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Analysis of Multi-Ancestry Cohort Uncovers Dozens of Genes Linked to Blood Lipid Levels

NEW YORK — Researchers have identified in a multi-ancestry cohort almost three dozen genes associated with blood lipid levels that are risk factors for atherosclerotic cardiovascular diseases.

While previous genome-wide association studies have linked more than 400 genetic loci to blood lipid levels, these loci explain between 9 percent and 12 percent of the phenotypic variance found among lipid traits.

In a new study, an international team of researchers has conducted gene-based association testing of blood lipid levels with rare and likely damaging gene variants using a dataset of more than 170,000 individuals of multiple ancestries. As they reported in the American Journal of Human Genetics on Monday, the researchers identified 35 genes linked to circulating lipid levels, including genes not previously associated with lipid levels, including ones found among individuals of differing ancestries.

"I would expect that genes that are associated across multiple ancestries to be more robust findings compared to ones we only see in one ancestry," senior author Gina Peloso from the Boston University School of Public Health said in an email. "We might not see the same variants in a gene associated in multiple ancestries, but finding genetic variants associated in different ancestries helps us cross validate the associations."

These genes were further enriched for the targets of cholesterol-lowering drugs and indicated that, contrary to other studies, the gene located closest to the GWAS index SNP may often be the functional gene.

For their analysis, the researchers combined data from four sources that amassed either exome or genome sequencing data alongside blood lipid level information and, in all, their dataset included more than 170,000 individuals including 97,493 Europeans, 30,025 South Asians, 16,507 Africans, 16,440 Hispanic individuals or Latinos, 10,420 East Asians, and 1,182 Samoans.

At the same time, the researchers focused on six lipid phenotypes for their analysis, including total cholesterol, LDL-Cl, HDL-C, non-HDL-C, triglycerides, and TG:HDL.

In a single-variant association analysis, the researchers uncovered hundreds of rare coding variants associated with those different lipid traits. But by then conducting a gene-based analysis of transcript-altering variants, they homed in on 35 genes that reached exome-wide significance. Most of these genes, the researchers noted, were associated with more than one lipid trait. Ten of them had not previously been associated with blood lipid phenotypes.

Most, 27, of these genes are located within 200 kilobases of GWAS-indexed SNPs for blood lipid traits, the researchers found. They further investigated whether these genes were linked to the corresponding lipid measurement, finding that they were, suggesting that the closest gene to a noncoding GWAS signal is most likely the causal one and should be prioritized for follow-up. They noted, though, that some previous studies have instead found the closest genes to a GWAS signal do not show an association with the phenotype under study.

"This could be due to the type of variation we tested — rare protein-altering variation — compared to looking at variation that might influence gene regulatory mechanisms," Peloso noted.

The genes the researchers identified through their gene-based analysis were broadly consistent across ancestry groups. For instance, three of the 17 genes associated with HDL-C showed that association in a least two ancestry groups at exome-wide significance, while five of the 14 genes linked to total cholesterol did, and four of the 10 genes linked to non-HDL-C did.

They further reported that these genes were enriched for LDL-C drug targets. "While the genes that we identified might represent drug targets, further work will be necessary to determine whether those genes are druggable and influence clinical events," she added.