Schizophrenia Bulletin Advance Access originally published online on September 26, 2007
Schizophrenia Bulletin 2008 34(3):458-465; doi:10.1093/schbul/sbm100
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Systematic Association Studies of Mitochondrial DNA Variations in Schizophrenia: Focus on the ND5 Gene
2 Department of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, University of Pittsburgh, 3811 O'Hara Street, Pittsburgh, PA 15213
3 Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136
4 Department of Psychology, University of Pittsburgh, Pittsburgh, PA 15213
5 Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15213
1 To whom correspondence should be addressed; Department of Psychiatry and Human Genetics, University of Pittsburgh School of Medicine and Graduate School of Public Health, Western Psychiatric Institute and Clinic, Room 443, Western Psychiatric Institute and Clinic, University of Pittsburgh, 3811 O'Hara Street, Pittsburgh, PA 15213; tel: 412-246-6353, fax: 412-246-6350, e-mail: nimga{at}pitt.edu.
Postmortem studies, as well as genetic association studies, have implicated mitochondrial dysfunction in schizophrenia (SZ). We conducted multistaged analysis to assess the involvement of mitochondrial DNA (mtDNA) variations in SZ. Initially, the entire mtDNA genome was sequenced in pools of DNA from SZ cases and controls (n = 180 in each group, set 1). Two polymorphisms localized to the NADH dehydrogenase subunit 5 (ND5) gene demonstrated suggestive case control allele frequency differences (mtDNA 13368 G/A, p = .019 and mtDNA 13708G/A, p = .043). Hence, the ND5 gene was sequenced in individual samples from the initial panel of cases and controls. Additional subjects from another independent set of cases and controls (set 2, cases, n = 244, controls n = 508) were also sequenced individually. No significant differences in allele frequencies for mtDNA 13368 G/A, and mtDNA 13708G/A were observed. However, we identified 216 other rare variants, 53 of which were reported earlier in association studies of other mitochondrial disorders. We compared the distribution of polymorphisms in both sets of cases and controls. No significant case-control differences were observed in the smaller, first set. In the second set, cases had more variants overall (p = 0.014), as well as synonymous variants (p = 0.02), but the difference for nonsynonymous variants was not significant (p = 0.19). Screening available first-degree relatives (n = 10) revealed 10 maternally inherited variations, suggesting that not all the variants are somatic mutations. Further investigations are warranted.
Keywords: mitochondria / schizophrenia / NADH dehydrogenase subunit 5 / pooled DNA sequencing / polymorphisms