Premenstrual disorders linked to major depression, with new genetic clues pointing to calcium channel dysfunction.

Every human being carries thousands of genes that are essential for normal biological function. Together, these genes constitute the genome, which differs between individuals in millions of ways. Genetic variation can occur as single nucleotide changes, known as single nucleotide polymorphisms (SNPs), or as larger structural alterations, such as insertions and deletions. These variations can influence an individual’s traits or phenotype, including susceptibility to specific diseases.

Genome-wide association studies (GWAS) are observational studies designed to identify associations between genetic variants, particularly SNPs, and traits such as common human diseases.

Recently, the first GWAS investigating premenstrual symptoms (PSs) and premenstrual disorders (PMDs) was conducted in two Nordic populations to explore their genetic architecture and the relationship between PSs and other psychiatric conditions.

The study included two cohorts: the Swedish LifeGene cohort, a prospective study with longitudinal follow-up involving 5,229 participants, and the Norwegian Mother, Father and Child Cohort Study (MoBa), a population-based cohort comprising 67,068 participants. Premenstrual symptoms were assessed using a modified version of the Premenstrual Symptoms Screening Tool (PSST) in the LifeGene cohort and by questionnaire at the 15th week of gestation in the MoBa cohort. In total, 17,511 women met the criteria for PSs and were compared with 54,786 controls.

The GWAS analyses was performed using linear regression implemented in PLINK2 and showed that one locus at 12p13.3 was highly significant. A variant near the CACNA1C gene (rs758170, on chromosome 12) was significantly associated with PSs (Odds ratio = 0.93). This gene encodes a calcium channel subunit important in neurodevelopment. It has previously been linked to bipolar disorder, schizophrenia, and other mood disorders, though notably, the association reached significance only in the larger MoBa cohort, not in LifeGene alone. Six other loci showed borderline significance, 3 of which were nominally significant in both cohorts. This included genes linked to immune function (CD38), though these findings need to be replicated further.

Premenstrual symptoms showed significant positive genetic correlations with all psychiatric disorders examined, with the strongest link found for major depression. Positive correlations were also observed with endometriosis and BMI. Notably, no significant correlation emerged with circulating steroid hormone levels, supporting the theory that PMDs stem from abnormal sensitivity to normal hormonal fluctuations, rather than abnormal hormone levels themselves.

Although the study relied on retrospective questionnaires for diagnosis, it offers the first genetic foothold into PMDs, reinforcing that these disorders share biological pathways with depression and anxiety. While polymorphisms in the CACNA1C gene have previously been implicated in bipolar disorder and schizophrenia, this study demonstrates its potential role in PMDs for the first time.

Replicating these findings in larger, more diverse cohorts will be essential to confirm this genetic signal and identify additional SNPs associated with premenstrual symptoms and disorders.

Reference

Hysaj E, Jaholkowski P, Shadrin AA, Bergstedt J, Lu Y, Bertone-Johnson E, Bulik CM, Landén M, Sandin S, Kowalec K, Hägg S, Di Florio A, Goldman D, Schmidt PJ, Valdimarsdóttir UA, Andreassen OA, Lu D. A Genome-Wide Association Study of Premenstrual Symptoms in Two Nordic Populations. Biol Psychiatry Glob Open Sci. 2026 Jun 29;6(5):100784. doi: 10.1016/j.bpsgos.2026.100784. PMID: 42633314; PMCID: PMC13499404.