Genetic determinants of survival in progressive supranuclear palsy: a genome-wide association study

摘要: Summary Background The genetic basis of variation in the progression primary tauopathies has not been determined. We aimed to identify determinants survival progressive supranuclear palsy (PSP). Methods In stage one this two genome-wide association study (GWAS), we included individuals with PSP, diagnosed according pathological and clinical criteria, from separate cohorts: 2011 PSP GWAS cohort, brain banks based at Mayo Clinic (Jacksonville, FL, USA) Munich (Germany), University College London PROSPECT study, a UK-wide longitudinal patients atypical parkinsonian syndromes. Individuals were if they had data available on sex, age motor symptom onset, disease duration (from onset death or date censoring, Dec 1, 2019, alive), phenotype (with reference 2017 Movement Disorder Society criteria). Genotype used do using Cox proportional hazards model. two, additional bank, which obtained after GWAS, for pooled analysis. assessed expression quantitative trait loci (eQTL) profile variants that passed significance our Functional Mapping Annotation platform, did colocalisation analyses eQTLGen PsychENCODE datasets. Findings Data collected analysed between Aug 2016, Feb 2020. 1001 white European ancestry one. found significant chromosome 12 (lead single nucleotide polymorphism rs2242367, p=7·5 × 10−10, hazard ratio 1·42 [95% CI 1·22–1·67]). rs2242367 was associated added (n=238; p=0·049, 1·22 [1·00–1·48]) analysis both stages (n=1239; p=1·3 × 10−10, 1·37 [1·25–1·51]). An eQTL database screen revealed is increased LRRK2 long intergenic non-coding RNAs (lncRNAs), LINC02555 AC079630.4, whole blood. Although detect signal LRRK2, eQTLs blood dataset posterior probability hypothesis 4 0·77, suggesting due shared causal variant. Interpretation Genetic locus PSP. mechanism might be through lncRNA-regulated effect because previously shown regulate expression. sporadic familial forms Parkinson's disease, finding suggests overlap Further functional studies will important assess potential modulation as disease-modifying therapy related tauopathies. Funding Association, CBD Solutions, Medical Research Council (UK).