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.
Sven J Van der LeeOlivia J ConwayIris JansenMinerva M CarrasquilloLuca KleineidamErik van den AkkerIsabel HernándezKristel R van EijkNajada StringaJason A ChenAnna ZettergrenTill F M AndlauerMonica Diez-FairenJavier Simon-SanchezAlberto LleóHenrik ZetterbergMarianne NygaardCornelis BlauwendraatJeanne E SavageJonas Mengel-FromSonia Moreno-GrauMichael WagnerJuan ForteaMichael J KeoghKaj BlennowIngmar SkoogManuel A FrieseOlga PletnikovaMiren ZulaicaCarmen LageItziar de RojasSteffi Riedel-HellerIgnacio Illán-GalaWei WeiBernard JeuneAdelina OrellanaFlorian Then BerghXue WangMarc HulsmanNina BekerNiccolo' TesiChristopher M MorrisBegoña IndakoetxeaLyduine E CollijMartin SchererEstrella Morenas-RodríguezJames W IronsideBart N M van BerckelDaniel AlcoleaHeinz WiendlSamantha L StricklandPau PastorEloy Rodríguez Rodrígueznull nullnull nullnull nullnull nullnull nullnull nullBradley F BoeveRonald C PetersenTanis J FermanJay A van GerpenMarcel J T ReindersRyan J UittiLluís TárragaWolfgang MaierOriol Dols-IcardoAmit KawaliaMaria Carolina DalmassoMercè BoadaUwe K ZettlNatasja M van SchoorMarian BeekmanMariet AllenEliezer MasliahAdolfo López de MunainAlexander PantelyatZbigniew K WszolekOwen A RossDennis W DicksonNeill R Graff-RadfordDavid KnopmanRosa RademakersAfina W LemstraYolande A L PijnenburgPhilip ScheltensThomas GasserPatrick F ChinneryBernhard HemmerMartijn A HuismanJuan TroncosoFermin MorenoEllen A NohrThorkild I A SørensenPeter HeutinkPascual Sánchez-JuanDanielle Posthumanull nullJordi ClarimónKaare ChristensenNilüfer Ertekin-TanerSonja W ScholzAlfredo RamirezAgustín RuizEline SlagboomWiesje M van der FlierHenne HolstegePublished in: Acta neuropathologica (2019)
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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