Fine-mapping of lipid regions in global populations discovers ethnic-specific signals and refines previously identified lipid loci

Niha Zubair; Mariaelisa Graff; Jose Luis Ambite; William S. Bush; Gleb Kichaev; Yingchang Lu; Ani Manichaikul; Wayne H.H. Sheu; Devin Absher; Themistocles L. Assimes; Suzette J. Bielinski; Erwin P. Bottinger; Petra Buzkova; Lee Ming Chuang; Ren Hua Chung; Barbara Cochran; Logan Dumitrescu; Omri Gottesman; Jeffrey W. Haessler; Christopher Haiman; Gerardo Heiss; Chao A. Hsiung; Yi Jen Hung; Chii Min Hwu; Jyh Ming J. Juang; Loic Le Marchand; I. Te Lee; Wen Jane Lee; Li An Lin; Danyu Lin; Shih Yi Lin; Rachel H. Mackey; Lisa W. Martin; Bogdan Pasaniuc; Ulrike Peters; Irene Predazzi; Thomas Quertermous; Alex P. Reiner; Jennifer Robinson; Jerome I. Rotter; Kelli K. Ryckman; Pamela J. Schreiner; Eli Stahl; Ran Tao; Michael Y. Tsai; Lindsay L. Waite; Tzung Dau Wang; Steven Buyske; Yii Der Ida Chen; Iona Cheng; Dana C. Crawford; Ruth J.F. Loos; Stephen S. Rich; Myriam Fornage; Kari E. North; Charles Kooperberg; Cara L. Carty

doi:10.1093/hmg/ddw358

Fine-mapping of lipid regions in global populations discovers ethnic-specific signals and refines previously identified lipid loci

Niha Zubair, Mariaelisa Graff, Jose Luis Ambite, William S. Bush, Gleb Kichaev, Yingchang Lu, Ani Manichaikul, Wayne H.H. Sheu, Devin Absher, Themistocles L. Assimes, Suzette J. Bielinski, Erwin P. Bottinger, Petra Buzkova, Lee Ming Chuang, Ren Hua Chung, Barbara Cochran, Logan Dumitrescu, Omri Gottesman, Jeffrey W. Haessler, Christopher HaimanGerardo Heiss, Chao A. Hsiung, Yi Jen Hung, Chii Min Hwu, Jyh Ming J. Juang, Loic Le Marchand, I. Te Lee, Wen Jane Lee, Li An Lin, Danyu Lin, Shih Yi Lin, Rachel H. Mackey, Lisa W. Martin, Bogdan Pasaniuc, Ulrike Peters, Irene Predazzi, Thomas Quertermous, Alex P. Reiner, Jennifer Robinson, Jerome I. Rotter, Kelli K. Ryckman, Pamela J. Schreiner, Eli Stahl, Ran Tao, Michael Y. Tsai, Lindsay L. Waite, Tzung Dau Wang, Steven Buyske, Yii Der Ida Chen, Iona Cheng, Dana C. Crawford, Ruth J.F. Loos, Stephen S. Rich, Myriam Fornage, Kari E. North, Charles Kooperberg, Cara L. Carty

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

Abstract

Genome-wide association studies have identified over 150 loci associated with lipid traits, however, no large-scale studies exist for Hispanics and other minority populations. Additionally, the genetic architecture of lipid-influencing loci remains largely unknown.We performed one of the most racially/ethnically diverse fine-mapping genetic studies of HDL-C, LDL-C, and triglycerides to-date using SNPs on the MetaboChip array on 54,119 individuals: 21,304 African Americans, 19,829 Hispanic Americans, 12,456 Asians, and 530 American Indians. The majority of signals found in these groups generalize to European Americans. While we uncovered signals unique to racial/ethnic populations, we also observed systematically consistent lipid associations across these groups. In African Americans, we identified three novel signals associated with HDL-C (LPL, APOA5, LCAT) and two associated with LDL-C (ABCG8, DHODH). In addition, using this population, we refined the location for 16 out of the 58 known MetaboChip lipid loci. These results can guide tailored screening efforts, reveal population-specific responses to lipid-lowering medications, and aid in the development of new targeted drug therapies.

Original language	English (US)
Pages (from-to)	5500-5512
Number of pages	13
Journal	Human molecular genetics
Volume	25
Issue number	24
DOIs	https://doi.org/10.1093/hmg/ddw358
State	Published - Dec 15 2016

Bibliographical note

Funding Information:
The PAGE consortium thanks the staff and participants of all PAGE studies for their important contributions. The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. The complete list of PAGE members can be found at http://www.pagestudy. org. Assistance with phenotype harmonization, SNP selection and annotation, data cleaning, data management, integration and dissemination, and general study coordination was provided by the PAGE Coordinating Center (U01HG004801-01 and its NHGRI ARRA supplement). The National Institutes of Mental Health also contributes to the support for the Coordinating Center. See Detailed Acknowledgment in Supplementary Information for PAGE study-specific acknowledgements. The PAGE program is funded by the National Human Genome Research Institute (NHGRI), supported by U01HG004803 (CALiCo), U01HG004798 (EAGLE), U01HG004802 (MEC), U01HG004790 (WHI), and U01HG004801 (Coordinating Center), and their respective NHGRI ARRA supplements.

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Zubair, N., Graff, M., Ambite, J. L., Bush, W. S., Kichaev, G., Lu, Y., Manichaikul, A., Sheu, W. H. H., Absher, D., Assimes, T. L., Bielinski, S. J., Bottinger, E. P., Buzkova, P., Chuang, L. M., Chung, R. H., Cochran, B., Dumitrescu, L., Gottesman, O., Haessler, J. W., ... Carty, C. L. (2016). Fine-mapping of lipid regions in global populations discovers ethnic-specific signals and refines previously identified lipid loci. Human molecular genetics, 25(24), 5500-5512. https://doi.org/10.1093/hmg/ddw358

Fine-mapping of lipid regions in global populations discovers ethnic-specific signals and refines previously identified lipid loci. / Zubair, Niha; Graff, Mariaelisa; Ambite, Jose Luis; Bush, William S.; Kichaev, Gleb; Lu, Yingchang; Manichaikul, Ani; Sheu, Wayne H.H.; Absher, Devin; Assimes, Themistocles L.; Bielinski, Suzette J.; Bottinger, Erwin P.; Buzkova, Petra; Chuang, Lee Ming; Chung, Ren Hua; Cochran, Barbara; Dumitrescu, Logan; Gottesman, Omri; Haessler, Jeffrey W.; Haiman, Christopher; Heiss, Gerardo; Hsiung, Chao A.; Hung, Yi Jen; Hwu, Chii Min; Juang, Jyh Ming J.; Marchand, Loic Le; Lee, I. Te; Lee, Wen Jane; Lin, Li An; Lin, Danyu; Lin, Shih Yi; Mackey, Rachel H.; Martin, Lisa W.; Pasaniuc, Bogdan; Peters, Ulrike; Predazzi, Irene; Quertermous, Thomas; Reiner, Alex P.; Robinson, Jennifer; Rotter, Jerome I.; Ryckman, Kelli K.; Schreiner, Pamela J.; Stahl, Eli; Tao, Ran; Tsai, Michael Y.; Waite, Lindsay L.; Wang, Tzung Dau; Buyske, Steven; Chen, Yii Der Ida; Cheng, Iona; Crawford, Dana C.; Loos, Ruth J.F.; Rich, Stephen S.; Fornage, Myriam; North, Kari E.; Kooperberg, Charles; Carty, Cara L.

In: Human molecular genetics, Vol. 25, No. 24, 15.12.2016, p. 5500-5512.

Research output: Contribution to journal › Article › peer-review

Zubair, N, Graff, M, Ambite, JL, Bush, WS, Kichaev, G, Lu, Y, Manichaikul, A, Sheu, WHH, Absher, D, Assimes, TL, Bielinski, SJ, Bottinger, EP, Buzkova, P, Chuang, LM, Chung, RH, Cochran, B, Dumitrescu, L, Gottesman, O, Haessler, JW, Haiman, C, Heiss, G, Hsiung, CA, Hung, YJ, Hwu, CM, Juang, JMJ, Marchand, LL, Lee, IT, Lee, WJ, Lin, LA, Lin, D, Lin, SY, Mackey, RH, Martin, LW, Pasaniuc, B, Peters, U, Predazzi, I, Quertermous, T, Reiner, AP, Robinson, J, Rotter, JI, Ryckman, KK, Schreiner, PJ, Stahl, E, Tao, R, Tsai, MY, Waite, LL, Wang, TD, Buyske, S, Chen, YDI, Cheng, I, Crawford, DC, Loos, RJF, Rich, SS, Fornage, M, North, KE, Kooperberg, C & Carty, CL 2016, 'Fine-mapping of lipid regions in global populations discovers ethnic-specific signals and refines previously identified lipid loci', Human molecular genetics, vol. 25, no. 24, pp. 5500-5512. https://doi.org/10.1093/hmg/ddw358

Zubair, Niha ; Graff, Mariaelisa ; Ambite, Jose Luis ; Bush, William S. ; Kichaev, Gleb ; Lu, Yingchang ; Manichaikul, Ani ; Sheu, Wayne H.H. ; Absher, Devin ; Assimes, Themistocles L. ; Bielinski, Suzette J. ; Bottinger, Erwin P. ; Buzkova, Petra ; Chuang, Lee Ming ; Chung, Ren Hua ; Cochran, Barbara ; Dumitrescu, Logan ; Gottesman, Omri ; Haessler, Jeffrey W. ; Haiman, Christopher ; Heiss, Gerardo ; Hsiung, Chao A. ; Hung, Yi Jen ; Hwu, Chii Min ; Juang, Jyh Ming J. ; Marchand, Loic Le ; Lee, I. Te ; Lee, Wen Jane ; Lin, Li An ; Lin, Danyu ; Lin, Shih Yi ; Mackey, Rachel H. ; Martin, Lisa W. ; Pasaniuc, Bogdan ; Peters, Ulrike ; Predazzi, Irene ; Quertermous, Thomas ; Reiner, Alex P. ; Robinson, Jennifer ; Rotter, Jerome I. ; Ryckman, Kelli K. ; Schreiner, Pamela J. ; Stahl, Eli ; Tao, Ran ; Tsai, Michael Y. ; Waite, Lindsay L. ; Wang, Tzung Dau ; Buyske, Steven ; Chen, Yii Der Ida ; Cheng, Iona ; Crawford, Dana C. ; Loos, Ruth J.F. ; Rich, Stephen S. ; Fornage, Myriam ; North, Kari E. ; Kooperberg, Charles ; Carty, Cara L. / Fine-mapping of lipid regions in global populations discovers ethnic-specific signals and refines previously identified lipid loci. In: Human molecular genetics. 2016 ; Vol. 25, No. 24. pp. 5500-5512.

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title = "Fine-mapping of lipid regions in global populations discovers ethnic-specific signals and refines previously identified lipid loci",

abstract = "Genome-wide association studies have identified over 150 loci associated with lipid traits, however, no large-scale studies exist for Hispanics and other minority populations. Additionally, the genetic architecture of lipid-influencing loci remains largely unknown.We performed one of the most racially/ethnically diverse fine-mapping genetic studies of HDL-C, LDL-C, and triglycerides to-date using SNPs on the MetaboChip array on 54,119 individuals: 21,304 African Americans, 19,829 Hispanic Americans, 12,456 Asians, and 530 American Indians. The majority of signals found in these groups generalize to European Americans. While we uncovered signals unique to racial/ethnic populations, we also observed systematically consistent lipid associations across these groups. In African Americans, we identified three novel signals associated with HDL-C (LPL, APOA5, LCAT) and two associated with LDL-C (ABCG8, DHODH). In addition, using this population, we refined the location for 16 out of the 58 known MetaboChip lipid loci. These results can guide tailored screening efforts, reveal population-specific responses to lipid-lowering medications, and aid in the development of new targeted drug therapies.",

author = "Niha Zubair and Mariaelisa Graff and Ambite, {Jose Luis} and Bush, {William S.} and Gleb Kichaev and Yingchang Lu and Ani Manichaikul and Sheu, {Wayne H.H.} and Devin Absher and Assimes, {Themistocles L.} and Bielinski, {Suzette J.} and Bottinger, {Erwin P.} and Petra Buzkova and Chuang, {Lee Ming} and Chung, {Ren Hua} and Barbara Cochran and Logan Dumitrescu and Omri Gottesman and Haessler, {Jeffrey W.} and Christopher Haiman and Gerardo Heiss and Hsiung, {Chao A.} and Hung, {Yi Jen} and Hwu, {Chii Min} and Juang, {Jyh Ming J.} and Marchand, {Loic Le} and Lee, {I. Te} and Lee, {Wen Jane} and Lin, {Li An} and Danyu Lin and Lin, {Shih Yi} and Mackey, {Rachel H.} and Martin, {Lisa W.} and Bogdan Pasaniuc and Ulrike Peters and Irene Predazzi and Thomas Quertermous and Reiner, {Alex P.} and Jennifer Robinson and Rotter, {Jerome I.} and Ryckman, {Kelli K.} and Schreiner, {Pamela J.} and Eli Stahl and Ran Tao and Tsai, {Michael Y.} and Waite, {Lindsay L.} and Wang, {Tzung Dau} and Steven Buyske and Chen, {Yii Der Ida} and Iona Cheng and Crawford, {Dana C.} and Loos, {Ruth J.F.} and Rich, {Stephen S.} and Myriam Fornage and North, {Kari E.} and Charles Kooperberg and Carty, {Cara L.}",

note = "Funding Information: The PAGE consortium thanks the staff and participants of all PAGE studies for their important contributions. The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. The complete list of PAGE members can be found at http://www.pagestudy. org. Assistance with phenotype harmonization, SNP selection and annotation, data cleaning, data management, integration and dissemination, and general study coordination was provided by the PAGE Coordinating Center (U01HG004801-01 and its NHGRI ARRA supplement). The National Institutes of Mental Health also contributes to the support for the Coordinating Center. See Detailed Acknowledgment in Supplementary Information for PAGE study-specific acknowledgements. The PAGE program is funded by the National Human Genome Research Institute (NHGRI), supported by U01HG004803 (CALiCo), U01HG004798 (EAGLE), U01HG004802 (MEC), U01HG004790 (WHI), and U01HG004801 (Coordinating Center), and their respective NHGRI ARRA supplements.",

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doi = "10.1093/hmg/ddw358",

language = "English (US)",

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T1 - Fine-mapping of lipid regions in global populations discovers ethnic-specific signals and refines previously identified lipid loci

AU - Zubair, Niha

AU - Graff, Mariaelisa

AU - Ambite, Jose Luis

AU - Bush, William S.

AU - Kichaev, Gleb

AU - Lu, Yingchang

AU - Manichaikul, Ani

AU - Sheu, Wayne H.H.

AU - Absher, Devin

AU - Assimes, Themistocles L.

AU - Bielinski, Suzette J.

AU - Bottinger, Erwin P.

AU - Buzkova, Petra

AU - Chuang, Lee Ming

AU - Chung, Ren Hua

AU - Cochran, Barbara

AU - Dumitrescu, Logan

AU - Gottesman, Omri

AU - Haessler, Jeffrey W.

AU - Haiman, Christopher

AU - Heiss, Gerardo

AU - Hsiung, Chao A.

AU - Hung, Yi Jen

AU - Hwu, Chii Min

AU - Juang, Jyh Ming J.

AU - Marchand, Loic Le

AU - Lee, I. Te

AU - Lee, Wen Jane

AU - Lin, Li An

AU - Lin, Danyu

AU - Lin, Shih Yi

AU - Mackey, Rachel H.

AU - Martin, Lisa W.

AU - Pasaniuc, Bogdan

AU - Peters, Ulrike

AU - Predazzi, Irene

AU - Quertermous, Thomas

AU - Reiner, Alex P.

AU - Robinson, Jennifer

AU - Rotter, Jerome I.

AU - Ryckman, Kelli K.

AU - Schreiner, Pamela J.

AU - Stahl, Eli

AU - Tao, Ran

AU - Tsai, Michael Y.

AU - Waite, Lindsay L.

AU - Wang, Tzung Dau

AU - Buyske, Steven

AU - Chen, Yii Der Ida

AU - Cheng, Iona

AU - Crawford, Dana C.

AU - Loos, Ruth J.F.

AU - Rich, Stephen S.

AU - Fornage, Myriam

AU - North, Kari E.

AU - Kooperberg, Charles

AU - Carty, Cara L.

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PY - 2016/12/15

Y1 - 2016/12/15

N2 - Genome-wide association studies have identified over 150 loci associated with lipid traits, however, no large-scale studies exist for Hispanics and other minority populations. Additionally, the genetic architecture of lipid-influencing loci remains largely unknown.We performed one of the most racially/ethnically diverse fine-mapping genetic studies of HDL-C, LDL-C, and triglycerides to-date using SNPs on the MetaboChip array on 54,119 individuals: 21,304 African Americans, 19,829 Hispanic Americans, 12,456 Asians, and 530 American Indians. The majority of signals found in these groups generalize to European Americans. While we uncovered signals unique to racial/ethnic populations, we also observed systematically consistent lipid associations across these groups. In African Americans, we identified three novel signals associated with HDL-C (LPL, APOA5, LCAT) and two associated with LDL-C (ABCG8, DHODH). In addition, using this population, we refined the location for 16 out of the 58 known MetaboChip lipid loci. These results can guide tailored screening efforts, reveal population-specific responses to lipid-lowering medications, and aid in the development of new targeted drug therapies.

AB - Genome-wide association studies have identified over 150 loci associated with lipid traits, however, no large-scale studies exist for Hispanics and other minority populations. Additionally, the genetic architecture of lipid-influencing loci remains largely unknown.We performed one of the most racially/ethnically diverse fine-mapping genetic studies of HDL-C, LDL-C, and triglycerides to-date using SNPs on the MetaboChip array on 54,119 individuals: 21,304 African Americans, 19,829 Hispanic Americans, 12,456 Asians, and 530 American Indians. The majority of signals found in these groups generalize to European Americans. While we uncovered signals unique to racial/ethnic populations, we also observed systematically consistent lipid associations across these groups. In African Americans, we identified three novel signals associated with HDL-C (LPL, APOA5, LCAT) and two associated with LDL-C (ABCG8, DHODH). In addition, using this population, we refined the location for 16 out of the 58 known MetaboChip lipid loci. These results can guide tailored screening efforts, reveal population-specific responses to lipid-lowering medications, and aid in the development of new targeted drug therapies.

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