Understanding whether and how shared genetic factors contribute to the comorbidity between stress-related disorders (SRDs) and cardiovascular disease (CVD) is important for integrated prevention and treatment, but current evidence remains limited. To address this gap, we integrated Swedish national registers (n = 4,123,631), UK Biobank (n = 502,291), and genome-wide association study summary statistics to explore shared genetic liability between SRDs and six CVD subtypes and to nominate pleiotropic loci, genes, and enriched pathways. Familial coaggregation analyses showed that the SRDs-CVD association attenuated with decreasing genetic relatedness among relatives, supporting the existence of shared genetic influences. Polygenic risk scores for SRDs significantly predicted a higher risk of any CVD and all subtypes (odds ratios = 1.05-1.09), and all SRDs-CVD pairs showed positive genetic correlations (rg = 0.09-0.35), whereas Mendelian randomization (MR) analyses did not support strong causal effects in either direction. Genome-wide cross-trait analyses identified 17 putative pleiotropic loci, and consensus-based gene mapping prioritized 16 putative pleiotropic genes. Enrichment analyses indicated that pleiotropic signals were enriched in processes related to hemostasis and coagulation, circulatory system development, and telomere maintenance. In validation analyses focusing on post-traumatic stress disorder (PTSD), we observed a similar pattern of genetic overlap with CVD and replicated a subset of loci, genes, and pathways. These findings support a genetic comorbidity framework in which shared genetic liability, largely driven by pleiotropic loci, contributes to the co-occurrence of SRDs and CVD and highlight candidate genes and biological processes for future experimental studies.
C. Hou, Yu Zeng, Huazhen Yang et al.· Genomics, Proteomics & Bioin...· 0 citations
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, K. Hu, J. Guintivano et al.· Research Square· 0 citations
Pre-existing psychiatric disorders have been associated with the severity of acute respiratory infections, including COVID-19, particularly in hospitalized populations. However, the underlying mechanisms, especially in community-based populations, remain unknown, limiting preparedness for future pandemics. We investigated the role of genetic liability for psychiatric disorders and related traits in COVID-19 and other respiratory infection severity among individuals reporting SARS-CoV-2 testing and available respiratory symptom data.
We included population-based cohort data from Denmark, Estonia, Iceland, Norway, and the United Kingdom (N = 78,507; 62% female; 41% SARS-CoV-2-positive; May 2020—March 2023). Respiratory infection severity was defined by self-reported days bedridden and an eleven-symptom composite score during the acute illness phase. Polygenic scores (PGSs) for eight psychiatric disorders and the personality trait neuroticism indexed genetic liability. Meta-analysed estimates from stepwise-adjusted regression analyses controlling for education, lifestyle, and psychiatric and somatic diagnosis history were used to assess associations between PGSs and acute respiratory infection severity, stratified by COVID-19 status.
Higher genetic liability to insomnia, major depression (MD), and neuroticism was consistently associated with longer time bedridden (relative risk ratios per 1 SD change in PGS: 1.07–1.14, 95% confidence intervals [CIs]: 1.03–1.21) and more symptoms (incident rate ratios [IRRs]: 1.02–1.04, 95% CIs: 1.01–1.05) due to COVID-19. PGSs for insomnia, MD, neuroticism, anxiety disorder, bipolar disorder, and schizophrenia were also linked to higher non-COVID-19 symptom count (IRRs: 1.01–1.05, 95% CIs: 1.00–1.07). These associations remained robust after adjustment for lifestyle, education and medical comorbidities. Individuals in the highest MD PGS decile reported 20% more symptoms in non-COVID-19 illness and 10% more in COVID-19 compared with the bottom decile. No consistent associations were detected with attention-deficit/hyperactivity disorder, alcohol dependence and post-traumatic stress disorder. No genetic link was observed with ischaemic heart disease or type 2 diabetes.
Shared genetics may contribute to the link between psychiatric conditions and respiratory infection severity in community settings. Our results underscore the role of psychiatric genetic liability, beyond diagnosed psychiatric disorders, in contributing to both COVID-19 and other respiratory infection severity. These findings provide insights that may improve future risk stratification and public health strategies targeting respiratory viruses.
K. Kõiv, R. Askeland, L. N. Christoffersen et al.· Genome Medicine· 0 citations
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