A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity.
The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target.
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D000483:Alleles D000544:Alzheimer Disease D000690:Amyotrophic Lateral Sclerosis D001921:Brain D003704:Dementia D057180:Frontotemporal Dementia D020022:Genetic Predisposition to Disease D055106:Genome-Wide Association Study D006801:Humans D020961:Lewy Body Disease D008136:Longevity D017628:Microglia D009103:Multiple Sclerosis D009154:Mutation D059906:Neuroimaging D010300:Parkinson Disease D051966:Phospholipase C gamma D012306:Risk
PLCG2 Dementia with Lewy bodies Frontotemporal dementia Longevity Neurodegenerative disease Amyotrophic lateral sclerosis Multiple sclerosis Alzheimer’s disease Parkinson’s disease Phospholipase C Gamma 2 Progressive supranuclear palsy