MITOCHONDRIAL DNA HAPLOGROUPS ARE ASSOCIATED WITH PSYCHIATRIC DISEASE: A NATION-WIDE STUDY OF 74,763 DANES
2019
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 stratificationin 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 spotsfrom 50,567
Danishpsychiatric 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
haplogroupin the
Danishpopulation. Psychiatric patients were identified from the
DanishPsychiatric 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
haplogroupdefining 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.
HaplogroupA is a risk factor for schizophrenia and
haplogroup Mis a protective factor for ADHD and affective disorder. However, both hgs A and M are infrequent in the
Danishpopulation 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.
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