Mitochondrial DNA point mutations and relative copy number in 1363 disease and control human brains.
Mitochondria play a key role in common neurodegenerative diseases and contain their own genome: mtDNA. Common inherited polymorphic variants of mtDNA have been associated with several neurodegenerative diseases, and somatic deletions of mtDNA have been found in affected brain regions. However, there are conflicting reports describing the role of rare inherited variants and somatic point mutations in neurodegenerative disorders, and recent evidence also implicates mtDNA levels. To address these issues we studied 1363 post mortem human brains with a histopathological diagnosis of Parkinson's disease (PD), Alzheimer's disease (AD), Frontotemporal dementia - Amyotrophic Lateral Sclerosis (FTD-ALS), Creutzfeldt Jacob disease (CJD), and healthy controls. We obtained high-depth whole mitochondrial genome sequences using off target reads from whole exome sequencing to determine the association of mtDNA variation with the development and progression of disease, and to better understand the development of mtDNA mutations and copy number in the aging brain. With this approach, we found a surprisingly high frequency of heteroplasmic mtDNA variants in 32.3% of subjects. However, we found no evidence of an association between rare inherited variants of mtDNA or mtDNA heteroplasmy and disease. In contrast, we observed a reduction in the amount of mtDNA copy in both AD and CJD. Based on these findings, single nucleotide variants of mtDNA are unlikely to play a major role in the pathogenesis of these neurodegenerative diseases, but mtDNA levels merit further investigation.
Institute of Genetic Medicine, Central Parkway, Newcastle University, Newcastle Upon Tyne, NE1 3BZ, UK.|Department of Clinical Neurosciences, University of Cambridge, University Neurology Unit, Level 5 'A' Block, Box 165 Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.
Wei
W
Wei
Institute of Genetic Medicine, Central Parkway, Newcastle University, Newcastle Upon Tyne, NE1 3BZ, UK.|Department of Clinical Neurosciences, University of Cambridge, University Neurology Unit, Level 5 'A' Block, Box 165 Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.|MRC Mitochondrial Biology Unit, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.
Michael J
MJ
Keogh
Institute of Genetic Medicine, Central Parkway, Newcastle University, Newcastle Upon Tyne, NE1 3BZ, UK.
Ian
I
Wilson
Institute of Genetic Medicine, Central Parkway, Newcastle University, Newcastle Upon Tyne, NE1 3BZ, UK.
Jonathan
J
Coxhead
Institute of Brain, Behaviour and Mental Health, University of Manchester, 2.014 AV Hill Building, Oxford Road, Manchester, M13 9PT, UK.
Sarah
S
Ryan
Institute of Brain, Behaviour and Mental Health, University of Manchester, 2.014 AV Hill Building, Oxford Road, Manchester, M13 9PT, UK.
Sara
S
Rollinson
Institute of Genetic Medicine, Central Parkway, Newcastle University, Newcastle Upon Tyne, NE1 3BZ, UK.
Helen
H
Griffin
Institute of Genetic Medicine, Central Parkway, Newcastle University, Newcastle Upon Tyne, NE1 3BZ, UK.
Marzena
M
Kurzawa-Akanbi
Institute of Genetic Medicine, Central Parkway, Newcastle University, Newcastle Upon Tyne, NE1 3BZ, UK.
Mauro
M
Santibanez-Koref
Department of Clinical Neurosciences, John Radcliffe Hospital, Level 3, West Wing, Headley Way, Oxford, OX3 9DU, UK.
Kevin
K
Talbot
Department of Clinical Neurosciences, John Radcliffe Hospital, Level 3, West Wing, Headley Way, Oxford, OX3 9DU, UK.
Martin R
MR
Turner
National CJD Research & Surveillance Unit, Centre for Clinical Brain Sciences, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK.
Chris-Anne
CA
McKenzie
Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, London, SE5 8AF, UK.
Claire
C
Troakes
Institute of Genetic Medicine, Central Parkway, Newcastle University, Newcastle Upon Tyne, NE1 3BZ, UK.
Johannes
J
Attems
National CJD Research & Surveillance Unit, Centre for Clinical Brain Sciences, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK.
Colin
C
Smith
Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, London, SE5 8AF, UK.
Safa
S
Al Sarraj
Institute of Genetic Medicine, Central Parkway, Newcastle University, Newcastle Upon Tyne, NE1 3BZ, UK.
Christopher M
CM
Morris
Department of Neuropathology, John Radcliffe Hospital, West Wing, Level 1, Oxford, OX3 9DU, UK.
Olaf
O
Ansorge
Institute of Brain, Behaviour and Mental Health, University of Manchester, 2.014 AV Hill Building, Oxford Road, Manchester, M13 9PT, UK.
Stuart
S
Pickering-Brown
National CJD Research & Surveillance Unit, Centre for Clinical Brain Sciences, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK. james.ironside@ed.ac.uk.
James W
JW
Ironside
Institute of Genetic Medicine, Central Parkway, Newcastle University, Newcastle Upon Tyne, NE1 3BZ, UK. pfc25@medschl.cam.ac.uk.|Department of Clinical Neurosciences, University of Cambridge, University Neurology Unit, Level 5 'A' Block, Box 165 Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK. pfc25@medschl.cam.ac.uk.|MRC Mitochondrial Biology Unit, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK. pfc25@medschl.cam.ac.uk.
Patrick F
PF
Chinnery
D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D001927:Brain Diseases / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D015331:Cohort Studies; D056915:DNA Copy Number Variations; D004272:DNA, Mitochondrial; D059472:Exome; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA
D004272:DNA, Mitochondrial
Dementia; Mitochondrial; Mutation; Neurodegeneration; Somatic