BackgroundMigraine is a common neurological disorder which affects a large proportion of the population. The Norfolk Island population is a genetically isolated population and is an ideal discovery cohort for genetic variants involved in complex disease susceptibility given the reduced genetic and environmental heterogeneity. Given that the majority of proteins responsible for mitochondrial functionare nuclear encoded, this study aimed to investigate the role of Nuclear Encoded Mitochondrial Protein (NEMP) genes in relation to migraine susceptibility. MethodsA gene-centric association analysis of NEMP genes was undertaken in the most related individuals (n=315) within the genetically isolated Norfolk Island population. The discovery phase included genes with three or more SNP associations (P<0.005), which were investigated further in a replication phase using an unrelated migraine case-control cohort (544 patients and 584 controls). ResultsThe discovery phase of the study implicated SNPs in 5 NEMP genes to be associated with migraine susceptibility (P<0.005). Replication analysis validated some of these implicated genes with SNPs in three NEMP genes shown to be associated with migraine in the replication cohort. These were CSNK1G3 (P=0.00037), ELOVL6 (P=0.00035) and SARDH (P=0.00081), which are involved in phosphorylation, fatty acid metabolism, and oxidative demethylation, respectively. ConclusionHere we provide evidence that variation in NEMP genes is associated with migraine susceptibility. This study provides evidence for a link between mitochondrial function and migraine susceptibility.