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

Premenstrual 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 (GWASs) to inform the genetic architecture of PMDs.

We conducted a GWAS of 17,511 women with premenstrual symptoms (PSs) and 54,786 control women of European ancestry from 2 Nordic population-based cohorts. PSs were assessed using questionnaires or identified as a clinical diagnosis of PMD in the nationwide health care registers. A GWAS was performed in each study before meta-analysis, followed by analyses of single nucleotide polymorphism (SNP)-based heritability (h ² _SNP) and genetic correlations to psychosocial and gynecological phenotypes.

In the meta-analysis, 1 locus at 12p13.3 (rs758170, CACNA1C, p = 1.53 × 10^-8, odds ratio [OR] = 0.93, 95% CI [0.90 to 0.95]) was associated with PSs; while the effect sizes were comparable between cohorts (LifeGene OR = 0.95 vs. MoBa [The Norwegian Mother, Father and Child Cohort Study] OR = 0.92, p for heterogeneity = .59), the association was not significant in LifeGene (p = .242). Moreover, we identified 6 loci with borderline significance, 3 of which were nominally significant in both cohorts (rs76665457, rs147346386, and rs4773561). The SNP-based heritability was estimated as 0.072 (SE = 0.01, p = 2.46 × 10^-12). The strongest correlation was with major depression (r _g = 0.62, 95% CI = [0.49 to 0.74], p = 3.04 × 10^-22).

This study provides initial genetic insights into the biology of PSs by identifying an SNP associated with PSs and genetic correlations with a range of psychosocial and gynecological traits. If confirmed in larger independent populations, these findings may advance our understanding of the underlying mechanisms of PMDs.