Premenstrual disorders across the life course : integrating epidemiology, genetics, and biological mechanisms

We found that women with PMDs have lower QOL, with QOL being even lower for those with PMDD. The association was significantly higher for women with PMDs and a history of psychiatric or somatic disorders.</p><p dir="ltr">In Study II, we assessed the risk of short-term and long-term sick leave and unemployment in women with PMDs compared to those without. To achieve this, we conducted a prospective cohort study using data from LifeGene and Swedish healthcare registers.

Women with PMDs had 35% higher risk of taking short-time sick leave and 69% higher risk of taking long-term sick leave. The association for unemployment was comparable, with women with PMDs having 27% higher risk for unemployment.</p><p dir="ltr">In Study III, we explored the disease landscape throughout the lifespan of women with and without PMDs and uncovered the comorbidity patterns across 18 disease system categories.

Based on Swedish healthcare registers, we performed a phenome-wide association study with population and sibling comparisons. We found that PMDs were associated with a wide range of diseases across various systems, notably mental disorders (depression and anxiety), gynecological conditions (dysmenorrhea), neoplasms (uterine leiomyoma), digestive system (irritable bowel syndrome), neurological (sleep disorders) and many more.

The associations remained statistically significant in the sibling comparison.</p><p dir="ltr">In Study IV, we uncovered a new genetic basis for premenstrual symptoms and determined genetic correlation with psychosocial and gynecological phenotypes. Carrying out a genome-wide association study (GWAS) meta- analysis using data from Swedish cohort LifeGene and Norwegian cohort MoBa with linkages to respective registers, we found that variant rs758170 in CACNA1C gene was associated with premenstrual symptoms.

We also explored the single nucleotide polymorphism (SNP)-based heritability and estimated it as 7.2%. Moreover, we found a genetic correlation of 0.62 between premenstrual symptoms and major depression.</p><p dir="ltr">In Study V, we investigated whether there is evidence for differential allelic expression (DAE) in reporter SNPs of genes involved in PMDD, which would further support evidence for existence of cis regulatory loci.

Using lymphoblastoid cell lines (LCLs) derived from women with and without PMDD, we performed allele-specific qRT-PCR assays and applied the delta delta Ct (ddCt) method, with genomic DNA (gDNA) as the reference, to assess DAE at 10 reporter SNPs across the 8 genes examined. We found evidence for DAE in 7 out of the 10 reporter SNPs examined. Further analysis leveraging expression quantitative trait loci (eQTL) showed consistent directionality between DAE and genotype-related expression effects in EBV-transformed lymphocytes tissue in GTEx for all reporter SNPs.</p><p dir="ltr">In conclusion, PMDs are associated with reduced QOL and increased risk of sick leave and unemployment.

Moreover, women with PMDs have higher risk for numerous health conditions across all disease categories, findings that could not be explained by genetic background as the associations remained evident in the sibling analysis when comparing exposed to non-exposed siblings. Through the first-ever GWAS conducted on premenstrual symptoms, we provided genetic insights into their biological underpinning and our finding on CACNA1C, which encodes for a calcium voltage-gate channel, reveals a new direction on the mechanisms of premenstrual symptoms.

Going further into biological mechanisms, detection of cis-acting functional loci supports a genetic basis for the differentially expressed alleles in the genes involved in PMDD.</p><h3 dir="ltr">List of scientific papers</h3><p dir="ltr">I. Qiwei Wang, Rebecka Keijser, Yufeng Chen, Hang Yu, <b>Elgeta Hysaj</b>, Sara Hägg, Unnur A. Valdimarsdóttir, Elizabeth Bertone-Johnson, Jurate Aleknaviciute and Donghao Lu. Premenstrual Disorders and Quality of Life in Sweden.

JAMA Network Open. 2025 Sep 23;8(9):e2533823. <a href="doi.org/10.1001/jamanetworkopen.2025.33823">https://doi.org/10.1001/jamanetworkopen.2025.33823</a></p><p dir="ltr">II. Hang Yu, Yihui Yang, <b>Elgeta Hysaj</b>, Alicia Nevriana, Sara Hägg, Unnur Anna Valdimarsdottir, Elizabeth Bertone-Johnson and Donghao Lu. Premenstrual disorders and risk of sick leave and unemployment: a prospective cohort study of 15 857 women in Sweden.

BMJ Mental Health. 2025 Jul 7;28(1):e301550. <a href="doi.org/10.1136/bmjment-2025-301550" target="_blank" rel="noreferrer">doi.org/10.1136/bmjment-2025-301550</a></p><p dir="ltr">III. <b>Elgeta Hysaj</b>, Yihui Yang, Jing Zhou, Yufeng Chen, Francesca Romana Cavallo, Jacob Bergstedt, Peter J. Schmidt, Elizabeth Bertone-Johnson, Unnur A. Valdimarsdottir, Donghao Lu. Phenome-Wide Association Study of Premenstrual Disorders: A Nationwide Register Based Study with Sibling Comparison in Sweden.

[Manuscript]</p><p dir="ltr">IV. <b>Elgeta Hysaj</b>*, Piotr Jaholkowski*, Alexey A. Shadrin*, Jacob Bergstedt, Yi Lu, Elizabeth Bertone-Johnson, Cynthia M. Bulik, Mikael Landen, Sven Sandin, Kaarina Kowalec, Sara Hägg, Arianna Di Florio, David Goldman, Peter J. Schmidt, Unnur A. Valdimarsdottir, Ole A. Andreassen# and Donghao Lu#. A Genome-Wide Association Study of Premenstrual Symptoms in Two Nordic Populations. Biological Psychiatry: Global Open Science. 2026 Sep;6(5):100784. <a href="doi.org/10.1016/j.bpsgos.2026.100784" target="_blank" rel="noreferrer">doi.org/10.1016/j.bpsgos.2026.100784</a></p><p dir="ltr">V. <b>Elgeta Hysaj</b>, Sarah Rudzinskas, Zhifeng Zhou, Jacob Bergstedt, Donghao Lu, Peter J. Schmidt, David Goldman.

Differential allelic expression identifies cis regulatory effects at genes implicated in premenstrual dysphoric disorder. [Manuscript]</p><p dir="ltr">*Equal contribution #Equal contribution</p>