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GWAS Links SNP to Increased Risk of Erectile Dysfunction

NEW YORK (GenomeWeb) – Researchers have linked a genetic variant affecting the SIM1 gene to an increased risk of erectile dysfunction among men.

Erectile dysfunction commonly occurs among men of middle age and older, and while risk factors like weight, age, and cardiovascular disease, contribute to the condition, about a third of the risk is thought to be genetic.

A Kaiser Permanente Northern California-led team of researchers conducted a genome-wide association study of more than 36,600 men to home in on a genetic locus linked to erectile dysfunction risk, an association they confirmed in about 222,000 additional men. As they reported today in the Proceedings of the National Academy of Sciences, the researchers further found that this locus interacts with the SIM1 gene, which is involved in weight homeostasis and sexual function.

"Identifying this SIM1 locus as a risk factor for erectile dysfunction is a big deal because it provides the long sought-after proof that there is a genetic component to the disease," first author, Eric Jorgenson, a research scientist at Kaiser Permanente Northern California, said in a statement. "Identifying the first genetic risk factor for erectile dysfunction is an exciting discovery because it opens the door for investigations into new, genetic-based therapies."

For the discovery phase of their analysis, Jorgenson and his colleagues drew upon 14,215 men who self-reported erectile dysfunction and 22,434 men who did not from the ethnically diverse Genetic Epidemiology Research in Adult Health and Aging cohort. Cases, they noted, were more likely to have a clinical diagnosis of erectile dysfunction or a prescription to treat it in their electronic health record.

In this cohort, the researchers linked a region on chromosome 6 to erectile dysfunction risk. With a Bayesian approach, they prioritized five SNPs in the region that likely included the causal one. They validated this set of SNPs in a separate cohort of 2,957 cases and 219,401 controls from the UK Biobank cohort. In particular, they focused on the one SNP that fell within an evolutionarily conserved region.

As the researchers initially relied on self-reported erectile dysfunction, they also imposed more stringent criteria on their cohort, finding that the association still held.

While body-mass index is known to influence erectile dysfunction risk, the researchers found that the SNP they uncovered did not appear to be influenced by BMI, suggesting that it has an independent effect on erectile dysfunction risk. They likewise found no correlation between this SNP and 177 other traits.

The region the researchers' SNP of interest falls in is a topologically associating domain that includes five genes: SIM1, MCHR2, PRDM13, CCNC, and USP45. SIM1, they noted, is evolutionarily conserved and encodes a transcription factor previously linked to both body weight and sexual function.

Chromatin conformation capture assays showed that the region around the SNP interacts with the SIM1 promoter. When they cloned the region encompassing this SNP into cells, they found that it appears to act as a SIM1 enhancer. This suggested to the researchers that this risk allele falls in an enhancer region that may regulate SIM1 expression.

These findings, the researchers said, point to a new mechanism involved in erectile dysfunction and could help guide the development of new treatments.

"This study points to a new research direction for erectile dysfunction that could help us identify other key genetic variants that trigger the disease and lead to investigations to better understand the precise mechanisms by which they operate," co-author Hunter Wessells from the University of Washington School of Medicine said in a statement. "Hopefully, this will translate into better treatments and, importantly, prevention approaches for the men and their partners who often suffer silently with this condition."