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.
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Contributors MJK: study concept and design, data acquisition, analysis and interpretation of data, drafting/revising the manuscript. WW: data generation and analysis. JA: data interpretation, mathematical analysis, drafting the manuscript. IW: data generation. JC: study design, coordination, data acquisition. MRT: data acquisition and interpretation. CAMcK: data acquisition and interpretation. CT: data acquisition and interpretation. JA: data acquisition and interpretation. CS: data acquisition and interpretation. SAlS: data acquisition and interpretation. CMM: data acquisition and interpretation. OA: data acquisition and interpretation. SP-B: data acquisition and interpretation. NJ: mathematical analysis and interpretation. JWI: study supervision, interpretation. PFC: study supervision, drafting the manuscript.
Funding MJK is a Wellcome Trust Clinical Research Training Fellow (103396/Z/13/Z). PFC is a Wellcome Trust Senior Fellow in Clinical Science (101876/Z/13/Z), and a UK NIHR Senior Investigator, who receives support from the Medical Research Council Mitochondrial Biology Unit (MC_UP_1501/2) and the National Institute for Health Research Biomedical Research Centre for Ageing and Age-Related Disease award to the Newcastle upon Tyne Hospitals National Health Service Foundation Trust.
Competing interests None declared.
Ethics approval Approved in each centre before DNA was extracted.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Data will be made publicly available through the European Genome Archive.
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