Trans-Ethnic Fine-Mapping of Lipid Loci Identifies Population-Specific Signals and Allelic Heterogeneity That Increases the Trait Variance Explained

Ying Wu; Lindsay L. Waite; Anne U. Jackson; Wayne H-H. Sheu; Steven Buyske; Devin Absher; Donna K. Arnett; Eric Boerwinkle; Lori L. Bonnycastle; Cara L. Carty; Iona Cheng; Barbara Cochran; Damien C. Croteau-Chonka; Logan Dumitrescu; Charles B. Eaton; Nora Franceschini; Xiuqing Guo; Brian E. Henderson; Lucia A. Hindorff; Eric Kim; Leena Kinnunen; Pirjo Komulainen; Wen-Jane Lee; Loic Le Marchand; Yi Lin; Jaana Lindstrom; Oddgeir Lingaas-Holmen; Sabrina L. Mitchell; Narisu Narisu; Jennifer G. Robinson; Fred Schumacher; Alena Stancakova; Jouko Sundvall; Yun-Ju Sung; Amy J. Swift; Wen-Chang Wang; Lynne Wilkens; Tom Wilsgaard; Alicia M. Young; Linda S. Adair; Christie M. Ballantyne; Petra Buzkova; Aravinda Chakravarti; Francis S. Collins; David Duggan; Alan B. Feranil; Low-Tone Ho; Yi-Jen Hung; Steven C. Hunt; Kristian Hveem; Jyh-Ming J. Juang; Antero Y. Kesaniemi; Johanna Kuusisto; Markku Laakso; Timo A. Lakka; I-Te Lee; Mark F. Leppert; Tara C. Matise; Leena Moilanen; Inger Njolstad; Ulrike Peters; Thomas Quertermous; Rainer Rauramaa; Jerome I. Rotter; Jouko Saramies; Jaakko Tuomilehto; Matti Uusitupa; Tzung-Dau Wang; Michael Boehnke; Christopher A. Haiman; Yii-Der I. Chen; Charles Kooperberg; Themistocles L. Assimes; Dana C. Crawford; Chao A. Hsiung; Kari E. North; Karen L. Mohlke

doi:10.1371/journal.pgen.1003379

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Trans-Ethnic Fine-Mapping of Lipid Loci Identifies Population-Specific Signals and Allelic Heterogeneity That Increases the Trait Variance Explained

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Trans-Ethnic Fine-Mapping of Lipid Loci Identifies Population-Specific Signals and Allelic Heterogeneity That Increases the Trait Variance Explained

Ying Wu, Lindsay L. Waite, Anne U. Jackson, Wayne H-H. Sheu, Steven Buyske, Devin Absher, Donna K. Arnett, Eric Boerwinkle, Lori L. Bonnycastle, Cara L. Carty, …

PLoS genetics, Vol.9(3), pp.e1003379-e1003379

01/03/2013

DOI: https://doi.org/10.1371/journal.pgen.1003379

PMCID: PMC3605054

PMID: 23555291

Abstract

Genetics & Heredity

Life Sciences & Biomedicine

Science & Technology

Genome-wide association studies (GWAS) have identified similar to 100 loci associated with blood lipid levels, but much of the trait heritability remains unexplained, and at most loci the identities of the trait-influencing variants remain unknown. We conducted a trans-ethnic fine-mapping study at 18, 22, and 18 GWAS loci on the Metabochip for their association with triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), respectively, in individuals of African American (n = 6,832), East Asian (n = 9,449), and European (n = 10,829) ancestry. We aimed to identify the variants with strongest association at each locus, identify additional and population-specific signals, refine association signals, and assess the relative significance of previously described functional variants. Among the 58 loci, 33 exhibited evidence of association at P, 1610 24 in at least one ancestry group. Sequential conditional analyses revealed that ten, nine, and four loci in African Americans, Europeans, and East Asians, respectively, exhibited two or more signals. At these loci, accounting for all signals led to a 1.3- to 1.8-fold increase in the explained phenotypic variance compared to the strongest signals. Distinct signals across ancestry groups were identified at PCSK9 and APOA5. Trans-ethnic analyses narrowed the signals to smaller sets of variants at GCKR, PPP1R3B, ABO, LCAT, and ABCA1. Of 27 variants reported previously to have functional effects, 74% exhibited the strongest association at the respective signal. In conclusion, trans-ethnic high-density genotyping and analysis confirm the presence of allelic heterogeneity, allow the identification of population-specific variants, and limit the number of candidate SNPs for functional studies.

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Title: Trans-Ethnic Fine-Mapping of Lipid Loci Identifies Population-Specific Signals and Allelic Heterogeneity That Increases the Trait Variance Explained
Creators - without role: Ying Wu - University of North Carolina at Chapel Hill
Lindsay L. Waite - HudsonAlpha Institute for Biotechnology
Anne U. Jackson - University of Michigan–Ann Arbor
Wayne H-H. Sheu - National Defense Medical Center
Steven Buyske - Rutgers, The State University of New Jersey
Devin Absher - HudsonAlpha Institute for Biotechnology
Donna K. Arnett - University of Alabama at Birmingham
Eric Boerwinkle - The University of Texas Health Science Center at Houston
Lori L. Bonnycastle - National Institutes of Health
Cara L. Carty - Fred Hutch Cancer Center
Iona Cheng - Cancer Center of Hawaii
Barbara Cochran - The University of Texas Health Science Center at Houston
Damien C. Croteau-Chonka - University of North Carolina at Chapel Hill
Logan Dumitrescu - Vanderbilt University
Charles B. Eaton - Brown University
Nora Franceschini - University of North Carolina at Chapel Hill
Xiuqing Guo - Cedars-Sinai Medical Center
Brian E. Henderson - University of Southern California
Lucia A. Hindorff - National Human Genome Research Institute
Eric Kim - Cedars-Sinai Medical Center
Leena Kinnunen - Finnish Institute for Health and Welfare
Pirjo Komulainen - University of Eastern Finland
Wen-Jane Lee - Taichung Veterans General Hospital
Loic Le Marchand - University of Hawaii System
Yi Lin - Fred Hutch Cancer Center
Jaana Lindstrom - Finnish Institute for Health and Welfare
Oddgeir Lingaas-Holmen - Norwegian University of Science and Technology
Sabrina L. Mitchell - Vanderbilt University
Narisu Narisu - National Human Genome Research Institute
Jennifer G. Robinson - University of Iowa
Fred Schumacher - Supreme Council Of Health
Alena Stancakova - University of Eastern Finland
Jouko Sundvall - Finnish Institute for Health and Welfare
Yun-Ju Sung - Washington University in St. Louis
Amy J. Swift - National Human Genome Research Institute
Wen-Chang Wang - Biostat
Lynne Wilkens - University of Hawaii System
Tom Wilsgaard - UiT The Arctic University of Norway
Alicia M. Young - Fred Hutch Cancer Center
Linda S. Adair - University of North Carolina at Chapel Hill
Christie M. Ballantyne - Baylor College of Medicine
Petra Buzkova - University of Washington
Aravinda Chakravarti - Johns Hopkins Medicine
Francis S. Collins - National Institutes of Health
David Duggan - Translational Genomics Research Institute
Alan B. Feranil - University of San Carlos
Low-Tone Ho - Taipei Veterans General Hospital
Yi-Jen Hung - National Defense Medical Center
Steven C. Hunt - University of Utah
Kristian Hveem - Norwegian University of Science and Technology
Jyh-Ming J. Juang - National Taiwan University Hospital
Antero Y. Kesaniemi - Oulu University Hospital
Johanna Kuusisto - Kuopio University Hospital
Markku Laakso - Kuopio University Hospital
Timo A. Lakka - University of Eastern Finland
I-Te Lee - Taichung Veterans General Hospital
Mark F. Leppert - University of Utah
Tara C. Matise - Rutgers, The State University of New Jersey
Leena Moilanen - Kuopio University Hospital
Inger Njolstad - College Station Medical Center
Ulrike Peters - Fred Hutch Cancer Center
Thomas Quertermous - Stanford University
Rainer Rauramaa - Kuopio University Hospital
Jerome I. Rotter - Cedars-Sinai Medical Center
Jouko Saramies - South Karelia Central Hospital
Jaakko Tuomilehto - Finnish Institute for Health and Welfare
Matti Uusitupa - University of Eastern Finland
Tzung-Dau Wang - National Taiwan University Hospital
Michael Boehnke - University of Michigan–Ann Arbor
Christopher A. Haiman - University of Southern California
Yii-Der I. Chen - Cedars-Sinai Medical Center
Charles Kooperberg - Fred Hutch Cancer Center
Themistocles L. Assimes - Stanford University
Dana C. Crawford - Vanderbilt University
Chao A. Hsiung - National Health Research Institutes
Kari E. North - University of North Carolina at Chapel Hill
Karen L. Mohlke - University of North Carolina at Chapel Hill
Publication Details: PLoS genetics, Vol.9(3), pp.e1003379-e1003379
Publisher: Public Library Science
Number of pages: 16
Grant note: National Human Genome Research Institute (NHGRI); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Human Genome Research Institute (NHGRI) City of Kuopio R37CA54281; R01 CA63; P01CA33619; U01CA136792; U01CA98758 / National Cancer Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) NSC96-2314-B-002-151; NSC98-2314-B-002-122-MY2; NSC 100-2314-B-002-115 / National Science Council of Taiwan; Ministry of Science and Technology, Taiwan Finnish Diabetes Research Foundation Finland's Slottery Machine Association Paivikki and Sakari Sohlberg Foundation Finnish Diabetes Association 2004310 / Directorate C-Public Health DK078150; TW05596; HL085144; DK062370; DK072193; DK093757 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA U01HG004801-01 / PAGE Coordinating Center University of Eastern Finland 5254 / Kuopio University Hospital from Ministry of Health and Social Affairs 4/26/2010 / Social Insurance Institution of Finland Finnish Foundation for Cardiovascular Research 5207 / Kuopio University Hospital Sigrid Juselius Foundation 627 / Ministry of Education and Culture of Finland University of Tromso 40058/07; 70103/06 / TEKES; Finnish Funding Agency for Technology & Innovation (TEKES) N01WH22110; 24152; 32100-2; 32105-6; 32108-9; 32111-13; 32115; 32118-32119; 32122; 42107-26; 42129-32; 44221 / U.S. Department of Health and Human Services NTUH.98-N1266; NTUH100-N1775; NTUH101-N2010; NTUH101-N; VN101-04; NTUH 101-S1784 / National Taiwan University Hospital; National Taiwan University hospital districts of Central Finland 211497 / Academy of Finland (AKA); Research Council of Finland National Institute for Health and Welfare NHGRI ARRA supplements Ministry of Social Affairs and Health in Finland Commission of the European Communities; European Union (EU) 96-2314-B-002-152; 101-2325-002-078; NSC 98-2314-B-075A-002-MY3 / NSC; Ministry of Science and Technology, Taiwan Finnish Heart Association 185764 / Norwegian Research Council; Research Council of Norway hospital districts of Pirkanmaa 56358 / Yrjo Jahnsson Foundation hospital districts of South Ostrobothnia 40058/07 / Finnish Funding Agency for Technology and Innovation; Finnish Funding Agency for Technology & Innovation (TEKES) 070014 / Nordic Centre of Excellence on Systems Biology in Controlled Dietary Interventions and Cohort Studies, SYSDIET N01-HC-55015; N01-HC-55016; N01-HC-55018; N01-HC-55019; N01-HC-55020; N01-HC-55021; N01-HC-55022; HL54471; HL54472; HL54473; HL54495; HL54496; HL54497; HL54509; HL54515; 2 R01 HL55673-12; HL087647 / National Heart, Lung, and Blood Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) PH-100-SP-01; BS-094-PP-01; PH-100-PP-03 / National Health Research Institutes; National Health Research Institutes, Japan U01HG004803; U01HG004802; U01HG004790 / NHGRI PAGE program Juho Vainio Foundation LSHM-CT-2004-005272 / European Commission; European Union (EU); European Commission Joint Research Centre TCVGH-1013001C; TCVGH-1013002D / Taichung Veterans General Hospital, Taichung, Taiwan National Institutes of Mental Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Mental Health (NIMH) 129293; 117844; 40758; 211497; 118590; 102318; 123885; 77299; 124243 / Academy of Finland; Research Council of Finland
Identifiers: 9939750908331
Academic Unit: King Abdulaziz University
Language: English
Resource Type: Journal article