Key result
Rare coding variants in 35 genes were associated with circulating lipid levels across multiple ancestries, including 10 genes not previously implicated using rare coding variation in population-based samples.
Why the study?
Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications.
Observational (n=172,067)
Yes
Large-scale multi-ancestry exome sequencing identified 35 genes associated with blood lipid levels, providing potential new targets for cardiovascular drug development.
Prioritizes genes for lipid drug development; leaves open clinical translation pending functional validation.
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.
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Hindy et al. (2020) conducted an observational in Dyslipidemia / Circulating lipid levels (n=172,067). Rare coding variants (MAF < 1%) vs. Absence of rare coding variants was evaluated on Association of rare coding variants with circulating lipid levels (LDL-C, HDL-C, non-HDL-C, TC, TG, TG:HDL). Rare coding variants in 35 genes were associated with circulating lipid levels across multiple ancestries, including 10 genes not previously implicated using rare coding variation in population-based samples.
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