Background Premenstrual disorder (PMD) and postpartum depression (PPD) have a strong phenotypic link and echo women’s hormone fluctuations. Yet, the extent to which they may be cross-inherited remains poorly understood. Methods Using the nationwide cohort of 907,841 women who born 1950-2007 and gave birth during 2001-2021 in Sweden, we estimated the cumulative incidence functions-based heritability and genetic correlation for PMD and PPD. We also analyzed genome-wide association study (GWAS) summary statistics from the largest European-ancestry cohorts for PMD (17,511 cases and 54,786 controls) and PPD (16,145 cases and 46,609 controls) using linkage disequilibrium score regression (LDSC). Fixed-effect cross-trait meta-analysis and imputed transcriptome-wide association analyses (TWAS) were conducted to identify shared loci and gene-tissue associations. Results The register-based heritability was 0.35 (95% CI: 0.29-0.41) for PMD and 0.31 (95% CI: 0.23-0.37) for PPD, with a positive genetic correlation between these disorders (rg = 0.47, 95% CI: 0.25–0.69). LDSC also showed a positive genetic correlation between PMD and PPD (rg = 0.66, SE = 0.10, P = 1.014×10−10), indicating sizable shared heritable influences. Cross-trait meta-analysis identified two novel genome-wide significant loci jointly associated with PMD and PPD, mapping to an intronic region of PCDH9 and the 3’ untranslated region of KCTD16. The KCTD16 locus implicates GABAB–mediated inhibitory signaling in both disorders. Consistent with this, TWAS revealed a hippocampus regulatory signal for KCTD16, with no detectable trend effects in other brain regions or peripheral tissues. Beyond the lead loci, TWAS suggested that the shared risk variants may partially act through genetically regulated gene expression across brain, endocrine and immune-related tissues. Conclusions Together, these findings provide the first evidence for sizable genetic overlap between PMD and PPD and highlight novel and convergent biological mechanisms underlying the abnormal brain response of some women to gonadal hormone fluctuations.
Susu Qu, Kejia Hu, J. Guintivano et al.· Research Square· 0 citations
Eating disorders—including anorexia nervosa (AN), bulimia nervosa and binge-eating disorder—are clinically distinct but exhibit symptom overlap and diagnostic crossover. Genomic analyses have mostly examined AN. Here we conducted a genomic meta-analysis of case–control studies of binge-eating behavior (BE; 39,279 cases, 1,227,436 controls), alongside analyses of AN (24,223 cases, 1,243,971 controls) and its subtypes (all European ancestries). We identified six BE-associated loci, including loci associated with a higher body mass index and impulse-control behaviors. AN genome-wide association studies yielded eight loci, validating six loci. Subsequent polygenic risk score analysis demonstrated an association with AN in two East Asian ancestry studies. BE and AN exhibited similar positive genetic correlations with psychiatric disorders but opposing genetic correlations with anthropometric traits. Most of the genetic signal in BE and AN was not shared with body mass index. We have extended eating disorder genomics beyond AN; future work will incorporate multiple diagnoses and global ancestries.
Jet D Termorshuizen, Helena L Davies, Sang-Hyuck Lee et al.· Nature Mental Health· 0 citations
Major depressive disorder (MDD) is a complex psychiatric disorder, characterized by a range of mood, cognitive, and neurovegetative symptoms. Current diagnostic criteria treat opposite symptom directions as equivalent; weight gain or loss, and increased or decreased sleep, each count toward a single diagnosis. We defined three subgroups of individuals meeting criteria for MDD: AERS+ (hypersomnia with increased appetite/weight gain), AERS- (insomnia with appetite/weight loss), and an Uncategorized group, and conducted genome-wide association meta-analyses for each (N_eff = 47,858, 156,624, and 215,828, respectively). We identified 27 genome-wide significant loci across subtypes, 4 for AERS+, 10 for AERS- and 13 for Uncategorized. AERS+ showed higher SNP-based heritability (10.9%) and lower polygenicity (1.7% of SNPs) than AERS- (7.9%; 2.9%) or Uncategorized (8.6%; 5.3%), with larger effect sizes at its associated loci. The AERS+ and AERS- subtypes were moderately genetically correlated (r_g= 0.64, se = 0.04). Metabolic traits emerged as a primary differentiator: AERS+ correlated positively with BMI, metabolic syndrome, and related traits, whereas AERS- correlated weakly in the opposite direction. These findings show that the directionality of neurovegetative symptoms indexes genetic heterogeneity within MDD, with metabolic biology as a central axis of differentiation.
A. Harder, Rujia Wang, Jacob Bergstedt et al.· medRxiv· 0 citations