Abstract
BackgroundVariation in mitochondrial DNA (mtDNA) has been indicated in migraine pathogenesis, but genetic studies to date have focused on candidate variants, with sparse findings. We aimed to perform the first mitochondrial genome-wide association study of migraine, examining both single variants and mitochondrial haplogroups.MethodsIn total, 71,860 participants from the population-based Nord-Trøndelag Health Study were genotyped. We excluded samples not passing quality control for nuclear genotypes, in addition to samples with low call rate and closely maternally related. We analysed 775 mitochondrial DNA variants in 4021 migraine cases and 14,288 headache-free controls, using logistic regression. In addition, we analysed 3831 cases and 13,584 controls who could be reliably assigned to a mitochondrial haplogroup. Lastly, we attempted to replicate previously reported mitochondrial DNA candidate variants.ResultsNeither of the mitochondrial variants or haplogroups were associated with migraine. In addition, none of the previously reported mtDNA candidate variants replicated in our data.ConclusionsOur findings do not support a major role of mitochondrial genetic variation in migraine pathophysiology, but a larger sample is needed to detect rare variants and future studies should also examine heteroplasmic variation, epigenetic changes and copy-number variation.
Highlights
It is well known that migraine tends to run in families, and twin studies examining migraine have estimated a heritability component of about 45% [1]
We aimed to explore whether migraine was associated with variants across the mitochondrial genome, and with mitochondrial haplogroups
In order to evaluate previous studies, we examined variants reported to be associated with migraine, or that are strongly implied in the mitochondrial encephalomyopathies MELAS, myoclonic epilepsy with ragged-red fibers (MERRF), Kearns-Sayre syndrome (KSS) and Leber hereditary optic neuropathy (LHON) [5,7,8]
Summary
It is well known that migraine tends to run in families, and twin studies examining migraine have estimated a heritability component of about 45% [1]. The human mitochondrial genome is a 16,596 base pair long, circular structure, which is maternally inherited [4]. It contains 37 genes, whereof 13 encode proteins involved in the respiratory chain, and the remaining encode ribosomal RNAs and transfer RNAs involved in the translation process [4]. Variation in mitochondrial DNA (mtDNA) has been indicated in migraine pathogenesis, but genetic studies to date have focused on candidate variants, with sparse findings. Conclusions: Our findings do not support a major role of mitochondrial genetic variation in migraine pathophysiology, but a larger sample is needed to detect rare variants and future studies should examine heteroplasmic variation, epigenetic changes and copy-number variation
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