Assessing the joint effects of mitochondrial function and human behavior on the risks of anxiety and depression

Psychiatric disorders have great health hazards and the exact pathogeny remains elusive now. We aim to explore the potential interaction effects of mitochondrial function and human behavior on the risks of anxiety and depression.The genome-wide association study (GWAS) data of mitochondrial function (N = 383,476-982,072) were obtained from published studies. Individual level genotype and phenotype data of anxiety, depression and behavioral factors (including drinking, smoking and physical activity) were all from the UK Biobank (N = 84,805-85,164). We first calculated the polygenic risk scores (PRS) of mitochondrial function as the instrumental variables, and then constructed linear regression analyses to systematically explore the potential interaction effects of mitochondrial function and human behavior on anxiety and depression.In total samples, we observed mitochondrial heteroplasmy (MtHz) vs. Drinking (PGAD-7 = 6.49 × 10-3; PPHQ-9 = 1.89 × 10-3) was positively associated with both anxiety and depression. In males, MtHz vs. Drinking (PMale = 3.46 × 10-5) was positively correlated with depression. In females, blood mitochondrial DNA copy number (mtDNA-CN) vs. Drinking (PFemale = 8.63 × 10-3) was negatively related to anxiety. Furthermore, we identified additional 6 suggestive interaction effects (P < 0.05) for anxiety and depression.Considering all subjects were from UK Biobank, it should be careful to extrapolate our findings to other populations with different genetic background.Our results suggest the significant impacts of mitochondrial function and human behavior interactions on the development of anxiety and depression, providing new clues for clarifying the pathogenesis of anxiety and depression.