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Polygenic overlap and shared genetic loci between loneliness, severe mental disorders, and cardiovascular disease risk factors suggest shared molecular mechanisms.

ABSTRACT: Clinical and epidemiological evidence suggest that loneliness is associated with severe mental disorders (SMDs) and increases the risk of cardiovascular disease (CVD). However, the mechanisms underlying the relationship between loneliness, SMDs, and CVD risk factors remain unknown. Here we explored overlapping genetic architecture and genetic loci shared between SMDs, loneliness, and CVD risk factors. We analyzed large independent genome-wide association study data on schizophrenia (SCZ), bipolar disorder (BD), major depression (MD), loneliness and CVD risk factors using bivariate causal mixture mode (MiXeR), which estimates the total amount of shared variants, and conditional false discovery rate to evaluate overlap in specific loci. We observed substantial genetic overlap between SMDs, loneliness and CVD risk factors, beyond genetic correlation. We identified 149 loci jointly associated with loneliness and SMDs (MD n?=?67, SCZ n?=?54, and BD n?=?28), and 55 distinct loci jointly associated with loneliness and CVD risk factors. A total of 153 novel loneliness loci were found. Most of the shared loci possessed concordant effect directions, suggesting that genetic risk for loneliness may increase the risk of both SMDs and CVD. Functional analyses of the shared loci implicated biological processes related to the brain, metabolic processes, chromatin and immune system. Altogether, the study revealed polygenic overlap between loneliness, SMDs and CVD risk factors, providing new insights into their shared genetic architecture and common genetic mechanisms.

SUBMITTER: Rodevand L

PROVIDER: S-EPMC7790035 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Polygenic overlap and shared genetic loci between loneliness, severe mental disorders, and cardiovascular disease risk factors suggest shared molecular mechanisms.

Rødevand Linn L Bahrami Shahram S Frei Oleksandr O Lin Aihua A Gani Osman O Shadrin Alexey A Smeland Olav B OB Connell Kevin S O' KSO Elvsåshagen Torbjørn T Winterton Adriano A Quintana Daniel S DS Hindley Guy F L GFL Werner Maren C F MCF Djurovic Srdjan S Dale Anders M AM Lagerberg Trine V TV Steen Nils Eiel NE Andreassen Ole A OA

Translational psychiatry 20210105 1

Clinical and epidemiological evidence suggest that loneliness is associated with severe mental disorders (SMDs) and increases the risk of cardiovascular disease (CVD). However, the mechanisms underlying the relationship between loneliness, SMDs, and CVD risk factors remain unknown. Here we explored overlapping genetic architecture and genetic loci shared between SMDs, loneliness, and CVD risk factors. We analyzed large independent genome-wide association study data on schizophrenia (SCZ), bipola ...[more]

PMID: 33414458

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Project description:Many psychiatric disorders are associated with impaired executive functioning (EF). The associated EF component varies by psychiatric disorders, and this variation might be due to genetic liability. We explored the genetic association between five psychiatric disorders and EF in clinically-recruited attention deficit hyperactivity disorder (ADHD) children using polygenic risk score (PRS) methodology. Genome-wide association study (GWAS) summary data for ADHD, major depressive disorder (MDD), schizophrenia (SZ), bipolar disorder (BIP) and autism were used to calculate the PRSs. EF was evaluated by the Stroop test for inhibitory control, the trail-making test for cognitive flexibility, and the digital span test for working memory in a Chinese ADHD cohort (n?=?1147). Exploratory factor analysis of the three measures identified one principal component for EF (EF-PC). Linear regression models were used to analyze the association between each PRS and the EF measures. The role of EF measures in mediating the effects of the PRSs on ADHD symptoms was also analyzed. The result showed the PRSs for MDD, ADHD and BIP were all significantly associated with the EF-PC. For each EF component, the association results were different for the PRSs of the five psychiatric disorders: the PRSs for ADHD and MDD were associated with inhibitory control (adjusted P?=?0.0183 and 0.0313, respectively), the PRS for BIP was associated with working memory (adjusted P?=?0.0416), and the PRS for SZ was associated with cognitive flexibility (adjusted P?=?0.0335). All three EF measures were significantly correlated with ADHD symptoms. In mediation analyses, the ADHD and MDD PRSs, which were associated with inhibitory control, had significant indirect effects on ADHD symptoms through the mediation of inhibitory control. These findings indicate that the polygenic risks for several psychiatric disorders influence specific executive dysfunction in children with ADHD. The results helped to clarify the relationship between risk genes of each mental disorder and the intermediate cognitive domain, which may further help elucidate the risk genes and motivate efforts to develop EF measures as a diagnostic marker and future treatment target.

Dataset Information

Polygenic overlap and shared genetic loci between loneliness, severe mental disorders, and cardiovascular disease risk factors suggest shared molecular mechanisms.

Publications

Polygenic overlap and shared genetic loci between loneliness, severe mental disorders, and cardiovascular disease risk factors suggest shared molecular mechanisms.

Similar Datasets

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