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Lookup NU author(s): Dr Michael Keogh, Dr Wei Wei, Dr Ian Wilson, Professor Johannes Attems, Dr Christopher Morris, Professor Patrick Chinnery
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Background Several studies suggest that multiple rare genetic variants in genes causing monogenic forms of neurodegenerative disorders interact synergistically to increase disease risk or reduce the age of onset, but these studies have not been validated in large sporadic case series.Methods We analysed 980 neuropathologically characterised human brains with Alzheimer’s disease (AD), Parkinson’s disease-dementia with Lewy bodies (PD-DLB), frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) and age-matched controls. Genetic variants were assessed using the American College of Medical Genetics criteria for pathogenicity. Individuals with two or more variants within a relevant disease gene panel were defined as ‘oligogenic’.Results The majority of oligogenic variant combinations consisted of a highly penetrant allele or known risk factor in combination with another rare but likely benign allele. The presence of oligogenic variants did not influence the age of onset or disease severity. After controlling for the single known major risk allele, the frequency of oligogenic variants was no different between cases and controls.Conclusions A priori, individuals with AD, PD-DLB and FTD-ALS are more likely to harbour a known genetic risk factor, and it is the burden of these variants in combination with rare benign alleles that is likely to be responsible for some oligogenic associations. Controlling for this bias is essential in studies investigating a potential role for oligogenic variation in neurodegenerative diseases.
Author(s): Keogh MJ, Wei W, Aryaman J, Wilson I, Talbot K, Turner MR, McKenzie C-A, Troakes C, Attems J, Smith C, AlSarraj S, Morris CM, Ansorge O, Pickering-Brown S, Jones N, Ironside JW, Chinnery PF
Publication type: Article
Publication status: Published
Journal: Journal of Neurology, Neurosurgery and Psychiatry
Year: 2018
Volume: 89
Issue: 8
Pages: 813-816
Print publication date: 01/08/2018
Online publication date: 13/01/2018
Acceptance date: 01/12/2017
Date deposited: 21/05/2018
ISSN (print): 0022-3050
ISSN (electronic): 1468-330X
Publisher: BMJ Publishing Group
URL: https://doi.org/10.1136/jnnp-2017-317234
DOI: 10.1136/jnnp-2017-317234
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