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Dozens of Variants Linked to Body Fat Distribution in Exome-Wide Analysis

NEW YORK (GenomeWeb) – Researchers have uncovered two dozen novel gene variants linked to how the body stores fat, including ones that may represent treatment targets.

When some people gain weight, they store fat on their hips, but others preferentially accumulate it at their waist or abdomen, and carrying central body fat is a known risk factor for cardiometabolic conditions like type 2 diabetes.

Researchers from the Genetics Investigation of Anthropometric Traits consortium conducted an exome-wide study that uncovered 15 common and nine low-frequency variants associated with waist-to-hip ratio among nearly 477,000 individuals. As they reported in Nature Genetics yesterday, the researchers found that these genes were commonly involved in lipid particle, adiponectin, and bone development pathways.

"By knowing the genes that determine where excess fat will be stored — is it preferentially at the hips or more often at the waist — we are a step closer in understanding the biology that explains why some people, when they gain weight, are at risk of diabetes or cardiovascular disease, and why others are not," co-senior author Ruth Loos from the Icahn School of Medicine at Mount Sinai said in a statement.

In their study, the researchers combined data on 344,369 individuals from 74 different studies who had been genotyped at more than 200,000 variants to uncover 70 variants with tentative ties to waist-to-hip ratio.

They examined those suggestive variants in an additional 132,177 people from the UK Biobank and DeCode cohorts, and, in all, found 56 variants in 51 genes associated with waist-to-hip ratio. These included 23 novel variants as well as 43 common variants and 13 low-frequency or rare variants.

These variants fell in a number of genes with ties to bone growth and lipid metabolism. For instance, one novel variant linked to increased waist-to-hip ratio fell within the fibroblast growth receptor 2 (FGFR2) gene. Mutations in this gene have previously been linked to skeletal deformities.

Another variant was within ACVR1C, which encodes a TGFB receptor and has a key role in cellular growth and differentiation, and another variant the researchers uncovered was in ANGPTL4, which encodes a glycosylated, secreted protein that helps regulate glucose homeostasis, triglyceride metabolism, and insulin sensitivity.

Some of the variants, though, had varying effects in men and women, the researchers noted. Nineteen of the coding variants they found had sex differences, with 16 of them having larger effects in women, as compared to men.

Through gene-set and pathway analyses, the researchers found that the variants they uncovered were enriched for roles in the metabolic aspects of obesity. For instance, they identified two significant adiponectin-related gene sets in their analysis and also implicated a lipid particle size gene set.

In all, the analysis suggested a role of skeletal biology, glucose homeostasis/insulin signaling, and adipocyte biology in waist-to-hip ratio. An eQTL analysis using Genotype-Tissue Expression project data also indicated that some of the genes the researchers identified affect the expression of other genes, including ones involved in adipocyte differentiation or insulin sensitivity.

In a functional analysis, researchers knocked down two Drosophila orthologs of genes they identified — PLXND1 and DNAH10 — to examine their effects on triglycerides and fat storage in the model organism. While knocking down the DNAH10 ortholog led to an increase in triglyceride levels, knocking down PLXND1 also led to a change in triglyceride storage.

According to the researchers, their results highlight the role of lipid metabolism in body-fat distribution and could inform further studies into central obesity and its link to cardiometabolic conditions. These findings, they added, accentuate a number of potential new targets for therapeutic intervention.