Variation at the LRRK2 locus determines the rate of disease progression in pro- gressive supranuclear palsy

Background The genetic basis of variation in the rate of disease progression in primary tauopathies is poorly understood. Here, we have conducted a genome-wide association study (GWAS) of Progressive Supranuclear Palsy cases using survival as a marker of disease progression. Methods Two independent, deeply-phenotyped, PSP cohorts of European ancestry underwent genotyp- ing and SNP imputation. Standard data quality control steps were used, including a MAF threshold of 1%. We used a cox-proportional hazards survival model GWAS that adjusted for sex, age at motor symptom onset, PSP phenotype and ethnicity (first three principal components). Results 1,001 PSP cases (2011 case-control GWAS, n=424; UCL PSP cohort, n=577) and 4,817,946 SNPs passed quality control steps and were available for analysis. We found a genome-wide significant signal on chromosome 12 with the lead SNP identified as rs2242367 (hazard ratio = 2.24, p-value = 7.5x10 -10 ). This signal replicated when each independent cohort was analysed separately. The risk allele at this SNP was associated with a 1 year reduction in survival. eQTL analyses revealed that rs2242367 and its tagging SNPs are eQTLs for LRRK2 expression in whole blood and brain. Conclusions We hypothesise that the whole blood eQTL signal may impact on monocyte-derived micro- glia-like cells and that increased LRRK2 expression may result in a reactive microglia-induced pro-inflam- matory state which drives ongoing accumulation of misfolded tau protein and clinical disease progression. e.jabbari@ucl.ac.uk