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Female-Specific Fat Distribution Gene, Regulatory Variant Emerge from Gene Expression Study

NEW YORK – A team led by researchers at the University of Chicago has tracked down a sex-specific genetic variant with ties to fat tissue distribution, particularly the presence of abdominal fat, as well as higher-than-usual blood cholesterol and triglyceride levels.

"Our data expand the knowledge on how the genome regulates adipocytes to control fat deposition, determining the impact of caloric excess on human health," co-senior and co-corresponding author Marcelo Nóbrega, a geneticist at the University of Chicago, and his colleagues wrote.

As they reported in Nature Genetics on Thursday, the researchers relied on a series of expression analysis, transcriptome-wide association study (TWAS), and massively parallel reporter assay (MPRA) approaches to search for genes associated with body mass index (BMI) and waist-to-hip ratio adjusted for BMI.

Using linkage disequilibrium score regression analyses on tissue-specific genes, for example, the team saw that elevated BMI coincided with expression shifts in the frontal cortex and other central nervous system tissues, while expression changes in subcutaneous adipose tissue and female reproductive tissue had potential ties to waist-to-hip adjusted for BMI.

Delving into these associations further, the researchers performed TWAS with genome-wide association study summary statistic data for nearly 681,300 well-phenotyped individuals enrolled through the GIANT Consortium. They also looked at gene expression profiles for post-mortem brain cortex samples from more than 400 CommonMind Consortium participants and adipose tissue expression results from the Genotype-Tissue Expression (GTEx) project.

Within a set of 460 genes with obesity-associated gene expression patterns in the brain's cortex, the researchers found some that had previously been linked to obesity, as well as new candidate genes. When it came to associations with waist-to-hip ratio adjusted for BMI, meanwhile, they flagged 42 genes in male and 91 genes in female participants.

The TWAS candidate genes — as well as the expression quantitative trait loci (eQTL) associated with them — seemed to have larger effect sizes in the female participants. That prompted a more detailed analyses of the top waist-to-hip ratio adjusted for BMI TWAS gene from a female-specific analysis, known as SNX10, along with an intronic SNP called rs1534696 linked to SNX10 expression in subcutaneous adipose tissue.

The adipose tissue-related eQTL activity for rs1534696 appeared similar between the sexes, the researchers explained. Even so, the variant only appeared to be associated with fat distribution, blood triglyceride levels, and high-density lipoprotein cholesterol levels in women, who also had higher SNX10 expression in their experiments.

"We have now identified a gene, out of the hundreds of genes that are involved in fat accumulation or obesity, that may be more likely to cause disease complications and, interestingly, it does so primarily in women," Nóbrega suggested in a statement, noting that "we think the road that led us to find SNX10 is a good way to identify other genes that are likely to be amenable to therapeutic development."

Along with follow-up mouse model experiments that pointed to a potential female-specific role for the SNX10 gene in adipose tissue development and function, the team explored the gene regulatory features behind the newly detected adipose distribution associations.

In particular, the analyses highlighted related enhancer activity involving variants falling in retrotransposons or "jumping genes" known as Alu repeats that stem from ancient viral infections and integrations into the genome.

Together, the authors explained, their results hint that "human patterns of fat deposition may be, in part, regulated through a subset of co-opted, primate-specific Alu retrotransposons, the [extent] to which remains to be determined along with the possible phenotypic differences emerging from the genetic variants within these Alu retrotransposons."