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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.

SUBMITTER: Zubair N

PROVIDER: S-EPMC5721937 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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

Zubair Niha N Graff Mariaelisa M Luis Ambite Jose J Bush William S WS Kichaev Gleb G Lu Yingchang Y Manichaikul Ani A Sheu Wayne H-H WH Absher Devin D Assimes Themistocles L TL Bielinski Suzette J SJ Bottinger Erwin P EP Buzkova Petra P Chuang Lee-Ming LM Chung Ren-Hua RH Cochran Barbara B Dumitrescu Logan L Gottesman Omri O Haessler Jeffrey W JW Haiman Christopher C Heiss Gerardo G Hsiung Chao A CA Hung Yi-Jen YJ Hwu Chii-Min CM Juang Jyh-Ming J JJ Le Marchand Loic L Lee I-Te IT Lee Wen-Jane WJ Lin Li-An LA Lin Danyu D Lin Shih-Yi SY Mackey Rachel H RH Martin Lisa W LW Pasaniuc Bogdan B Peters Ulrike U Predazzi Irene I Quertermous Thomas T Reiner Alex P AP Robinson Jennifer J Rotter Jerome I JI Ryckman Kelli K KK Schreiner Pamela J PJ Stahl Eli E Tao Ran R Tsai Michael Y MY Waite Lindsay L LL Wang Tzung-Dau TD Buyske Steven S Ida Chen Yii-Der YD Cheng Iona I Crawford Dana C DC Loos Ruth J F RJF Rich Stephen S SS Fornage Myriam M North Kari E KE Kooperberg Charles C Carty Cara L CL

Human molecular genetics 20161201 24

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 Ameri ...[more]

PMID: 28426890

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Project description:Carotid plaque is a subclinical measure of atherosclerosis. We have previously shown measures of carotid plaque to be heritable in a sample of 100 Dominican families and found evidence for linkage and association of common variants (CVs) on 7q36, 11p15, 14q32 and 15q23 with plaque presence. Our current study aimed to refine these regions further and identify rare variants (RVs) influencing plaque presence. Therefore, we performed targeted sequencing of the one LOD unit down region on 7q36, 11p15, 14q32 and 15q23 in 12 Dominican families with evidence for linkage to plaque presence. Gene-based RV analyses were performed using the Sequence Association Test for familial data (F-SKAT) under two filtering algorithms; 1. all exonic RVs and 2. non-synonymous RVs. Replication analyses were performed using a sample of 22 Dominican families and 556 unrelated Dominicans with Exome Array data. To identify additional non-synonymous RVs influencing plaque, we looked for co-segregation of RVs with plaque in each of the sequenced families. Our most strongly associated gene with evidence for replication was AMPD3 which showed suggestive association with plaque presence in the sequenced families (exonic RV p = 0.003, nonsynonymous RV p = 0.005) and replication families (exonic RV p = 0.04, nonsynonymous RV p = 0.02). Examination of the sequenced family pedigrees revealed two missense variants on chromosome 11 which co-segregated with plaque presence in one of our families; rs61751342 (located in DENND2B), and rs61760882 (located in RNF141). The rs61751342 missense variant is an eQTL for SCUBE2 in the atrial appendage. Notably, SCUBE2 encodes a protein which interacts with vascular endothelial growth factor (VEGF) receptor 2 to regulate VEGF-induced angiogenesis, thus providing biologic plausibility for this gene in atherosclerosis. In conclusion, using targeted sequencing of previously-identified linkage regions, we have identified suggestive evidence for the role of RVs in carotid plaque pathogenesis.

Dataset Information

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

Publications

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

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