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Study Points to Pathways, Conditions Influenced by 'Sex-Heterogeneous SNPs'

NEW YORK – By digging into the effects of autosomal SNPs with distinct activity in male or female individuals, a University of California at San Francisco team has demonstrated the potential health and biological consequences of such "sex-heterogeneous SNPs" (sex-het-SNPs).

"Most complex diseases show some degree of sex difference, in prevalence, manifestations, symptoms, comorbidities, and/or treatments and their side effects, requiring sex-personalized healthcare," the authors wrote, adding that male-female biological differences "are evident in physiology, yet genetic loci on the sex chromosomes have not yet explained sex differences in many heritable metabolic, autoimmune, and neuropsychiatric conditions and their underlying quantitative risk traits."

For a paper published in PLOS Genetics on Thursday, the researchers brought together data on up to 20 biometric traits, along with genome-wide summary statistics, for hundreds of thousands of men or women profiled for the UK Biobank project or the "Genetic investigation of anthropometric traits" (GIANT) consortium to narrow in on more than 2,300 predicted sex-het SNPs — variants that they subsequently analyzed in relation to dozens of measured or self-reported traits or conditions.

"This study refined our prior observation that SNPs with sex differences in effect on anthropometric traits have a disproportionate role in disease risk," senior author Lauren Weiss, a human genetics researcher at the University of California at San Francisco, said in an email. "By increasing the power of the set of SNPs we could examine, we were able to look for patterns in biological processes involved and genetic regulatory mechanisms impacted by these SNPs with sex differences."

In particular, the team saw overrepresentation of sex-het-SNPs in and around the transcription start sites; near cytoskeletal and calcium channel genes; genes related to skeletal muscle, cardiac, brain, or mitochondrial function; or genes in pathways that are active during stem cell, skeletal, or muscle development.

The sex-het-SNPs also overlapped with expression quantitative trait loci (QTL) that are active in the brain and other tissue types, as well as methylation QTL sites that are known to influence DNA methylation during development.

When it came to sex-het-SNPs linked to specific traits or conditions, meanwhile, the researchers highlighted distinct male and female variants with ties to conditions ranging from heart failure, asthma, or type 2 diabetes to anorexia nervosa, schizophrenia, autism spectrum disorder, or attention deficit hyperactivity disorder (ADHD).

"We conclude that genetic polymorphisms with sexually dimorphic effects on biometric traits not only contribute to fundamental embryogenic processes, but later in life play an outsized role in disease risk," the authors wrote, adding that sex-het SNPs "disproportionately influence gene expression and have a greater influence on disorders of body and brain than other expression-regulatory variation."

For her part, Weiss noted that these and other findings from the analyses may inform future studies on biological traits or conditions with sex-related differences by providing an initial look at the sex differences linked to the common variants peppered across the autosomal chromosomes.

"We hope this work helps us to understand the genetic underpinnings of sexual dimorphism and its relationship with both early development and later disease risk," Weiss said in a statement.