole), Stöckl, D. (Doris), Tworoger, S. (Shelley), Uitterlinden, A.G. (André), Gils, C.H. (Carla) van, Vasan, R.S. (Ramachandran Srini), Wichmann, H.E. (Erich), Zhai, G. (Guangju), Bhasin, S. (Shalender), Bidlingmaier, M. (Martin), Chanock, S.J. (Stephen), Vivo, I. (Immaculata) de, Harris, T.B. (Tamara), Hunter, D. (David), Kähönen, M. (Mika), Ouyang, P. (Pamela), Spector, T.D. (Timothy), Schouw, Y.T. (Yvonne) van der, Viikari, J. (Jorma), Wallaschofski, H. (Henri), McCarthy, M.I. (Mark), Frayling, T.M. (Timothy), Murray, J.C. (Jeffrey), Franks, S. (Steve), Jarvelin, M.-R. (Marjo-Riitta), Jong, F.A. (Floris) de, Raitakari, O. (Olli), Teumer, A. (Alexander), Ohlsson, C. (Claes), Murabito, J. (Joanne), Perry, J.R.B. (John), Coviello, A.D. (Andrea), Haring, R. (Robin), Wellons, M. (Melissa), Vaidya, D. (Dhananjay), Lehtimäki, T. (Terho), Keildson, S. (Sarah), Lunetta, K.L. (Kathryn), He, C. (Chunyan), Fornage, M. (Myriam), Lagou, V. (Vasiliki), Mangino, M. (Massimo), Onland-Moret, N.C. (Charlotte), Chen, B.H. (Brian), Eriksson, J. (Joel), Garcia, M. (Melissa), Liu, Y. (YongMei), Koster, A. (Annemarie), Lohman, K. (Kurt), Lyytikäinen, L.-P. (Leo-Pekka), Petersen, A.K., Prescott, C.A.J., Stolk, L. (Lisette), Vandenput, L. (Liesbeth), Wood, A.R. (Andrew), Zhuang, W.V., Ruokonen, A. (Aimo), Hartikainen, A.L., Pouta, A. (Anneli), Bandinelli, S. (Stefania), Biffar, R. (Reiner), Brabant, G. (Georg), Cox, D.G. (David), Cummings, S., Ferrucci, L. (Luigi), Gunter, M.J. (Marc J.), Hankinson, S.E. (Susan), Martikainen, H. (Hannu), Hofman, A. (Albert), Homuth, G. (Georg), Illig, T. (Thomas), Jansson, J.O., Johnson, A.D. (Andrew), Karasik, D. (David), Karlsson, M. (Magnus), Kettunen, J. (Johannes), Kiel, D.P. (Douglas), Kraft, P. (Peter), Ljunggren, O. (Östen), Lorentzon, M. (Mattias), Maggio, M. (Marcello), Markus, M.R.P. (Marcello R. P.), Mellström, D. (Dan), Miljkovic, I. (Iva), Mirel, D. (Daniel), Nelson, S. (Sarah), Morin Papunen, L. (Laure), Peeters, P.H.M., Prokopenko, I. (Inga), Raffel, L.J. (Leslie), Reincke, M. (Martin), Reiner, A.P. (Alex), Rexrode, K. (Kathryn), Rivadeneira Ramirez, F. (Fernando), Schwartz, S.M. (Stephen), Siscovick, D.S. (David), Soranzo, N. (Nicole), Stöckl, D. (Doris), Tworoger, S. (Shelley), Uitterlinden, A.G. (André), Gils, C.H. (Carla) van, Vasan, R.S. (Ramachandran Srini), Wichmann, H.E. (Erich), Zhai, G. (Guangju), Bhasin, S. (Shalender), Bidlingmaier, M. (Martin), Chanock, S.J. (Stephen), Vivo, I. (Immaculata) de, Harris, T.B. (Tamara), Hunter, D. (David), Kähönen, M. (Mika), Ouyang, P. (Pamela), Spector, T.D. (Timothy), Schouw, Y.T. (Yvonne) van der, Viikari, J. (Jorma), Wallaschofski, H. (Henri), McCarthy, M.I. (Mark), Frayling, T.M. (Timothy), Murray, J.C. (Jeffrey), Franks, S. (Steve), Jarvelin, M.-R. (Marjo-Riitta), Jong, F.A. (Floris) de, Raitakari, O. (Olli), Teumer, A. (Alexander), Ohlsson, C. (Claes), Murabito, J. (Joanne), and Perry, J.R.B. (John)

Abstract

Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG, PRMT6, GCKR, ZBTB10, JMJD1C, SLCO1B1, NR2F2, ZNF652, TDGF3, LHCGR, BAIAP2L1, and UGT2B15. These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only. Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained ~15.6% and ~8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance.

Published
2012
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43. Multiple loci are associated with white blood cell phenotypes

Author

Nalls, M.A. (Michael), Couper, D. (David), Tanaka, T. (Toshiko), Rooij, F.J.A. (Frank) van, Chen, M-H. (Ming-Huei), Smith, A.V. (Albert Vernon), Toniolo, D. (Daniela), Zakai, N.A. (Neil), Yang, Q. (Qiong Fang), Greinacher, A. (Andreas), Wood, A.R. (Andrew), Garcia, M. (Melissa), Gasparini, P. (Paolo), Liu, Y. (YongMei), Lumley, T. (Thomas), Folsom, A.R. (Aaron), Reiner, A.P. (Alex), Gieger, C. (Christian), Lagou, V. (Vasiliki), Felix, J.F. (Janine), Völzke, H. (Henry), Gouskova, N.A. (Natalia), Biffi, A. (Alessandro), Döring, A. (Angela), Völker, U. (Uwe), Chong, S. (Sean), Wiggins, K.L. (Kerri), Rendon, A. (Augusto), Dehghan, A. (Abbas), Moore, M. (Matt), Taylor, K.D. (Kent), Wilson, J.G. (James), Lettre, G. (Guillaume), Hofman, A. (Albert), Bis, J.C. (Joshua), Pirastu, N. (Nicola), Fox, C.S. (Caroline), Meisinger, C. (Christa), Sambrook, J.G. (Jennifer), Arepalli, S. (Sampath), Nauck, M. (Matthias), Prokisch, H. (Holger), Stephens, J. (Jonathan), Glazer, N.L. (Nicole), Cupples, L.A. (Adrienne), Okada, Y. (Yukinori), Takahashi, A. (Atsushi), Kamatani, Y. (Yoichiro), Matsuda, K. (Koichi), Tsunoda, T. (Tatsuhiko), Kubo, M. (Michiaki), Nakamura, Y. (Yusuke), Yamamoto, K. (Kazuhiko), Stumvoll, M. (Michael), Tönjes, A. (Anke), Prokopenko, I. (Inga), Illig, T. (Thomas), Patel, K.V. (Kushang), Garner, S.F. (Stephen), Kuhnel, B. (Brigitte), Mangino, M. (Massimo), Oostra, B.A. (Ben), Thein, S.L., Coresh, J. (Josef), Wichmann, H.E. (Heinz Erich), Menzel, S. (Stephan), Lin, J., Pistis, G. (Giorgio), Uitterlinden, A.G. (André), Spector, T.D. (Timothy), Teumer, A. (Alexander), Eiriksdottir, G. (Gudny), Gudnason, V. (Vilmundur), Bandinelli, S. (Stefania), Frayling, T.M. (Timothy), Chakravarti, A. (Aravinda), Tikka-Kleemola, P. (Päivi), Melzer, D. (David), Ouwehand, W.H. (Willem), Levy, D. (Daniel), Boerwinkle, E.A. (Eric), Singleton, A. (Andrew), Hernandez, D.G. (Dena), Longo, D.L. (Dan), Soranzo, N. (Nicole), Witteman, J.C.M. (Jacqueline), Psaty, B.M. (Bruce), Ferrucci, L. (Luigi), Harris, T.B. (Tamara), O'Donnell, C.J. (Christopher), Ganesh, S.K. (Santhi), Nalls, M.A. (Michael), Couper, D. (David), Tanaka, T. (Toshiko), Rooij, F.J.A. (Frank) van, Chen, M-H. (Ming-Huei), Smith, A.V. (Albert Vernon), Toniolo, D. (Daniela), Zakai, N.A. (Neil), Yang, Q. (Qiong Fang), Greinacher, A. (Andreas), Wood, A.R. (Andrew), Garcia, M. (Melissa), Gasparini, P. (Paolo), Liu, Y. (YongMei), Lumley, T. (Thomas), Folsom, A.R. (Aaron), Reiner, A.P. (Alex), Gieger, C. (Christian), Lagou, V. (Vasiliki), Felix, J.F. (Janine), Völzke, H. (Henry), Gouskova, N.A. (Natalia), Biffi, A. (Alessandro), Döring, A. (Angela), Völker, U. (Uwe), Chong, S. (Sean), Wiggins, K.L. (Kerri), Rendon, A. (Augusto), Dehghan, A. (Abbas), Moore, M. (Matt), Taylor, K.D. (Kent), Wilson, J.G. (James), Lettre, G. (Guillaume), Hofman, A. (Albert), Bis, J.C. (Joshua), Pirastu, N. (Nicola), Fox, C.S. (Caroline), Meisinger, C. (Christa), Sambrook, J.G. (Jennifer), Arepalli, S. (Sampath), Nauck, M. (Matthias), Prokisch, H. (Holger), Stephens, J. (Jonathan), Glazer, N.L. (Nicole), Cupples, L.A. (Adrienne), Okada, Y. (Yukinori), Takahashi, A. (Atsushi), Kamatani, Y. (Yoichiro), Matsuda, K. (Koichi), Tsunoda, T. (Tatsuhiko), Kubo, M. (Michiaki), Nakamura, Y. (Yusuke), Yamamoto, K. (Kazuhiko), Stumvoll, M. (Michael), Tönjes, A. (Anke), Prokopenko, I. (Inga), Illig, T. (Thomas), Patel, K.V. (Kushang), Garner, S.F. (Stephen), Kuhnel, B. (Brigitte), Mangino, M. (Massimo), Oostra, B.A. (Ben), Thein, S.L., Coresh, J. (Josef), Wichmann, H.E. (Heinz Erich), Menzel, S. (Stephan), Lin, J., Pistis, G. (Giorgio), Uitterlinden, A.G. (André), Spector, T.D. (Timothy), Teumer, A. (Alexander), Eiriksdottir, G. (Gudny), Gudnason, V. (Vilmundur), Bandinelli, S. (Stefania), Frayling, T.M. (Timothy), Chakravarti, A. (Aravinda), Tikka-Kleemola, P. (Päivi), Melzer, D. (David), Ouwehand, W.H. (Willem), Levy, D. (Daniel), Boerwinkle, E.A. (Eric), Singleton, A. (Andrew), Hernandez, D.G. (Dena), Longo, D.L. (Dan), Soranzo, N. (Nicole), Witteman, J.C.M. (Jacqueline), Psaty, B.M. (Bruce), Ferrucci, L. (Luigi), Harris, T.B. (Tamara), O'Donnell, C.J. (Christopher), and Ganesh, S.K. (Santhi)

Abstract

White blood cell (WBC) count is a common clinical measure from complete blood count assays, and it varies widely among healthy individuals. Total WBC count and its constituent subtypes have been shown to be moderately heritable, with the heritability estimates varying across cell types. We studied 19,509 subjects from seven cohorts in a discovery analysis, and 11,823 subjects from ten cohorts for replication analyses, to determine genetic factors influencing variability within the normal hematological range for total WBC count and five WBC subtype measures. Cohort specific data was supplied by the CHARGE, HeamGen, and INGI consortia, as well as independent collaborative studies. We identified and replicated ten associations with total WBC count and five WBC subtypes at seven different genomic loci (total WBC count-6p21 in the HLA region, 17q21 near ORMDL3, and CSF3; neutrophil count-17q21; basophil count-3p21 near RPN1 and C3orf27; lymphocyte count-6p21, 19p13 at EPS15L1; monocyte count-2q31 at ITGA4, 3q21, 8q24 an intergenic region, 9q31 near EDG2), including three previously reported associations and seven novel associations. To investigate functional relationships among variants contributing to variability in the six WBC traits, we utilized gene expression- and pathways-based analyses. We implemented gene-clustering algorithms to evaluate functional connectivity among implicated loci and showed functional relationships across cell types. Gene expression data from whole blood was utilized to show that significant biological consequences can be extracted from our genome-wide analyses, with effect estimates for significant loci from the meta-analyses being highly corellated with the proximal gene expression. In addition, collaborative efforts between the groups contributing to this study and related studies conducted by the COGENT and RIKEN groups allowed for the examination of effect homogeneity for genome-wide significant associations across populations of diverse

Published
2011
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44. Common genetic variation near the connexin-43 gene is associated with resting heart rate in African Americans: A genome-wide association study of 13,372 participants

Author

Deo, R., primary, Nalls, M.A., additional, Avery, C.L., additional, Smith, J.G., additional, Evans, D.S., additional, Keller, M.F., additional, Butler, A.M., additional, Buxbaum, S.G., additional, Li, G., additional, Miguel Quibrera, P., additional, Smith, E.N., additional, Tanaka, T., additional, Akylbekova, E.L., additional, Alonso, A., additional, Arking, D.E., additional, Benjamin, E.J., additional, Berenson, G.S., additional, Bis, J.C., additional, Chen, L.Y., additional, Chen, W., additional, Cummings, S.R., additional, Ellinor, P.T., additional, Evans, M.K., additional, Ferrucci, L., additional, Fox, E.R., additional, Heckbert, S.R., additional, Heiss, G., additional, Hsueh, W.C., additional, Kerr, K.F., additional, Limacher, M.C., additional, Liu, Y., additional, Lubitz, S.A., additional, Magnani, J.W., additional, Mehra, R., additional, Marcus, G.M., additional, Murray, S.S., additional, Newman, A.B., additional, Njajou, O., additional, North, K.E., additional, Paltoo, D.N., additional, Psaty, B.M., additional, Redline, S.S., additional, Reiner, A.P., additional, Robinson, J.G., additional, Rotter, J.I., additional, Samdarshi, T.E., additional, Schnabel, R.B., additional, Schork, N.J., additional, Singleton, A.B., additional, Siscovick, D., additional, Soliman, E.Z., additional, Sotoodehnia, N., additional, Srinivasan, S.R., additional, Taylor, H.A., additional, Trevisan, M., additional, Zhang, Z., additional, Zonderman, A.B., additional, Newton-Cheh, C., additional, and Whitsel, E.A., additional

Published
2013
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45. The use of phenome-wide association studies (PheWAS) for exploration of novel genotype-phenotype relationships and pleiotropy discovery

Author

Pendergrass, S.A., primary, Brown-Gentry, K., additional, Dudek, S.M., additional, Torstenson, E.S., additional, Ambite, J.L., additional, Avery, C.L., additional, Buyske, S., additional, Cai, C., additional, Fesinmeyer, M.D., additional, Haiman, C., additional, Heiss, G., additional, Hindorff, L.A., additional, Hsu, C.-N., additional, Jackson, R.D., additional, Kooperberg, C., additional, Le Marchand, L., additional, Lin, Y., additional, Matise, T.C., additional, Moreland, L., additional, Monroe, K., additional, Reiner, A.P., additional, Wallace, R., additional, Wilkens, L.R., additional, Crawford, D.C., additional, and Ritchie, M.D., additional

Published
2011
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46. Association between patterns of nucleotide variation across the three fibrinogen genes and plasma fibrinogen levels: the Coronary Artery Risk Development in Young Adults (CARDIA) study

Author

REINER, A.P., primary, CARTY, C.L., additional, CARLSON, C.S., additional, WAN, J.Y., additional, RIEDER, M.J., additional, SMITH, J.D., additional, RICE, K., additional, FORNAGE, M., additional, JAQUISH, C.E., additional, WILLIAMS, O.D., additional, TRACY, R.P., additional, LEWIS, C.E., additional, SISCOVICK, D.S., additional, BOERWINKLE, E., additional, and NICKERSON, D.A., additional

Published
2006
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