Examining mitochondrial genetic variation in obsessive-compulsive disorder

Abstract Obsessive-compulsive disorder (OCD) is a severe neuropsychiatric disorder with clear evidence of genetic vulnerability, although specific risk factors are not fully understood. Mitochondrial dysfunction has been implicated in other severe neuropsychiatric disorders, particularly through its role in oxidative stress, and thus merits exploration in OCD. Here we first examined the association of a set of 59 mitochondrial single nucleotide polymorphisms (SNPs) with OCD symptom severity. These SNPs are located inside 28 nuclear-encoded mitochondrial genes involved in oxidative phosphorylation, oxidative stress, mitochondrial biogenesis, inflammation, and apoptosis. We used linear regression to test for the association of this SNP set with symptom severity using the Yale-Brown Obsessive Compulsive Scale (YBOCS). We found a nominally significant association for rs3820189 in the 5’ of the MFN2 gene with YBOCS total score (N = 346; Puncorrected= 0.002). We also conducted gene-based and gene-set (pathway) analyses on nuclear-encoded mitochondrial genes and pathways with OCD risk using MAGMA. We found the gene ADCK1 to be associated with OCD (p = 0.00005, q = 0.05). No mitochondrial pathways were associated with OCD risk. To further examine mitochondrial genetic variation in OCD risk, we then examined mitochondrial (mt) DNA (mtDNA), the circular genome located inside each mitochondrion. We utilized the Toronto OCD sample (N = 215) and the 1000 Genome Project (N = 485) as healthy controls for discovery. For replication, we compared individual-level data from the Psychiatric Genomics Consortium (PGC) OCD Working Group release 2017 (N = 1691) with the Wellcome Trust sample (N = 2616) as controls. After data cleaning, 58 common mtDNA SNPs (minor allele frequency greater than 1%) were available for analysis. Meta-analysis across the significant mtDNA variants shared between both samples revealed five SNPs significantly associated with OCD risk which survived Nyholt correction: NC_012920.1:m.1719G > A (P = 1.489E-05), NC_012920.1:m.3010G > A (P = 2.423E-05), NC_012920.1:m.10398A > G (P = 3.172E-04), NC_012920.1:m.11914G > A (P = 6.085E-04) and NC_012920.1:m.6260G > A (P = 7.792E-04). To the best of our knowledge, this is the largest study to report the involvement of mitochondrial variants in OCD risk. Further investigations and validation of our findings are warranted.