Polygenic risk score analyses of major psychiatric disorders in association with premenstrual dysphoric disorder in patients with bipolar disorder
M.J. Choi1, H.J. Lee2, E.Y. Cho3, E.H. Jang1,3, K.E. Lee4, H. Yu5, J.E. Ahn3, Y. Choi3, S.J. Rhee4, W. Myung5,6, T.H. Ha5,6, K.S. Hong7,8, K. Ha7,8, S.H. Kim2, Y.M. Ahn2,6, J.H. Baek1
1Samsung Medical Center, Sungkyunkwan University School of Medicine, Department of Psychiatry, Seoul, Korea, Republic of, 2Seoul National University Hospital, Department of Neuropsychiatry, Seoul, Korea, Republic of, 3Samsung Medical Center, Samsung Institute of Future Medicine, Seoul, Korea, Republic of, 4Seoul National University Hospital, Biomedical Research Institute, Seoul, Korea, Republic of, 5Seoul National University Bundang Hospital, Department of Neuropsychiatry, Seongnam, Korea, Republic of, 6Seoul National University College of Medicine, Department of Psychiatry, Seoul, Korea, Republic of, 7University of British Columbia, Department of Psychiatry, Vancouver, BC, Canada, 8Lions Gate Hospital-Vancouver Coastal Health, Department of Psychiatry, British Columbia, Canada
Background: The cyclic nature of premenstrual dysphoric disorder (PMDD) mirrors the mood instability characteristic of bipolar disorder (BD). PMDD is more prevalent among women with BD than in the general population and is frequently associated with a more debilitating illness course. While recent evidence suggests that PMDD shares genetic liabilities with major psychiatric disorders—including BD and attention-deficit/hyperactivity disorder (ADHD)—the specific clinical and genetic mechanisms underlying this association remain poorly understood.
Aims & Objectives: This study sought to identify distinct clinical and genetic factors associated with PMDD in Korean female patients with BD. We compared lifetime clinical characteristics between patients with and without PMDD and investigated the associations between polygenic risk scores (PRSs) for five major psychiatric disorders—schizophrenia (SCZ), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), ADHD, and BD—and both PMDD status (diagnosis) and premenstrual symptom severity.
Method: Korean female patients with BD were recruited from multiple university-affiliated hospitals. Premenstrual symptoms and associated functional impairments were evaluated using validated scales. Clinical features, psychiatric comorbidities, and lifetime illness characteristics were assessed through semi-structured clinical interviews and self-report questionnaires. Following stringent quality control and imputation, 9,556,467 single-nucleotide variants (SNVs) were analyzed. PRSs were calculated using the PRS-CSx framework.
Results: Of the 532 participants with complete data, 211 (39.7%) met the criteria for PMDD. Compared to the non-PMDD group, individuals with PMDD were younger, more likely to be diagnosed with bipolar II disorder, and showed significant differences in marital and occupational status. Clinically, PMDD was associated with an earlier age of BD onset, a predominance of hypomanic and major depressive episodes, and a lower frequency of psychotic features during mania. Notably, patients with PMDD exhibited significantly higher childhood and adulthood ADHD symptom scores. While no PRS was significantly associated with the categorical presence of PMDD after covariate adjustment, higher ADHD PRS significantly correlated with greater premenstrual symptom severity in linear regression models. Furthermore, ADHD PRS was consistently associated with higher ADHD symptom scores across multiple clinical measures.
Discussion & Conclusions: Our findings indicate that genetic liability for ADHD is more closely linked to the dimension of premenstrual symptom severity than to a categorical PMDD diagnosis. The concordance between genetic and clinical ADHD phenotypes in relation to premenstrual symptoms suggests a shared biological vulnerability.
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