This article requires a subscription to view the full text. If you have a subscription you may use the login form below to view the article. Access to this article can also be purchased.
Abstract
Objective: To assess the influence of common mitochondrial DNA (mtDNA) sequence variation on multiple sclerosis (MS) risk in cases and controls part of an international consortium.
Methods: We analyzed 115 high-quality mtDNA variants and common haplogroups from a previously published genome-wide association study among 7,391 cases from the International Multiple Sclerosis Genetics Consortium and 14,568 controls from the Wellcome Trust Case Control Consortium 2 project from 7 countries. Significant single nucleotide polymorphism and haplogroup associations were replicated in 3,720 cases and 879 controls from the University of California, San Francisco.
Results: An elevated risk of MS was detected among haplogroup JT carriers from 7 pooled clinic sites (odds ratio [OR] = 1.15, 95% confidence interval [CI] = 1.07–1.24, p = 0.0002) included in the discovery study. The increased risk of MS was observed for both haplogroup T (OR = 1.17, 95% CI = 1.06–1.29, p = 0.002) and haplogroup J carriers (OR = 1.11, 95% CI = 1.01–1.22, p = 0.03). These haplogroup associations with MS were not replicated in the independent sample set. An elevated risk of primary progressive (PP) MS was detected for haplogroup J participants from 3 European discovery populations (OR = 1.49, 95% CI = 1.10–2.01, p = 0.009). This elevated risk was borderline significant in the US replication population (OR = 1.43, 95% CI = 0.99–2.08, p = 0.058) and remained significant in pooled analysis of discovery and replication studies (OR = 1.43, 95% CI = 1.14–1.81, p = 0.002). No common individual mtDNA variants were associated with MS risk.
Conclusions: Identification and validation of mitochondrial genetic variants associated with MS and PPMS may lead to new targets for treatment and diagnostic tests for identifying potential responders to interventions that target mitochondria.
GLOSSARY
- CI=
- confidence interval;
- GWAS=
- genome-wide association study;
- IMSGC=
- International Multiple Sclerosis Genetics Consortium;
- LHON=
- Leber hereditary optic neuropathy;
- MAF=
- minor allele frequency;
- MS=
- multiple sclerosis;
- mtDNA=
- mitochondrial DNA;
- OR=
- odds ratio;
- PCA=
- primary component analysis;
- PD-ADS=
- pediatric acquired demyelination syndrome;
- PPMS=
- primary progressive MS;
- ROS=
- reactive oxygen species;
- SNP=
- single nucleotide polymorphism;
- WTCCC2=
- Wellcome Trust Case Control Consortium 2
Footnotes
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
- Received September 26, 2014.
- Accepted in final form April 7, 2015.
- © 2015 American Academy of Neurology
AAN Members
We have changed the login procedure to improve access between AAN.com and the Neurology journals. If you are experiencing issues, please log out of AAN.com and clear history and cookies. (For instructions by browser, please click the instruction pages below). After clearing, choose preferred Journal and select login for AAN Members. You will be redirected to a login page where you can log in with your AAN ID number and password. When you are returned to the Journal, your name should appear at the top right of the page.
AAN Non-Member Subscribers
Purchase access
Letters: Rapid online correspondence
- Mitochondrial DNA sequence variation in multiple sclerosis
REQUIREMENTS
You must ensure that your Disclosures have been updated within the previous six months. Please go to our Submission Site to add or update your Disclosure information.
Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.
If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.
Submission specifications:
- Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
- Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
- Submit only on articles published within 6 months of issue date.
- Do not be redundant. Read any comments already posted on the article prior to submission.
- Submitted comments are subject to editing and editor review prior to posting.
You May Also be Interested in
Topics Discussed
Alert Me
Recommended articles
Mitochondrial DNA haplogroups and mutations in children with acquired central demyelination
Two-stage association study and meta-analysis of mitochondrial DNA variants in Parkinson disease
Do old HLA and mitochondrial DNA variants associate with demyelination types in young patients?
Clinical features of MS associated with Leber hereditary optic neuropathy mtDNA mutations