Evaluating ANO6 as a Parkinson's disease candidate gene: a human genetic investigation of common and rare variant associations

Abstract

ANO6 (TMEM16F), a Ca2{square}-activated lipid scramblase and ion channel, has been implicated in -synuclein secretion and propagation, a hallmark of Parkinsons disease (PD). To evaluate whether genetic variation in ANO6 contributes to PD risk, we analyzed common and rare variants across large-scale datasets. Relying on genome-wide association study (GWAS) summary statistics from 63,555 PD cases, 17,700 proxy cases, and 1.7 million controls, we identified seven noncoding common variants within ANO6 that reached genome-wide significance, but these signals were driven by linkage disequilibrium (LD) with the nearby LRRK2 p.G2019S variant. We further tested rare variant burden in 4,879 PD cases and 65,279 controls. Rare variant burden analysis showed significant enrichment only when all rare variants were aggregated (meta-analysis PFDR = 0.02), with no signal detected in functional categories. Overall, human genetic data does not support an important role for ANO6 in PD.