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Clinical Trial
. 2018 Dec 10;13(12):e0208828.
doi: 10.1371/journal.pone.0208828. eCollection 2018.

Schizophrenia-associated mt-DNA SNPs exhibit highly variable haplogroup affiliation and nuclear ancestry: Bi-genomic dependence raises major concerns for link to disease

Christian M Hagen  1 , Vanessa F Gonçalves  2 , Paula L Hedley  1 , Jonas Bybjerg-Grauholm  1 , Marie Bækvad-Hansen  1 , Christine S Hansen  1 , Jørgen K Kanters  3 , Jimmi Nielsen  4 , Ole Mors  5 , Alfonso B Demur  6 , Thomas D Als  7 , Merete Nordentoft  8 , Anders Børglum  7 , Preben B Mortensen  9 , James Kennedy  2 , Thomas M Werge  6 , David M Hougaard  1 , Michael Christiansen  1   3
Affiliations
Clinical Trial

Schizophrenia-associated mt-DNA SNPs exhibit highly variable haplogroup affiliation and nuclear ancestry: Bi-genomic dependence raises major concerns for link to disease

Christian M Hagen et al. PLoS One. .

Abstract

Mitochondria play a significant role in human diseases. However, disease associations with mitochondrial DNA (mtDNA) SNPs have proven difficult to replicate. An analysis of eight schizophrenia-associated mtDNA SNPs, in 23,743 Danes without a psychiatric diagnosis and 2,538 schizophrenia patients, revealed marked inter-allelic differences in mitochondrial haplogroup affiliation and nuclear ancestry. This bi-genomic dependence could entail population stratification. Only two mitochondrial SNPs, m.15043A and m.15218G, were significantly associated with schizophrenia. However, these associations disappeared when corrected for haplogroup affiliation and nuclear ancestry. The extensive bi-genomic dependence documented here is a major concern when interpreting historic, as well as designing future, mtDNA association studies.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. The percentage distribution of mtDNA hgs, per allele, among control individuals.
Fig 2
Fig 2
PCA of A. mtDNA (PC1 versus PC3) and B. gDNA (PC1 versus PC2), with the m.15043A (filled diamonds) and m.15043G (filled circles) alleles. Only persons with “European” mtDNA haplogroup (H, HV, V, U, K, J & T) were included. The PCA was performed using PCs defined by control samples.
Fig 3
Fig 3. The percentage distribution of nuclear ancestries, per allele, among control individuals.
Fig 4
Fig 4. Association between individual mtDNA SNPs and schizophrenia as a function of the selection of the involved persons.
(All hgs: All persons, EU hgs: persons with a “classical European” mtDNA hg; EU_hgs_DANES: persons with both a European mtDNA hg and a Danish nuclear ancestry and ALL_hgs_DANES: persons with a Danish nuclear ancestry).
See this image and copyright information in PMC

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