Edwin Jabbari1, Shunsuke Koga2, Rebecca R Valentino2, Regina H Reynolds3, Raffaele Ferrari4, Manuela M X Tan5, James B Rowe6, Clifton L Dalgard7, Sonja W Scholz8, Dennis W Dickson2, Thomas T Warner9, Tamas Revesz9, Günter U Höglinger10, Owen A Ross2, Mina Ryten3, John Hardy11, Maryam Shoai4, Huw R Morris12. 1. Department of Clinical and Movement Neurosciences, University College London Queen Square Institute of Neurology, London, UK; Movement Disorders Centre, University College London Queen Square Institute of Neurology, London, UK. Electronic address: e.jabbari@ucl.ac.uk. 2. Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. 3. Department of Neurodegenerative Disease, University College London Queen Square Institute of Neurology, London, UK; NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London, UK; Great Ormond Street Institute of Child Health, Genetics and Genomic Medicine, University College London, London, UK. 4. Department of Neurodegenerative Disease, University College London Queen Square Institute of Neurology, London, UK. 5. Department of Clinical and Movement Neurosciences, University College London Queen Square Institute of Neurology, London, UK; Movement Disorders Centre, University College London Queen Square Institute of Neurology, London, UK. 6. Department of Clinical Neurosciences, University of Cambridge, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. 7. Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA. 8. Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA; Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. 9. Reta Lila Weston Institute, University College London Queen Square Institute of Neurology, London, UK; Queen Square Brain Bank for Neurological Disorders, University College London Queen Square Institute of Neurology, London, UK. 10. German Center for Neurodegenerative Diseases, Munich, Germany; Department of Neurology, Hannover Medical School, Hannover, Germany. 11. Department of Neurodegenerative Disease, University College London Queen Square Institute of Neurology, London, UK; Reta Lila Weston Institute, University College London Queen Square Institute of Neurology, London, UK; Dementia Research Institute at University College London, University College London Queen Square Institute of Neurology, London, UK; Institute for Advanced Study, The Hong Kong University of Science and Technology, Hong Kong Special Administrative Region, China. 12. Department of Clinical and Movement Neurosciences, University College London Queen Square Institute of Neurology, London, UK; Movement Disorders Centre, University College London Queen Square Institute of Neurology, London, UK. Electronic address: h.morris@ucl.ac.uk.
Abstract
BACKGROUND: The genetic basis of variation in the progression of primary tauopathies has not been determined. We aimed to identify genetic determinants of survival in progressive supranuclear palsy (PSP). METHODS: In stage one of this two stage genome-wide association study (GWAS), we included individuals with PSP, diagnosed according to pathological and clinical criteria, from two separate cohorts: the 2011 PSP GWAS cohort, from brain banks based at the Mayo Clinic (Jacksonville, FL, USA) and in Munich (Germany), and the University College London PSP cohort, from brain banks and the PROSPECT study, a UK-wide longitudinal study of patients with atypical parkinsonian syndromes. Individuals were included if they had clinical data available on sex, age at motor symptom onset, disease duration (from motor symptom onset to death or to the date of censoring, Dec 1, 2019, if individuals were alive), and PSP phenotype (with reference to the 2017 Movement Disorder Society criteria). Genotype data were used to do a survival GWAS using a Cox proportional hazards model. In stage two, data from additional individuals from the Mayo Clinic brain bank, which were obtained after the 2011 PSP GWAS, were used for a pooled analysis. We assessed the expression quantitative trait loci (eQTL) profile of variants that passed genome-wide significance in our GWAS using the Functional Mapping and Annotation of GWAS platform, and did colocalisation analyses using the eQTLGen and PsychENCODE datasets. FINDINGS: Data were collected and analysed between Aug 1, 2016, and Feb 1, 2020. Data were available for 1001 individuals of white European ancestry with PSP in stage one. We found a genome-wide significant association with survival at 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 with survival in the individuals added in stage two (n=238; p=0·049, 1·22 [1·00-1·48]) and in the pooled analysis of both stages (n=1239; p=1·3 × 10-10, 1·37 [1·25-1·51]). An eQTL database screen revealed that rs2242367 is associated with increased expression of LRRK2 and two long intergenic non-coding RNAs (lncRNAs), 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 of 0·77, suggesting colocalisation due to a single shared causal variant. INTERPRETATION: Genetic variation at the LRRK2 locus was associated with survival in PSP. The mechanism of this association might be through a lncRNA-regulated effect on LRRK2 expression because 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. FUNDING: PSP Association, CBD Solutions, Medical Research Council (UK).
BACKGROUND: The genetic basis of variation in the progression of primary tauopathies has not been determined. We aimed to identify genetic determinants of survival in progressive supranuclear palsy (PSP). METHODS: In stage one of this two stage genome-wide association study (GWAS), we included individuals with PSP, diagnosed according to pathological and clinical criteria, from two separate cohorts: the 2011 PSP GWAS cohort, from brain banks based at the Mayo Clinic (Jacksonville, FL, USA) and in Munich (Germany), and the University College London PSP cohort, from brain banks and the PROSPECT study, a UK-wide longitudinal study of patients with atypical parkinsonian syndromes. Individuals were included if they had clinical data available on sex, age at motor symptom onset, disease duration (from motor symptom onset to death or to the date of censoring, Dec 1, 2019, if individuals were alive), and PSP phenotype (with reference to the 2017 Movement Disorder Society criteria). Genotype data were used to do a survival GWAS using a Cox proportional hazards model. In stage two, data from additional individuals from the Mayo Clinic brain bank, which were obtained after the 2011 PSP GWAS, were used for a pooled analysis. We assessed the expression quantitative trait loci (eQTL) profile of variants that passed genome-wide significance in our GWAS using the Functional Mapping and Annotation of GWAS platform, and did colocalisation analyses using the eQTLGen and PsychENCODE datasets. FINDINGS: Data were collected and analysed between Aug 1, 2016, and Feb 1, 2020. Data were available for 1001 individuals of white European ancestry with PSP in stage one. We found a genome-wide significant association with survival at 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 with survival in the individuals added in stage two (n=238; p=0·049, 1·22 [1·00-1·48]) and in the pooled analysis of both stages (n=1239; p=1·3 × 10-10, 1·37 [1·25-1·51]). An eQTL database screen revealed that rs2242367 is associated with increased expression of LRRK2 and two long intergenic non-coding RNAs (lncRNAs), 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 of 0·77, suggesting colocalisation due to a single shared causal variant. INTERPRETATION: Genetic variation at the LRRK2 locus was associated with survival in PSP. The mechanism of this association might be through a lncRNA-regulated effect on LRRK2 expression because 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. FUNDING: PSP Association, CBD Solutions, Medical Research Council (UK).
Authors: Julie Lake; Xylena Reed; Rebekah G Langston; Mike A Nalls; Ziv Gan-Or; Mark R Cookson; Andrew B Singleton; Cornelis Blauwendraat; Hampton L Leonard Journal: Mov Disord Date: 2021-09-20 Impact factor: 9.698
Authors: Kurt Farrell; SoongHo Kim; Natalia Han; Megan A Iida; Elias M Gonzalez; Marcos Otero-Garcia; Jamie M Walker; Timothy E Richardson; Alan E Renton; Shea J Andrews; Brian Fulton-Howard; Jack Humphrey; Ricardo A Vialle; Kathryn R Bowles; Katia de Paiva Lopes; Kristen Whitney; Diana K Dangoor; Hadley Walsh; Edoardo Marcora; Marco M Hefti; Alicia Casella; Cheick T Sissoko; Manav Kapoor; Gloriia Novikova; Evan Udine; Garrett Wong; Weijing Tang; Tushar Bhangale; Julie Hunkapiller; Gai Ayalon; Robert R Graham; Jonathan D Cherry; Etty P Cortes; Valeriy Y Borukov; Ann C McKee; Thor D Stein; Jean-Paul Vonsattel; Andy F Teich; Marla Gearing; Jonathan Glass; Juan C Troncoso; Matthew P Frosch; Bradley T Hyman; Dennis W Dickson; Melissa E Murray; Johannes Attems; Margaret E Flanagan; Qinwen Mao; M-Marsel Mesulam; Sandra Weintraub; Randy L Woltjer; Thao Pham; Julia Kofler; Julie A Schneider; Lei Yu; Dushyant P Purohit; Vahram Haroutunian; Patrick R Hof; Sam Gandy; Mary Sano; Thomas G Beach; Wayne Poon; Claudia H Kawas; María M Corrada; Robert A Rissman; Jeff Metcalf; Sara Shuldberg; Bahar Salehi; Peter T Nelson; John Q Trojanowski; Edward B Lee; David A Wolk; Corey T McMillan; C Dirk Keene; Caitlin S Latimer; Thomas J Montine; Gabor G Kovacs; Mirjam I Lutz; Peter Fischer; Richard J Perrin; Nigel J Cairns; Erin E Franklin; Herbert T Cohen; Towfique Raj; Inma Cobos; Bess Frost; Alison Goate; Charles L White Iii; John F Crary Journal: Acta Neuropathol Date: 2021-11-01 Impact factor: 15.887
Authors: Maria Stamelou; Gesine Respondek; Nikolaos Giagkou; Jennifer L Whitwell; Gabor G Kovacs; Günter U Höglinger Journal: Nat Rev Neurol Date: 2021-08-23 Impact factor: 42.937
Authors: Maura Malpetti; Luca Passamonti; Peter Simon Jones; Duncan Street; Timothy Rittman; Timothy D Fryer; Young T Hong; Patricia Vàsquez Rodriguez; William Richard Bevan-Jones; Franklin I Aigbirhio; John Tiernan O'Brien; James Benedict Rowe Journal: J Neurol Neurosurg Psychiatry Date: 2021-03-17 Impact factor: 13.654
Authors: Sterre C M de Boer; Lina Riedl; Sven J van der Lee; Markus Otto; Sarah Anderl-Straub; Ramon Landin-Romero; Federica Sorrentino; Jay L P Fieldhouse; Lianne M Reus; Blanca Vacaflor; Glenda Halliday; Daniela Galimberti; Janine Diehl-Schmid; Simon Ducharme; Olivier Piguet; Yolande A L Pijnenburg Journal: J Alzheimers Dis Date: 2021 Impact factor: 4.472