Trans-ethnic meta-regression of genome-wide association studies accounting for ancestry increases power for discovery and improves fine-mapping resolution

被引：146

作者：

Magi, Reedik ^{[1
]}

Horikoshi, Momoko ^{[2
,3
]}

Sofer, Tamar ^{[4
]}

Mahajan, Anubha ^{[2
]}

Kitajima, Hidetoshi ^{[2
]}

Franceschini, Nora ^{[5
]}

McCarthy, Mark I. ^{[2
,6
,7
]}

Morris, Andrew P. ^{[1
,2
,8
,9
]}

机构：

[1] Univ Tartu, Estonian Genome Ctr, Tartu, Estonia

[2] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[3] RIKEN, Ctr Integrat Med Sci, Lab Endocrinol Metab & Kidney Dis, Yokohama, Kanagawa, Japan

[4] Univ Washington, Dept Biostat, Seattle, WA 98195 USA

[5] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA

[6] Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England

[7] Oxford Univ Hosp Trust, Oxford NIHR Biomed Res Ctr, Oxford, England

[8] Univ Liverpool, Dept Biostat, Block F Waterhouse Bldg,1-5 Brownlow St, Liverpool L69 3GL, Merseyside, England

[9] Univ Liverpool, Dept Mol & Clin Pharmacol, Liverpool, Merseyside, England

来源：

HUMAN MOLECULAR GENETICS | 2017年 / 26卷 / 18期

基金：

英国惠康基金; 美国国家卫生研究院;

关键词：

DIABETES SUSCEPTIBILITY LOCI; GENOTYPE IMPUTATION; GLOBAL POPULATIONS; CAUSAL VARIANTS; METAANALYSIS; ANNOTATION; SIGNALS; ARCHITECTURE; AFRICAN; REGIONS;

D O I：

10.1093/hmg/ddx280

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Trans-ethnic meta-analysis of genome-wide association studies (GWAS) across diverse populations can increase power to detect complex trait loci when the underlying causal variants are shared between ancestry groups. However, heterogeneity in allelic effects between GWAS at these loci can occur that is correlated with ancestry. Here, a novel approach is presented to detect SNP association and quantify the extent of heterogeneity in allelic effects that is correlated with ancestry. We employ trans-ethnic meta-regression to model allelic effects as a function of axes of genetic variation, derived from a matrix of mean pairwise allele frequency differences between GWAS, and implemented in the MR-MEGA software. Through detailed simulations, we demonstrate increased power to detect association for MR-MEGA over fixed-and random-effects meta-analysis across a range of scenarios of heterogeneity in allelic effects between ethnic groups. We also demonstrate improved fine-mapping resolution, in loci containing a single causal variant, compared to these meta-analysis approaches and PAINTOR, and equivalent performance to MANTRA at reduced computational cost. Application of MR-MEGA to trans-ethnic GWAS of kidney function in 71,461 individuals indicates stronger signals of association than fixed-effects meta-analysis when heterogeneity in allelic effects is correlated with ancestry. Application of MR-MEGA to fine-mapping four type 2 diabetes susceptibility loci in 22,086 cases and 42,539 controls highlights: (i) strong evidence for heterogeneity in allelic effects that is correlated with ancestry only at the index SNP for the association signal at the CDKAL1 locus; and (ii) 99% credible sets with six or fewer variants for five distinct association signals.

引用

页码：3639 / 3650

页数：12

共 43 条

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Yoneyama, Sachiko ;

Bush, William S. ;

Goodloe, Robert ;

Ritchie, Marylyn D. ;

Crawford, Dana ;

Gross, Myron ;

Fornage, Myriam ;

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Lee, I-Te ;

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Ferreira, Teresa ;

Lee, Yeji ;

Raimondo, Anne ;

Maegi, Reedik ;

Reschen, Michael E. ;

Mahajan, Anubha ;

Locke, Adam ;

Rayner, N. William ;

Robertson, Neil ;

Scott, Robert A. ;

Prokopenko, Inga ;

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Green, Todd ;

Sparso, Thomas ;

Thuillier, Dorothee ;

Yengo, Loic ;

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Franberg, Mattias ;

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van de Bunt, Martijn ;

Chalisey, Anil ;

Kang, Hyun Min ;

Voight, Benjamin F. ;

Abecasis, Goncalo R. ;

Almgren, Peter ;

Baldassarre, Damiano ;

Balkau, Beverley ;

Benediktsson, Rafn .

NATURE GENETICS, 2015, 47 (12) :1415-+

← 1 2 3 4 5 →

共 43 条

[1] Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans [J].

Al Olama, Ali Amin ;

Dadaev, Tokhir ;

Hazelett, Dennis J. ;

Li, Qiuyan ;

Leongamornlert, Daniel ;

Saunders, Edward J. ;

Stephens, Sarah ;

Cieza-Borrella, Clara ;

Whitmore, Ian ;

Garcia, Sara Benlloch ;

Giles, Graham G. ;

Southey, Melissa C. ;

Fitzgerald, Liesel ;

Gronberg, Henrik ;

Wiklund, Fredrik ;

Aly, Markus ;

Henderson, Brian E. ;

Schumacher, Fredrick ;

Haiman, Christopher A. ;

Schleutker, Johanna ;

Wahlfors, Tiina ;

Tammela, Teuvo L. ;

Nordestgaard, Borge G. ;

Key, Tim J. ;

Travis, Ruth C. ;

Neal, David E. ;

Donovan, Jenny L. ;

Hamdy, Freddie C. ;

Pharoah, Paul ;

Pashayan, Nora ;

Khaw, Kay-Tee ;

Stanford, Janet L. ;

Thibodeau, Stephen N. ;

Mcdonnell, Shannon K. ;

Schaid, Daniel J. ;

Maier, Christiane ;

Vogel, Walther ;

Luedeke, Manuel ;

Herkommer, Kathleen ;

Kibel, Adam S. ;

Cybulski, Cezary ;

Wokolorczyk, Dominika ;

Kluzniak, Wojciech ;

Cannon-Albright, Lisa ;

Brenner, Hermann ;

Butterbach, Katja ;

Arndt, Volker ;

Park, Jong Y. ;

Sellers, Thomas ;

Lin, Hui-Yi .

HUMAN MOLECULAR GENETICS, 2015, 24 (19) :5589-5602

[2] A global reference for human genetic variation [J].

Altshuler, David M. ;

Durbin, Richard M. ;

Abecasis, Goncalo R. ;

Bentley, David R. ;

Chakravarti, Aravinda ;

Clark, Andrew G. ;

Donnelly, Peter ;

Eichler, Evan E. ;

Flicek, Paul ;

Gabriel, Stacey B. ;

Gibbs, Richard A. ;

Green, Eric D. ;

Hurles, Matthew E. ;

Knoppers, Bartha M. ;

Korbel, Jan O. ;

Lander, Eric S. ;

Lee, Charles ;

Lehrach, Hans ;

Mardis, Elaine R. ;

Marth, Gabor T. ;

McVean, Gil A. ;

Nickerson, Deborah A. ;

Wang, Jun ;

Wilson, Richard K. ;

Boerwinkle, Eric ;

Doddapaneni, Harsha ;

Han, Yi ;

Korchina, Viktoriya ;

Kovar, Christie ;

Lee, Sandra ;

Muzny, Donna ;

Reid, Jeffrey G. ;

Zhu, Yiming ;

Chang, Yuqi ;

Feng, Qiang ;

Fang, Xiaodong ;

Guo, Xiaosen ;

Jian, Min ;

Jiang, Hui ;

Jin, Xin ;

Lan, Tianming ;

Li, Guoqing ;

Li, Jingxiang ;

Li, Yingrui ;

Liu, Shengmao ;

Liu, Xiao ;

Lu, Yao ;

Ma, Xuedi ;

Tang, Meifang ;

Wang, Bo .

NATURE, 2015, 526 (7571) :68-+

[3] An integrated map of genetic variation from 1,092 human genomes [J].

Altshuler, David M. ;

Durbin, Richard M. ;

Abecasis, Goncalo R. ;

Bentley, David R. ;

Chakravarti, Aravinda ;

Clark, Andrew G. ;

Donnelly, Peter ;

Eichler, Evan E. ;

Flicek, Paul ;

Gabriel, Stacey B. ;

Gibbs, Richard A. ;

Green, Eric D. ;

Hurles, Matthew E. ;

Knoppers, Bartha M. ;

Korbel, Jan O. ;

Lander, Eric S. ;

Lee, Charles ;

Lehrach, Hans ;

Mardis, Elaine R. ;

Marth, Gabor T. ;

McVean, Gil A. ;

Nickerson, Deborah A. ;

Schmidt, Jeanette P. ;

Sherry, Stephen T. ;

Wang, Jun ;

Wilson, Richard K. ;

Gibbs, Richard A. ;

Dinh, Huyen ;

Kovar, Christie ;

Lee, Sandra ;

Lewis, Lora ;

Muzny, Donna ;

Reid, Jeff ;

Wang, Min ;

Wang, Jun ;

Fang, Xiaodong ;

Guo, Xiaosen ;

Jian, Min ;

Jiang, Hui ;

Jin, Xin ;

Li, Guoqing ;

Li, Jingxiang ;

Li, Yingrui ;

Li, Zhuo ;

Liu, Xiao ;

Lu, Yao ;

Ma, Xuedi ;

Su, Zhe ;

Tai, Shuaishuai ;

Tang, Meifang .

NATURE, 2012, 491 (7422) :56-65

[4] Fine mapping of QT interval regions in global populations refines previously identified QT interval loci and identifies signals unique to African and Hispanic descent populations [J].

Avery, Christy L. ;

Wassel, Christina L. ;

Richard, Melissa A. ;

Highland, Heather M. ;

Bien, Stephanie ;

Zubair, Niha ;

Soliman, Elsayed Z. ;

Fornage, Myriam ;

Bielinski, Suzette J. ;

Tao, Ran ;

Seyerle, Amanda A. ;

Shah, Sanjiv J. ;

Lloyd-Jones, Donald M. ;

Buyske, Steven ;

Rotter, Jerome I. ;

Post, Wendy S. ;

Rich, Stephen S. ;

Hindorff, Lucia A. ;

Jeff, Janina M. ;

Shohet, Ralph V. ;

Sotoodehnia, Nona ;

Lin, Dan Yu ;

Whitsel, Eric A. ;

Peters, Ulrike ;

Haiman, Christopher A. ;

Crawford, Dana C. ;

Kooperberg, Charles ;

North, Kari E. .

HEART RHYTHM, 2017, 14 (04) :572-580

[5] FINEMAP: efficient variable selection using summary data from genome-wide association studies [J].

Benner, Christian ;

Spencer, Chris C. A. ;

Havulinna, Aki S. ;

Salomaa, Veikko ;

Ripatti, Samuli ;

Pirinen, Matti .

BIOINFORMATICS, 2016, 32 (10) :1493-1501

[6] Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer [J].

Bojesen, Stig E. ;

Pooley, Karen A. ;

Johnatty, Sharon E. ;

Beesley, Jonathan ;

Michailidou, Kyriaki ;

Tyrer, Jonathan P. ;

Edwards, Stacey L. ;

Pickett, Hilda A. ;

Shen, Howard C. ;

Smart, Chanel E. ;

Hillman, Kristine M. ;

Mai, Phuong L. ;

Lawrenson, Kate ;

Stutz, Michael D. ;

Lu, Yi ;

Karevan, Rod ;

Woods, Nicholas ;

Johnston, Rebecca L. ;

French, Juliet D. ;

Chen, Xiaoqing ;

Weischer, Maren ;

Nielsen, Sune F. ;

Maranian, Melanie J. ;

Ghoussaini, Maya ;

Ahmed, Shahana ;

Baynes, Caroline ;

Bolla, Manjeet K. ;

Wang, Qin ;

Dennis, Joe ;

McGuffog, Lesley ;

Barrowdale, Daniel ;

Lee, Andrew ;

Healey, Sue ;

Lush, Michael ;

Tessier, Daniel C. ;

Vincent, Daniel ;

Bacot, Francis ;

Vergote, Ignace ;

Lambrechts, Sandrina ;

Despierre, Evelyn ;

Risch, Harvey A. ;

Gonzalez-Neira, Anna ;

Rossing, Mary Anne ;

Pita, Guillermo ;

Doherty, Jennifer A. ;

Alvarez, Nuria ;

Larson, Melissa C. ;

Fridley, Brooke L. ;

Schoof, Nils ;

Chang-Claude, Jenny .

NATURE GENETICS, 2013, 45 (04) :371-384

[7] Fine Mapping Causal Variants with an Approximate Bayesian Method Using Marginal Test Statistics [J].

Chen, Wenan ;

Larrabee, Beth R. ;

Ovsyannikova, Inna G. ;

Kennedy, Richard B. ;

Haralambieva, Iana H. ;

Poland, Gregory A. ;

Schaid, Daniel J. .

GENETICS, 2015, 200 (03) :719-+

[8] Genomic control for association studies [J].

Devlin, B ;

Roeder, K .

BIOMETRICS, 1999, 55 (04) :997-1004

Fernandez-Rhodes, Lindsay ;

Gong, Jian ;

Haessler, Jeffrey ;

Franceschini, Nora ;

Graff, Mariaelisa ;

Nishimura, Katherine K. ;

Wang, Yujie ;

Highland, Heather M. ;

Yoneyama, Sachiko ;

Bush, William S. ;

Goodloe, Robert ;

Ritchie, Marylyn D. ;

Crawford, Dana ;

Gross, Myron ;

Fornage, Myriam ;

Buzkova, Petra ;

Tao, Ran ;

Isasi, Carmen ;

Aviles-Santa, Larissa ;

Daviglus, Martha ;

Mackey, Rachel H. ;

Houston, Denise ;

Gu, C. Charles ;

Ehret, Georg ;

Nguyen, Khanh-Dung H. ;

Lewis, Cora E. ;

Leppert, Mark ;

Irvin, Marguerite R. ;

Lim, Unhee ;

Haiman, Christopher A. ;

Le Marchand, Loic ;

Schumacher, Fredrick ;

Wilkens, Lynne ;

Lu, Yingchang ;

Bottinger, Erwin P. ;

Loos, Ruth J. L. ;

Sheu, Wayne H. -H. ;

Guo, Xiuqing ;

Lee, Wen-Jane ;

Hai, Yang ;

Hung, Yi-Jen ;

Absher, Devin ;

Wu, I-Chien ;

Taylor, Kent D. ;

Lee, I-Te ;

Liu, Yeheng ;

Wang, Tzung-Dau ;

Quertermous, Thomas ;

Juang, Jyh-Ming J. ;

Rotter, Jerome I. .

HUMAN GENETICS, 2017, 136 (06) :771-800

[10] Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci [J].

Gaulton, Kyle J. ;

Ferreira, Teresa ;

Lee, Yeji ;

Raimondo, Anne ;

Maegi, Reedik ;

Reschen, Michael E. ;

Mahajan, Anubha ;

Locke, Adam ;

Rayner, N. William ;

Robertson, Neil ;

Scott, Robert A. ;

Prokopenko, Inga ;

Scott, Laura J. ;

Green, Todd ;

Sparso, Thomas ;

Thuillier, Dorothee ;

Yengo, Loic ;

Grallert, Harald ;

Wahl, Simone ;

Franberg, Mattias ;

Strawbridge, Rona J. ;

Kestler, Hans ;

Chheda, Himanshu ;

Eisele, Lewin ;

Gustafsson, Stefan ;

Steinthorsdottir, Valgerdur ;

Thorleifsson, Gudmar ;

Qi, Lu ;

Karssen, Lennart C. ;

van Leeuwen, Elisabeth M. ;

Willems, Sara M. ;

Li, Man ;

Chen, Han ;

Fuchsberger, Christian ;

Kwan, Phoenix ;

Ma, Clement ;

Linderman, Michael ;

Lu, Yingchang ;

Thomsen, Soren K. ;

Rundle, Jana K. ;

Beer, Nicola L. ;

van de Bunt, Martijn ;

Chalisey, Anil ;

Kang, Hyun Min ;

Voight, Benjamin F. ;

Abecasis, Goncalo R. ;

Almgren, Peter ;

Baldassarre, Damiano ;

Balkau, Beverley ;

Benediktsson, Rafn .

NATURE GENETICS, 2015, 47 (12) :1415-+

← 1 2 3 4 5 →