The brain-heart axis: Integrative analysis of the shared genetic etiology between neuropsychiatric disorders and cardiovascular disease

Abstract

Background: Multiple observational studies have reported substantial comorbidity between neuropsychiatric disorders and cardiovascular disease (CVD), but the underlying mechanisms remain largely unknown.

Methods: Using GWAS summary datasets of 8 neuropsychiatric disorders and 6 cardiovascular diseases, an integrative analysis incorporating linkage-disequilibrium-score-regression (LDSC), Mendelian randomization (MR), functional mapping and annotation (FUMA), and functional enrichment analysis, was conducted to investigate shared genetic etiology of the brain-heart axis from the whole genome level, single-nucleotide polymorphism (SNP) level, gene level, and biological pathway level.

Results: In LDSC analysis, 18 pairwise traits between neuropsychiatric disorders and CVD were identified with significant genetic overlaps, revealing extensive genome-wide genetic correlations. In bidirectional MR analysis, 19 pairwise traits were identified with significant causal relationships. Genetic liabilities to neuropsychiatric disorders, particularly attention-deficit hyperactivity disorder and major depressive disorder, conferred extensive significant causal effects on the risk of CVD, while hypertension seemed to be a risk factor for multiple neuropsychiatric disorders, with no significant heterogeneity or pleiotropy. In FUMA analysis, 13 shared independent significant SNPs and 887 overlapping protein-coding genes were detected between neuropsychiatric disorders and CVD. With GO and KEEG functional enrichment analysis, biological pathways of the brain-heart axis were highly concentrated in neurotransmitter synaptic transmission, lipid metabolism, aldosterone synthesis and secretion, glutathione metabolism, and MAPK signaling pathway.

Conclusion: Extensive genetic correlations and genetic overlaps between neuropsychiatric disorders and CVD were identified in this study, which might provide some new insights into the brain-heart axis and the therapeutic targets in clinical practice.

Keywords: Cardiovascular disease; FUMA; LDSC; Mendelian randomization; Neuropsychiatric disorders; The brain-heart Axis.