Mitochondrial Genetic Variants Associated with Bipolar Disorder and Schizophrenia in a Japanese Population

Abstract

Background: Bipolar disorder (BD) and schizophrenia (SZ) are genetic psychotic disorders (PSY) with maternal inheritance. Some studies have investigated whether genetic variants in the mitochondrial chromosome are associated with BD and SZ. However, the genetic variants identified as being associated are not identical among studies, and the participants were limited to individuals of European ancestry. Here, we investigate associations of genome-wide genetic variants in the mitochondrial chromosome with BD, SZ, and PSY in a Japanese population. Methods: After performing quality control for individuals and genetic variants, we investigated whether mitochondrial genetic variants [minor allele frequency (MAF)>0.01, n=45 variants) are associated with BD, SZ, and PSY in 420 Japanese individuals consisting of patients with BD (n=51), patients with SZ (n=172), and healthy controls (HCs, n=197). Results: Five mitochondrial genetic variants (rs111033358, rs200165736, rs200478835, rs200044200, and rs28359178), two genetic variants (rs199713564 and rs200478835), and five genetic variants (rs199713564, rs200999343, rs200478835, rs28359178, and rs201250154) appeared to be associated with BD, SZ and PSY, respectively (Puncorr<0.05). Of these variants, three (rs200478835, rs200044200 and rs28359178 on or near NADH dehydrogenase) and one (rs200478835) were significantly associated with BD and PSY, respectively, even after correcting for multiple comparisons (PGC=0.045–4.9×10-3). In particular, individuals with the minor G-allele of rs200044200, a missense variant, were only observed among patients with BD (MAF=0.059) but not HCs (MAF=0) (odds ratio=∞). Three patients commonly had neuropsychiatric family histories. Conclusions: We suggest that mitochondrial genetic variants in NADH dehydrogenase-related genes may contribute to the pathogenesis of BD and PSY in the Japanese population through dysfunction of energy production.

Genome-wide DNA methylation risk scores for schizophrenia derived from blood and brain tissues further explain the genetic risk in patients stratified by polygenic risk scores for schizophrenia and bipolar disorder

“…Briefly, all participants were of Japanese descent and had no biological first-degree or second-degree relatives among the participants. The participants were recruited from the Schizophrenia Non-Affected Relative Project 12–14 41–46. The patients were recruited from Kanazawa Medical University Hospital.…”