title: Gene-centric analysis implicates nuclear encoded mitochondrial protein gene variants in migraine susceptibility.
abstract: BACKGROUND
  Migraine 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 function are nuclear encoded, this study aimed to investigate the role of Nuclear Encoded Mitochondrial Protein (NEMP) genes in relation to migraine susceptibility.
  
  
  METHODS
  A 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).
  
  
  RESULTS
  The 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 wereCSNK1G3(P= 0.00037), ELOVL6(P= 0.00035) andSARDH(P= 0.00081), which are involved in phosphorylation, fatty acid metabolism, and oxidative demethylation, respectively.
  
  
  CONCLUSIONS
  Here 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.
authors.affiliation: Genomics Research Centre Institute for Biomedical Health and Innovation School of Biomedical Sciences Queensland University of Technology Brisbane Queensland 4059 Australia.
authors.forename: Shani
authors.initials: S
authors.lastname: Stuart
authors.affiliation: Genomics Research Centre Institute for Biomedical Health and Innovation School of Biomedical Sciences Queensland University of Technology Brisbane Queensland 4059 Australia.
authors.forename: Miles C
authors.initials: MC
authors.lastname: Benton
authors.affiliation: Genomics Research Centre Institute for Biomedical Health and Innovation School of Biomedical Sciences Queensland University of Technology Brisbane Queensland 4059 Australia.
authors.forename: David A
authors.initials: DA
authors.lastname: Eccles
authors.affiliation: Genomics Research Centre Institute for Biomedical Health and Innovation School of Biomedical Sciences Queensland University of Technology Brisbane Queensland 4059 Australia.
authors.forename: Heidi G
authors.initials: HG
authors.lastname: Sutherland
authors.affiliation: Genomics Research Centre Institute for Biomedical Health and Innovation School of Biomedical Sciences Queensland University of Technology Brisbane Queensland 4059 Australia.
authors.forename: Larisa M
authors.initials: LM
authors.lastname: Haupt
authors.affiliation: Genomics Research Centre Institute for Biomedical Health and Innovation School of Biomedical Sciences Queensland University of Technology Brisbane Queensland 4059 Australia.
authors.forename: Rodney A
authors.initials: RA
authors.lastname: Lea
authors.affiliation: Genomics Research Centre Institute for Biomedical Health and Innovation School of Biomedical Sciences Queensland University of Technology Brisbane Queensland 4059 Australia.
authors.forename: Lyn R
authors.identifier: 0000-0002-6774-5475
authors.initials: LR
authors.lastname: Griffiths
keywords: Complex disease; Norfolk Island; gene centric; migraine; mitochondrial dysfunction; neurogenetics; nuclear encoded mitochondrial protein genes