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

Jabbari, Edwin, Shunsuke, Koga, Valentino, Rebecca R, Reynolds, Regina H, Ferrari, Raffaele, Tan, Manuela M X, Rowe, James B, Dalgard, Clifton L, Scholz, Sonja W, Dickson, Dennis W, Warner, Thomas T, Revesz, Tamas, Höglinger, Günter U, Ross, Owen A, Ryten, Mina, Hardy, John, Shoai, Maryam, Morris, Huw R, Leigh, Nigel P and PSP Genetics Group, (2021) Genetic determinants of survival in progressive supranuclear palsy: a genome-wide association study. The Lancet Neurology, 20 (2). pp. 107-116. ISSN 1474-4422

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Summary Background
The genetic basis of variation in the progression of primary tauopathies has not been determined. Here, we used a genome-wide association study (GWAS) to identify genetic determinants of survival in progressive supranuclear palsy (PSP).

Data were collected and analysed between 1st August 2016 and 1st February 2020. In stage one, we collected pathological and clinical-criteria diagnosed PSP cases from two separate cohorts (2011 PSP GWAS cohort cases from the Mayo Clinic and Munich brain banks; UCL PSP cohort cases from UK brain banks and the PROSPECT study). Cases were included if they had clinical data available on sex, age at motor symptom onset, disease duration (from motor symptom onset to death) and PSP phenotype (with reference to the 2017 Movement Disorder Society criteria). Genotype data from these cases were used to conduct a survival GWAS using a Cox-proportional hazards model. In stage two, replication data from additional Mayo Clinic brain bank cases, which were obtained after the 2011 PSP GWAS, were used for a pooled analysis. We assessed the eQTL profile of variants which passed genome-wide significance in our GWAS using the FUMA platform, and conducted colocalisation analyses using the eQTLGen and PsychENCODE datasets.

Data were available for 1,001 PSP cases of white European ancestry in stage one. We found a genome-wide significant association with survival at chromosome 12 (lead SNP: rs2242367 – p=7.5x10ˉ10; hazard ratio (95% confidence interval)=1.42 (1.22-1.67)). In stage two, the 3 addition of 238 cases resulted in significant pooled association statistics for rs2242367 (n=1,239; p=1.3x10ˉ10; hazard ratio (95% confidence interval)=1.37 (1.25-1.51). An eQTL database screen revealed that rs2242367 is associated with increased expression of LRRK2 and long intergenic non-coding (lnc) RNAs, LINC02555 and AC079630.4, in whole blood. Although we did not detect a colocalisation signal for LRRK2, analysis of the PSP survival signal and eQTLs for LINC02555 in the eQTLGen blood dataset revealed a posterior probability of hypothesis 4 (PP4) of 0.77, suggesting colocalisation due to a single shared causal variant.

Genetic variation at the LRRK2 locus was associated with survival in PSP. The mechanism of this association may be through a lncRNA-regulated effect on LRRK2 expression as LINC02555 has previously been shown to regulate LRRK2 expression. LRRK2 has been associated with sporadic and familial forms of Parkinson’s disease, and our finding suggests a genetic overlap with PSP. Further functional studies will be important to assess the potential of LRRK2 modulation as a disease-modifying therapy for PSP and related tauopathies.

Item Type: Article
Schools and Departments: Brighton and Sussex Medical School > Neuroscience
SWORD Depositor: Mx Elements Account
Depositing User: Mx Elements Account
Date Deposited: 28 Jan 2021 15:31
Last Modified: 18 Jun 2021 01:00

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