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Visceral Adiposity GWAS Identifies Hundreds of Genetic Loci

NEW YORK – Researchers in Sweden have linked more than a hundred novel genetic loci to visceral adiposity through a genome-wide association study.

Visceral adipose tissue, or fat stored around the internal organs, is a key risk factor for developing cardiovascular and metabolic disease, but only four SNPs had been linked previously to visceral adipose tissue (VAT) mass.

In their new study, researchers led by Uppsala University's Åsa Johansson uncovered more than 200 loci linked to VAT mass, including about 100 that had not been connected to any adiposity-linked phenotype before. As they reported in Nature Medicine today, the researchers uncovered through a Mendelian randomization analysis that visceral fat appeared to be a causal risk factor for certain cardiometabolic diseases and that type 2 diabetes risk was particularly high for women.

"We were surprised that visceral fat was more strongly linked to risk of disease in women compared to men," Johansson, an associate professor of molecular epidemiology at Uppsala University, said in a statement. "Adding an extra kilogram of visceral fat can increase the risk of type 2 diabetes more than seven times in women, while the same amount of fat accumulation only increases the risk a little more than two times in men."

Because measuring VAT is time consuming and expensive, the researchers developed VAT mass prediction models. They based these models on data from more than 4,000 individuals in the UK Biobank for whom dual-energy X-ray absorptiometry-based measurements of VAT were available.

Using this prediction tool, the researchers estimated VAT mass of individuals from the UK Biobank to conduct a genome-wide association study on a cohort of 325,153 individuals. They identified 209 loci associated with predicted VAT mass. While some of these associations were at loci previously linked to obesity or BMI — such as FTO and MC4R — 102 of them had never before been linked to an adiposity-related phenotype.

One of these novel loci, HMBS, is linked to adipogenesis by its role in mitochondrial respiration, the researchers noted. Additionally, the associated SNPs in HMBS overlapped with an eQTL there, indicating that gene regulation might be behind this association with VAT. In a follow-up functional analysis, the researchers found that one allele was associated with alterations to HMBS promoter activity and that the same allele was also linked to increased HMBS expression and increased predicted VAT. This, they noted, suggests increased HMBS expression could stimulate adipogenesis and the expansion of adipose tissue.

A number of these loci were enriched for genes expressed in the brain and central nervous system, which suggested to the researchers that VAT mass is a behavioral trait that is influenced by eating and exercising habits.

Predicted VAT mass was also linked to increased risk of hypertension, hyperlipidemia, type 2 diabetes, and heart attack or anginas, even after adjusting for BMI. This risk was stronger among women compared to men, the researchers noted, especially for type 2 diabetes.

Through a Mendelian randomization analysis, the researchers found that VAT mass appears causal for these cardiometabolic conditions and, again, that this risk was much greater in women than men. For every one-kilogram increase in VAT mass, a woman's risk of developing type 2 diabetes rose slightly more than sevenfold, while such an increase in a man increased his diabetes risk by just 2.5 fold.

The relationship between predicted VAT and disease, though, was non-linear. They noted that a one-kilogram increase in predicted VAT was generally linked to a boost in disease risk, but that a saturation of disease risk occurs for all four conditions at high predicted VAT.

"Nonlinear effects like this are very interesting to study and may help us to understand the biology behind the link between visceral fat and disease," added Torgny Karlsson, a statistician at Uppsala, in a statement.