OR15-2 Risk Variants at the MYO10 Locus are Associated with Metabolic Traits

PCOS confers an increased risk for obesity-related comorbidities. It has been challenging to identify precise risk genes associated with the pathogenesis of PCOS. A novel variant located within MYO10 intron 2 (rs9312937) was identified in a PCOS GWAS in the genetically isolated Finnish and related Estonian populations. We identified PCOS risk variants at the MYO10 locus in additional PCOS populations. We hypothesized that PCOS risk variants at the locus were associated with metabolic traits. Women from Iceland (n=1347) and Boston (n=591) were diagnosed with PCOS using the Rotterdam criteria and NIH criteria, respectively, with a non-overlapping replication cohort (n=586) identified using an algorithm incorporating ICD codes and natural language processing. Controls included population controls from Iceland (effective n=1200), well-phenotyped controls from Boston (n=441) and a cohort with no PCOS diagnoses or features in the electronic medical record (EMR; n=749). We performed an association study to identify variants in the MYO10 locus associated with PCOS. We also examined the association of variants in MYO10 and 15 independent phenotypic traits in women of European ethnicity from the Boston PCOS cohort. Data were log-normalized and analyzed using linear regression, then corrected for the false discovery rate using the Benjamini-Hochberg procedure. Two novel risk variants for PCOS were identified within intron 2 of MYO10, rs31506-T (p = 1.6×10-05, OR 0.83 [95% CI 0.77-0.91]) and rs253336-A (p = 2.4×10-06, 0.82 [0.75-0.89]). The rs31506 variant is in moderate linkage disequilibrium with the novel variant rs9312937 (r(2) ≥ 0.4) and rs253336 (r(2) ≥ 0.4). The variant rs31506 maps to enhancer sites in pancreas, osteoblast and fetal adrenal cells, whereas rs253336 maps to methylation sites in adipose stem cells and ovary (pubs.broadinstitute.org/mammals/haploreg). Neither variant had eQTLs, and expression was highest in lung, thyroid, neurons, breast and ovary (gtexportal.org). Among cases and controls, the variant rs253336 was associated with BMI (β=0.015±0.0057; p=0.01), waist circumference (β=0.011±0.0047; p=0.02), hip circumference β=0.010±0.0035; p=0.003) and triglycerides (β=0.028±0.013; p=0.03). The variant rs31506 was also associated with BMI (β=0.0065±0.0027; p=0.02), waist circumference (β=0.0051±0.0022; p=0.02), hip circumference (β=0.0039±0.0017; p=0.02), HDL (β=-0.0083±0.0037; p=0.02) and triglycerides (β=0.018±0.0063; p=0.003). The association between rs253336 and hip circumference, and rs31506 and triglyceride levels remained significant after correction. There was no association between the variants and BMI in the subjects identified through the EMR. We identified two novel risk variants for PCOS in intron 2 of MYO10 (rs31506 and rs253336), a gene recently implicated within a risk locus for PCOS. We also demonstrated that the variants are associated with hip circumference and triglyceride levels. Previous data demonstrate increased expression of MYO10 in omental adipose of obese type 2 diabetics and an association with lean body mass. The data suggest a potential role for MYO10 in the metabolic etiology of PCOS. Presentation: Sunday, June 12, 2022 11:00 a.m. - 12:30 p.m.