Genome-Wide Association Study of Distressing Premenstrual Symptoms in Two Nordic Populations

BackgroundPremenstrual disorders (PMDs) are characterized by affective and physical symptoms before menses, likely due to abnormal sensitivity to normal hormone fluctuations. While sizable heritability has been indicated in twin studies, there are no genome-wide association studies (GWAS) to inform the genetic architecture of PMDs. MethodsWe conducted a GWAS of 17,511 women with distressing premenstrual symptoms (DPS) and 54,789 women controls of European ancestry from two Nordic population-based cohorts. DPS were assessed using questionnaire or identified as a clinical diagnosis of PMDs in the nationwide healthcare registers. GWAS was performed in each study before meta-analysis, analyses of single nucleotide polymorphism (SNP)-based heritability (h2) and genetic correlations to psychosocial and gynecological phenotypes, as well as blood levels of gonadal steroids. ResultsIn the meta-analysis, one locus at 12p13.3 (rs758170, CACNA1C, P=1.53x10-8, OR=0.93, 95% CI 0.90-0.95) was associated with DPS. The SNP-based heritability was estimated 0.072 (SE=0.01, P=2.46 x10-12). Statistically significant genetic correlations (rg) were found between DPS and all major psychiatric disorders, with the strongest correlation with major depression (rg=0.62, CI 0.49-0.74, P=3.04x10-22). Weaker correlations were noted to gynecological conditions such as endometriosis (rg=0.17, CI 0.01-0.32, P=0.029), while gonadal steroid hormone levels in blood were uncorrelated. ConclusionThis study provides the first direct insights into the genetic architecture of PMDs by identifying a SNP associated with DPS and genetic correlations to other conditions. If confirmed in larger independent populations, these findings may advance our understanding of the underlying mechanisms of PMDs.