Meta-analysis of lipid-traits in Hispanics identifies novel loci, population-specific effects, and tissue-specific enrichment of eQTLs.

Jennifer E Below,Eric R Gamazon,Yun Li,Yingchang Lu,Miguel Cruz,Hua Tang,Nancy J Cox,Ani Manichakul,S Krithika,Jason Torres,Jerome I Rotter,Stephen S Rich,Esteban J Parra,Andrew P Morris,Qing Duan,Kent D Taylor,Craig L Hanis,Omri Gottesman,Xin Qun Wang ,Erwin P Böttinger ,Y D Ida Chen ,Jesús Peralta‐Romero ,Ruth J.f Loos ,Sophie I Candille ,Adán Valladares‐Salgado

doi:10.1038/srep19429

Abstract

We performed genome-wide meta-analysis of lipid traits on three samples of Mexican and Mexican American ancestry comprising 4,383 individuals, and followed up significant and highly suggestive associations in three additional Hispanic samples comprising 7,876 individuals. Genome-wide significant signals were observed in or near CELSR2, ZNF259/APOA5, KANK2/DOCK6 and NCAN/MAU2 for total cholesterol, LPL, ABCA1, ZNF259/APOA5, LIPC and CETP for HDL cholesterol, CELSR2, APOB and NCAN/MAU2 for LDL cholesterol, and GCKR, TRIB1, ZNF259/APOA5 and NCAN/MAU2 for triglycerides. Linkage disequilibrium and conditional analyses indicate that signals observed at ABCA1 and LIPC for HDL cholesterol and NCAN/MAU2 for triglycerides are independent of previously reported lead SNP associations. Analyses of lead SNPs from the European Global Lipids Genetics Consortium (GLGC) dataset in our Hispanic samples show remarkable concordance of direction of effects as well as strong correlation in effect sizes. A meta-analysis of the European GLGC and our Hispanic datasets identified five novel regions reaching genome-wide significance: two for total cholesterol (FN1 and SAMM50), two for HDL cholesterol (LOC100996634 and COPB1) and one for LDL cholesterol (LINC00324/CTC1/PFAS). The top meta-analysis signals were found to be enriched for SNPs associated with gene expression in a tissue-specific fashion, suggesting an enrichment of tissue-specific function in lipid-associated loci.

Highlights

Cardiovascular disease (CVD) is one of the leading causes of death in the United States in every census category[1]
Native American reference samples were not plotted in the principal components representation of GENE TCHOL CELSR2 NCAN HDL ABCA1 ZNF259/APOA5 CETP LDL CELSR2 TRIG ZNF259/APOA5 MAU2
For the signals that we identified in the Hispanic sample and that have been previously reported in European populations, we explored in more detail the pattern of linkage disequilibrium (LD) between the lead SNP in Europeans (GLGC lead SNP) and the lead SNP in our Hispanic meta-analysis

Summary

Introduction

Cardiovascular disease (CVD) is one of the leading causes of death in the United States in every census category (non-Hispanic Whites, Blacks, Hispanic/Latino, Asian/Pacific Islanders and American Indian/Alaska Natives)[1]. In Mexico, a study based on the Mexican National Health and Nutrition Survey (ENSANUT 2006) indicated even higher prevalence at the same thresholds: 43.6% for total cholesterol concentrations, 46% for LDL cholesterol, 60.5% for HDL cholesterol, and 31.5% for triglycerides[3]. Given the relevance of dyslipidemia as a risk factor for CVD, and the important public health impact of this disease, it is not surprising that substantial efforts have been directed at deciphering the genetic architecture of lipid traits. In this respect, GWAS have proven to be very successful; and to date more than 150 loci have been associated with plasma lipid traits[4,5]. We followed up the lead SNPs corresponding to the genome-wide and highly suggestive signals in three additional Hispanic samples (MESA, WHI and IPM BioMe Biobank) with 7,876 individuals

Methods

Results

Conclusion