Rare coding variants in 35 genes associate with circulating lipid levels – a multi-ancestry analysis of 170,000 exomes

Summary
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 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. Ten of these: ALB, SRSF2, JAK2, CREB3L3, TMEM136, VARS, NR1H3, PLA2G12A, PPARG and STAB1 have not been implicated for lipid levels using rare coding variation in population-based samples. We prioritize 32 genes identified in array-based genome-wide association study (GWAS) loci based on gene-based associations, of which three: EVI5, SH2B3, and PLIN1, had no prior evidence of rare coding variant associations. Most of the associated genes showed evidence of association in multiple ancestries. Also, 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 (SNP). 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.
Competing Interest Statement
PN reports investigator-initiated grants from Amgen, Apple, and Boston Scientific, is a scientific advisor to Apple, Blackstone Life Sciences, and Novartis, and spousal employment at Vertex, all unrelated to the present work. A.V.K. has served as a scientific advisor to Sanofi, Medicines Company, Maze Pharmaceuticals, Navitor Pharmaceuticals, Verve Therapeutics, Amgen, and Color; received speaking fees from Illumina, MedGenome, Amgen, and the Novartis Institute for Biomedical Research; received sponsored research agreements from the Novartis Institute for Biomedical Research and IBM Research, and reports a patent related to a genetic risk predictor (20190017119). CJW spouse employed at Regeneron. Dr. Emery is currently an employee of Celgene/Bristol Myers Squibb. Celgene/Bristol Myers Squibb had no role in the funding, design, conduct, and interpretation of this study. MEM receives funding from Regeneron unrelated to this work. EEK has received speaker honoraria from Illumina, Inc and Regeneron Pharmceuticals. BMP serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. LAC has consulted with the Dyslipidemia Foundation on lipid projects in the Framingham Heart Study. PTE is supported by a grant from Bayer AG to the Broad Institute focused on the genetics and therapeutics of cardiovascular disease. PTE has consulted for Bayer AG, Novartis, MyoKardia and Quest Diagnostics. SAL receives sponsored research support from Bristol Myers Squibb / Pfizer, Bayer AG, Boehringer Ingelheim, Fitbit, and IBM, and has consulted for Bristol Myers Squibb / Pfizer, Bayer AG, and Blackstone Life Sciences. The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. MMcC has served on advisory panels for Pfizer, NovoNordisk and Zoe Global, has received honoraria from Merck, Pfizer, Novo Nordisk and Eli Lilly, and research funding from Abbvie, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, NovoNordisk, Pfizer, Roche, Sanofi Aventis, Servier, and Takeda. As of June 2019, MMcC is an employee of Genentech, and a holder of Roche stock. MEJ holds shares in Novo Nordisk A/S. H.M.K. is an employee of Regeneron Pharmaceuticals; he owns stock and stock options for Regeneron Pharmaceuticals. MEJ has received research grants form Astra Zeneca, Boehringer Ingelheim, Amgen, Sanofi. SK is founder of Verve Therapeutics.
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