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

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

Authors

Christian M Hagen¹, Vanessa F Gonçalves², Paula L Hedley¹, Jonas Bybjerg-Grauholm¹, Marie Bækvad-Hansen¹, Christine S Hansen¹, Jørgen K Kanters³, Jimmi Nielsen⁴, Ole Mors⁵, Alfonso B Demur⁶, Thomas D Als⁷, Merete Nordentoft⁸, Anders Børglum⁷, Preben B Mortensen⁹, James Kennedy², Thomas M Werge⁶, David M Hougaard¹, Michael Christiansen^{1

3}

Affiliations

¹ Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
² Centre for Addiction and Mental Health, University of Toronto, Toronto, Canada.
³ Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁴ Aalborg Psychiatric Hospital, Aalborg University Hospital, Aalborg, Denmark.
⁵ Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
⁶ Mental Health Centre, Sct Hans, Capital Region of Denmark, Denmark.
⁷ Institute of Medical Genetics, Aarhus University, Aarhus, Denmark.
⁸ Mental Health Centre, Capital Region of Denmark, Denmark.
⁹ Center for Register Research, Institute of Economics, Aarhus University, Aarhus, Denmark.

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.

Publication types

Clinical Trial
Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Child
DNA, Mitochondrial / genetics*
Female
Genetic Predisposition to Disease*
Humans
Male
Polymorphism, Single Nucleotide*
Schizophrenia / genetics*

Substances

DNA, Mitochondrial

Grants and funding

The iPSYCH study was funded by The Lundbeck Foundation Initiative for Integrative Psychiatric Research. We further gratefully acknowledge the financial support of The Jascha Foundation, The Strategic Research Council (“Heart Safe”), The Augustinus Foundation, The Lundbeck Foundation (Grant no. R67-A6552), and Familien Hede Nielsens Fond. This research has been conducted using the Danish National Biobank resource, supported by the Novo Nordisk Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.