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Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency < 1%) predicted damaging coding variation by using sequence data from >170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels; some of these genes have not been previously associated with lipid levels when using rare coding variation from population-based samples. We prioritize 32 genes in array-based genome-wide association study (GWAS) loci based on aggregations of rare coding variants; three (EVI5, SH2B3, and PLIN1) had no prior association of rare coding variants with lipid levels. Most of our associated genes showed evidence of association among multiple ancestries. Finally, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes and for genes closest to GWAS index single-nucleotide polymorphisms (SNPs). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels.

Original publication

DOI

10.1016/j.ajhg.2021.11.021

Type

Journal article

Journal

American journal of human genetics

Publication Date

01/2022

Volume

109

Pages

81 - 96

Addresses

Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Clinical Sciences, Lund University, Malmö, Sweden; Department of Population Medicine, Qatar University College of Medicine, QU Health, Doha, Qatar.

Keywords

AMP-T2D-GENES, Myocardial Infarction Genetics Consortium, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, NHLBI TOPMed Lipids Working Group