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.

Fig. 1. Venn diagrams of unique and shared polygenic variants.

Venn diagrams showing polygenic overlap (gray) between A) loneliness (orange) and major depression (MD) (green), B) schizophrenia (SCZ) (green), C) bipolar disorder (BD) (green), and D) body mass index (BMI) (green). The numbers indicate the estimated quantity of causal variants (in thousands) per component, explaining 90% of SNP heritability in each phenotype, followed by the standard error. The size of the circles reflects the degree of polygenicity. Figures generated from MiXeR.

Fig. 2. Common genetic variants jointly associated with loneliness and MD, BD, SCZ, and BMI at conjFDR <0.05.

Manhattan plots for loneliness and A) major depression, B) bipolar disorder, C) schizophrenia and D) body mass index. Manhattan plots showing the −log10 transformed conjFDR values for each SNP on the y axis and chromosomal positions along the x axis. SNPs with conjunction FDR < 0.05 (i.e., −log10 FDR > 1.3) are shown with enlarged data points. A black circle around the enlarged data points indicates the most significant SNP in each LD block. The figure shows the localization of the “conjunctional loci”, and further details are provided in Supplementary Tables 17–20. MD major depression, SCZ schizophrenia, BD bipolar disorder, BMI body mass index, conjFDR conjunctional FDR.

Fig. 3. Common genetic variants jointly associated with SMDs, BMI and loneliness at conjFDR <0.05.

Manhattan plot showing the −log10 transformed conjFDR values for each SNP on the y axis and chromosomal positions along the x axis. SNPs with conjunction FDR < 0.05 (i.e., −log10 FDR > 1.3) are shown with enlarged data points. A black circle around the enlarged data points indicates the most significant SNP in each LD block. The figure shows the localization of the “conjunctional loci”. SMDs severe mental disorders, MD major depression, SCZ schizophrenia, BD bipolar disorder, BMI body mass index, conjFDR conjunctional FDR.