Variation at the LRRK2 locus determines the rate of disease progression in pro- gressive supranuclear palsy. Issue 6 (27th May 2022)

• Record Type: Journal Article
• Authors: Jabbari, Edwin; Tan, Manuela; Jaunmuktane, Zane; Holton, Janice; Revesz, Tamas; Warner, Thomas; Lees, Andrew; Ryten, Mina; Hardy, John; Morris, Huw
• Is Part Of: Journal of neurology, neurosurgery and psychiatry. Volume 93:Issue 6(2022)
• Page Start: A5
• Page End: A5
• Publication Date: 2022-05-27
• Subjects: Neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; Psychiatry -- Periodicals; 616.8
• DOI: 10.1136/jnnp-2022-ABN.13
• Languages: English
• ISSNs: 0022-3050

Abstract

Abstract : 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-mail]