13 - MITOCHONDRIAL DNA HAPLOGROUPS ARE ASSOCIATED WITH PSYCHIATRIC DISEASE: A NATION-WIDE STUDY OF 74,763 DANES

Abstract

Background Disturbed mitochondrial function has been implicated in psychiatric disease. All mitochondria contain a small maternally inherited DNA (mtDNA) of 16.6 kb. Through evolution and genetic drift, the mtDNA sequence has become fixed into haplogroups (hgs) with a characteristic population and geographical distribution. Different hgs exhibit variable functional capacity and have been demonstrated to be susceptibility factors for various, predominantly degenerative, diseases. Associations with Parkinsons and Alzheimers diseases, as well as cardiac, metabolic and psychiatric disorders have been reported. These findings have prompted the suggestion that variations in mitochondrial function might be susceptibility factors for disease. However, reports on association between mtDNA hgs and disease have frequently been conflicting. This is partly due to population stratification in examined populations and low-powered study designs. We analysed the association between mtDNA hgs and psychiatric disease using a very large geographically unbiased cohort, iPSYCH, comprising 2% of Danes as controls and 50,000+ psychiatric patients. Methods Using DNA extracted from dried blood spots from 50,567 Danish psychiatric patients (ADHD: 13,103; ASD: 12,891; Anorexia: 2,124; BD: 1,242; SCZ: 2,438, and AD: 16,225) and 24,196 controls we examined the association between psychiatric disease and mtDNA haplogroup in the Danish population. Psychiatric patients were identified from the Danish Psychiatric Central Registry. DNA was obtained from the Danish Neonatal Screening Biobank. Haplotyping was performed using the PGC developed PsychChip v.1.0. containing 418 SNPs in mtDNA. The SNP data were manually analysed and haplotyped according to haplogroup defining SNPs in Phylotree. Results Hg M was associated with affective disorder (n = 17260) with an OR of 0.47 (cfi.95%: 0.39 – 0.58) (p = 1*10–14), ADHD (n = 13395) with an OR of 0.50 (0.40 – 0.62)(p = 2*10–11). Among patients belonging to the macro-hg N, patients with schizophrenia (n = 2589), had a high proportion of hg A (n = 45), OR: 4.52 (cfi.95%: 3.0 – 6.7)(p = 1.2*10–12). No significant associations between mtDNA hgs and BD or ASD were found. In a mitoGWAS for all six conditions, three mitoSNPs were highly associated with affective disorder (p-values ranging from 2*10E-25 – 2*10E-21), ADHD (p-values: 2*10E-11 – 1*10E-10), and anorexia (p-values: 6*10E -8 - 6*10E-7) and another mitoSNP with schizophrenia (p = 2*10–11). Discussion Psychiatric disease seems to be bigenomic diseases with contributions from both the mitochondrial and nuclear genome. Haplogroup A is a risk factor for schizophrenia and haplogroup M is a protective factor for ADHD and affective disorder. However, both hgs A and M are infrequent in the Danish population and markers of Greenlandic and Asian origin, respectively. So it will be important through studies of interaction between mtDNA and the genomic DNA to precisely define the role of each of these factors in the etiology of psychiatric disease.