title: MutPred mutational load analysis shows mildly deleterious mitochondrial DNA variants are not more prevalent in Alzheimer's patients, but may be under-represented in healthy older individuals.
abstract: Mitochondrial DNA (mtDNA) association studies have been conducted for over a decade using the haplogroup (lineage) association method, but this frequently produces conflicting results. Here we analyzed complete mtDNA sequence data of Alzheimer's disease (AD) patients and aged controls, from the United Kingdom (UK) and the United States (US), using a new "mutational load" method. We calculated a pathogenicity score for each of the non-synonymous substitutions of the mtDNA sequences to produce a "total mutational load" for each sequence, and compared the mutational loads of cases and controls. Using these mutational load measures, we found no evidence to support the cumulative role of mtDNA variants as a susceptibility factor in AD; that is, AD patients (UK and US cohorts) did not have higher "mutational loads" than controls. However, the US aged controls, who are significantly older than the UK ones, with many showing evidence of being healthy and having good cognition in old age, had significantly lower "mutational loads". This finding suggests that low mtDNA mutational load is more prevalent in healthy older people.
authors.affiliation: Centre for Neuroinflammation & Neurodegeneration, Division of Brain Sciences, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, United Kingdom; Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne NE1 8ST, United Kingdom.
authors.forename: Ilse S
authors.initials: IS
authors.lastname: Pienaar
authors.affiliation: Matrilinex LLC, San Diego, CA 92122, USA; Department of Radiation Therapy, UTMB, Galveston, TX, United States.
authors.forename: Neil
authors.initials: N
authors.lastname: Howell
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, United Kingdom; Centre for Human Metabonomics, North-West University, Potchefstroom, South Africa. Electronic address: j.l.elson@ncl.ac.uk.
authors.forename: Joanna L
authors.initials: JL
authors.lastname: Elson
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology*; D004272:DNA, Mitochondrial / Q000235:genetics*; D056726:Genetic Association Studies; D006801:Humans; D008875:Middle Aged; D059645:Mutation Rate; D020125:Mutation, Missense; D006113:United Kingdom; D014481:United States
chemical_list: D004272:DNA, Mitochondrial
keywords: Alzheimer's disease; Mitochondrial DNA (mtDNA); MutPred; Mutational load; mtDNA population variation