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 PLC gamma 2 pathway as drug-target.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Neurosciences (hsv//eng)

Keyword

Alzheimer's disease

Frontotemporal dementia

Dementia with Lewy bodies

Progressive supranuclear palsy

Parkinson's disease

Amyotrophic lateral sclerosis

Multiple sclerosis

Neurodegenerative disease

Longevity

PLCG2

Phospholipase C Gamma 2

genome-wide association

phospholipase-c-gamma

genetic architecture

innate immunity

activation

apoe

autoimmunity

inflammation

replication

mechanisms

Neurosciences & Neurology

Pathology

Publication and Content Type

ref (subject category)

art (subject category)