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 Lindström; Oddgeir Lingaas-Holmen; Sabrina L. Mitchell; Narisu Narisu; Jennifer G. Robinson; Fred Schumacher; Alena Stančáková; 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 Bůžková; 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. Kesäniemi; Johanna Kuusisto; Markku Laakso; Timo A. Lakka; I. Te Lee; Mark F. Leppert; Tara C. Matise; Leena Moilanen; Inger Njølstad; 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

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 KimLeena Kinnunen, Pirjo Komulainen, Wen Jane Lee, Loic Le Marchand, Yi Lin, Jaana Lindström, Oddgeir Lingaas-Holmen, Sabrina L. Mitchell, Narisu Narisu, Jennifer G. Robinson, Fred Schumacher, Alena Stančáková, 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 Bůžková, 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. Kesäniemi, Johanna Kuusisto, Markku Laakso, Timo A. Lakka, I. Te Lee, Mark F. Leppert, Tara C. Matise, Leena Moilanen, Inger Njølstad, 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

College of Public Health

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Abstract

Genome-wide association studies (GWAS) have identified ~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<1×10^-4 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.

Original language	English
Article number	e1003379
Journal	PLoS Genetics
Volume	9
Issue number	3
DOIs	https://doi.org/10.1371/journal.pgen.1003379
State	Published - 2013

Funding

Funders	Funder number
National Center for Research Resources	P20RR020649
National Center for Research Resources

ASJC Scopus subject areas

Ecology, Evolution, Behavior and Systematics
Molecular Biology
Genetics
Genetics(clinical)
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1371/journal.pgen.1003379

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Wu, Y., Waite, L. L., Jackson, A. U., Sheu, W. H. H., Buyske, S., Absher, D., Arnett, D. K., Boerwinkle, E., Bonnycastle, L. L., Carty, C. L., Cheng, I., Cochran, B., Croteau-Chonka, D. C., Dumitrescu, L., Eaton, C. B., Franceschini, N., Guo, X., Henderson, B. E., Hindorff, L. A., ... Mohlke, K. L. (2013). Trans-Ethnic Fine-Mapping of Lipid Loci Identifies Population-Specific Signals and Allelic Heterogeneity That Increases the Trait Variance Explained. PLoS Genetics, 9(3), Article e1003379. https://doi.org/10.1371/journal.pgen.1003379

@article{04d25a4d19724060b0d9652cc6e2ac43,

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

abstract = "Genome-wide association studies (GWAS) have identified ~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<1×10-4 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.",

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

year = "2013",

doi = "10.1371/journal.pgen.1003379",

language = "English",

volume = "9",

number = "3",

}

Wu, Y, Waite, LL, Jackson, AU, Sheu, WHH, Buyske, S, Absher, D, Arnett, DK, Boerwinkle, E, Bonnycastle, LL, Carty, CL, Cheng, I, Cochran, B, Croteau-Chonka, DC, Dumitrescu, L, Eaton, CB, Franceschini, N, Guo, X, Henderson, BE, Hindorff, LA, Kim, E, Kinnunen, L, Komulainen, P, Lee, WJ, Le Marchand, L, Lin, Y, Lindström, J, Lingaas-Holmen, O, Mitchell, SL, Narisu, N, Robinson, JG, Schumacher, F, Stančáková, A, Sundvall, J, Sung, YJ, Swift, AJ, Wang, WC, Wilkens, L, Wilsgaard, T, Young, AM, Adair, LS, Ballantyne, CM, Bůžková, P, Chakravarti, A, Collins, FS, Duggan, D, Feranil, AB, Ho, LT, Hung, YJ, Hunt, SC, Hveem, K, Juang, JMJ, Kesäniemi, AY, Kuusisto, J, Laakso, M, Lakka, TA, Lee, IT, Leppert, MF, Matise, TC, Moilanen, L, Njølstad, I, Peters, U, Quertermous, T, Rauramaa, R, Rotter, JI, Saramies, J, Tuomilehto, J, Uusitupa, M, Wang, TD, Boehnke, M, Haiman, CA, Chen, YDI, Kooperberg, C, Assimes, TL, Crawford, DC, Hsiung, CA, North, KE & Mohlke, KL 2013, 'Trans-Ethnic Fine-Mapping of Lipid Loci Identifies Population-Specific Signals and Allelic Heterogeneity That Increases the Trait Variance Explained', PLoS Genetics, vol. 9, no. 3, e1003379. https://doi.org/10.1371/journal.pgen.1003379

TY - JOUR

T1 - Trans-Ethnic Fine-Mapping of Lipid Loci Identifies Population-Specific Signals and Allelic Heterogeneity That Increases the Trait Variance Explained

AU - Wu, Ying

AU - Waite, Lindsay L.

AU - Jackson, Anne U.

AU - Sheu, Wayne H.H.

AU - Buyske, Steven

AU - Absher, Devin

AU - Arnett, Donna K.

AU - Boerwinkle, Eric

AU - Bonnycastle, Lori L.

AU - Carty, Cara L.

AU - Cheng, Iona

AU - Cochran, Barbara

AU - Croteau-Chonka, Damien C.

AU - Dumitrescu, Logan

AU - Eaton, Charles B.

AU - Franceschini, Nora

AU - Guo, Xiuqing

AU - Henderson, Brian E.

AU - Hindorff, Lucia A.

AU - Kim, Eric

AU - Kinnunen, Leena

AU - Komulainen, Pirjo

AU - Lee, Wen Jane

AU - Le Marchand, Loic

AU - Lin, Yi

AU - Lindström, Jaana

AU - Lingaas-Holmen, Oddgeir

AU - Mitchell, Sabrina L.

AU - Narisu, Narisu

AU - Robinson, Jennifer G.

AU - Schumacher, Fred

AU - Stančáková, Alena

AU - Sundvall, Jouko

AU - Sung, Yun Ju

AU - Swift, Amy J.

AU - Wang, Wen Chang

AU - Wilkens, Lynne

AU - Wilsgaard, Tom

AU - Young, Alicia M.

AU - Adair, Linda S.

AU - Ballantyne, Christie M.

AU - Bůžková, Petra

AU - Chakravarti, Aravinda

AU - Collins, Francis S.

AU - Duggan, David

AU - Feranil, Alan B.

AU - Ho, Low Tone

AU - Hung, Yi Jen

AU - Hunt, Steven C.

AU - Hveem, Kristian

AU - Juang, Jyh Ming J.

AU - Kesäniemi, Antero Y.

AU - Kuusisto, Johanna

AU - Laakso, Markku

AU - Lakka, Timo A.

AU - Lee, I. Te

AU - Leppert, Mark F.

AU - Matise, Tara C.

AU - Moilanen, Leena

AU - Njølstad, Inger

AU - Peters, Ulrike

AU - Quertermous, Thomas

AU - Rauramaa, Rainer

AU - Rotter, Jerome I.

AU - Saramies, Jouko

AU - Tuomilehto, Jaakko

AU - Uusitupa, Matti

AU - Wang, Tzung Dau

AU - Boehnke, Michael

AU - Haiman, Christopher A.

AU - Chen, Yii Der I.

AU - Kooperberg, Charles

AU - Assimes, Themistocles L.

AU - Crawford, Dana C.

AU - Hsiung, Chao A.

AU - North, Kari E.

AU - Mohlke, Karen L.

PY - 2013

Y1 - 2013

N2 - Genome-wide association studies (GWAS) have identified ~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<1×10-4 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.

AB - Genome-wide association studies (GWAS) have identified ~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<1×10-4 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.

UR - http://www.scopus.com/inward/record.url?scp=84875996758&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84875996758&partnerID=8YFLogxK

U2 - 10.1371/journal.pgen.1003379

DO - 10.1371/journal.pgen.1003379

M3 - Article

C2 - 23555291

AN - SCOPUS:84875996758

SN - 1553-7390

VL - 9

JO - PLoS Genetics

JF - PLoS Genetics

IS - 3

M1 - e1003379

ER -

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

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