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; Vanessa F. Gonçalves; Paula L. Hedley; Jonas Bybjerg-Grauholm; Marie Bækvad-Hansen; Christine S. Hansen; Jørgen K. Kanters; Jimmi Nielsen; Ole Mors; Alfonso B. Demur; Thomas D. Als; Merete Nordentoft; Anders Børglum; Preben B. Mortensen; James Kennedy; Thomas M. Werge; David M. Hougaard; Michael Christiansen

doi:10.1371/journal.pone.0208828

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, Vanessa F. Gonçalves, Paula L. Hedley, Jonas Bybjerg-Grauholm, Marie Bækvad-Hansen, Christine S. Hansen, Jørgen K. Kanters, Jimmi Nielsen, Ole Mors, Alfonso B. Demur, Thomas D. Als, Merete Nordentoft, Anders Børglum, Preben B. Mortensen, James Kennedy, Thomas M. Werge, David M. Hougaard, Michael Christiansen^*

^*Corresponding author for this work

4 Citations (Scopus)

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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.

Original language	English
Article number	e0208828
Journal	PLoS ONE
Volume	13
Issue number	12
Number of pages	14
ISSN	1932-6203
DOIs	https://doi.org/10.1371/journal.pone.0208828
Publication status	Published - 1 Dec 2018

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Hagen, C. M., Gonçalves, V. F., Hedley, P. L., Bybjerg-Grauholm, J., Bækvad-Hansen, M., Hansen, C. S., Kanters, J. K., Nielsen, J., Mors, O., Demur, A. B., Als, T. D., Nordentoft, M., Børglum, A., Mortensen, P. B., Kennedy, J., Werge, T. M., Hougaard, D. M., & Christiansen, M. (2018). Schizophrenia-associated mt-DNA SNPs exhibit highly variable haplogroup affiliation and nuclear ancestry: Bi-genomic dependence raises major concerns for link to disease. PLoS ONE, 13(12), Article e0208828. https://doi.org/10.1371/journal.pone.0208828

Schizophrenia-associated mt-DNA SNPs exhibit highly variable haplogroup affiliation and nuclear ancestry: Bi-genomic dependence raises major concerns for link to disease. / Hagen, Christian M.; Gonçalves, Vanessa F.; Hedley, Paula L. et al.
In: PLoS ONE, Vol. 13, No. 12, e0208828, 01.12.2018.

Research output: Contribution to journal › Journal article › Research › peer-review

Hagen, CM, Gonçalves, VF, Hedley, PL, Bybjerg-Grauholm, J, Bækvad-Hansen, M, Hansen, CS, Kanters, JK, Nielsen, J, Mors, O, Demur, AB, Als, TD, Nordentoft, M, Børglum, A, Mortensen, PB, Kennedy, J, Werge, TM, Hougaard, DM & Christiansen, M 2018, 'Schizophrenia-associated mt-DNA SNPs exhibit highly variable haplogroup affiliation and nuclear ancestry: Bi-genomic dependence raises major concerns for link to disease', PLoS ONE, vol. 13, no. 12, e0208828. https://doi.org/10.1371/journal.pone.0208828

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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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AU - Gonçalves, Vanessa F.

AU - Hedley, Paula L.

AU - Bybjerg-Grauholm, Jonas

AU - Bækvad-Hansen, Marie

AU - Hansen, Christine S.

AU - Kanters, Jørgen K.

AU - Nielsen, Jimmi

AU - Mors, Ole

AU - Demur, Alfonso B.

AU - Als, Thomas D.

AU - Nordentoft, Merete

AU - Børglum, Anders

AU - Mortensen, Preben B.

AU - Kennedy, James

AU - Werge, Thomas M.

AU - Hougaard, David M.

AU - Christiansen, Michael

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

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