title: Analysis of European case-control studies suggests that common inherited variation in mitochondrial DNA is not involved in susceptibility to amyotrophic lateral sclerosis.
abstract: While some cases of familial ALS can be entirely attributed to known inherited variation, the majority (∼ 90%) are sporadic, where the cause(s) are not entirely understood. Both genetic and environmental factors may contribute to susceptibility. Mitochondrial damage, a common feature of neurodegenerative disease, is observed in most patients and inherited polymorphism in the mitochondrial genome has been suggested as a contributing factor. We used an economic and efficient method to test whether such involvement is probable. We genotyped 22 mtDNA coding region SNPs and sequenced the mtDNA hypervariable region 1 to determine the position of each mitochondrial genome within the genealogy of mitochondrial haplotypes in samples of ALS patients (n = 700) and controls (n = 462) from two European populations. We compared haplotype and haplogroup distribution in cases and controls drawn from the same populations. No statistical difference was observed between cases and controls at either the haplogroup or haplotype level (p = ≥  0.2). In conclusion, it is unlikely that common, shared genetic variants in the mitochondrial genome contribute substantially to ALS. Combining the data with other studies will allow meta-analysis to look for variants with modest effect sizes. The sequencing of complete mitochondrial genomes will be required to assess the role of rare mutations.
authors.affiliation: The Centre for Genetic Anthropology, University College London Genetics Institute, Research Department of Genetics, Evolution and Environment, University College London, London WC1E 6BT, UK. katejeingram@hotmail.com
authors.forename: Catherine J E
authors.initials: CJ
authors.lastname: Ingram
authors.forename: Michael E
authors.initials: ME
authors.lastname: Weale
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Plaster
authors.forename: Karen E
authors.initials: KE
authors.lastname: Morrison
authors.forename: Emily F
authors.initials: EF
authors.lastname: Goodall
authors.forename: Hardev S
authors.initials: HS
authors.lastname: Pall
authors.forename: Marcus
authors.initials: M
authors.lastname: Beck
authors.forename: Sibylle
authors.initials: S
authors.lastname: Jablonka
authors.forename: Michael
authors.initials: M
authors.lastname: Sendtner
authors.forename: Elizabeth M C
authors.initials: EM
authors.lastname: Fisher
authors.forename: Neil
authors.initials: N
authors.lastname: Bradman
authors.forename: Dalia
authors.initials: D
authors.lastname: Kasperavičiūtė
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D054629:Genome, Mitochondrial; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial