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Joint Genome-wide Association Study of Progressive Supranuclear Palsy Identifies Novel Susceptibility Loci and Genetic Correlation to Neurodegenerative Diseases

Chen, JA; Chen, Z; Won, H; Huang, AY; Lowe, JK; Wojta, K; Yokoyama, JS; ... Coppola, G; + view all (2018) Joint Genome-wide Association Study of Progressive Supranuclear Palsy Identifies Novel Susceptibility Loci and Genetic Correlation to Neurodegenerative Diseases. Molecular Neurodegeneration , 13 (41) 10.1186/s13024-018-0270-8. Green open access

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Abstract

BACKGROUND: Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease for which the genetic contribution is incompletely understood. METHODS: We conducted a joint analysis of 5,523,934 imputed SNPs in two newly-genotyped progressive supranuclear palsy cohorts, primarily derived from two clinical trials (Allon davunetide and NNIPPS riluzole trials in PSP) and a previously published genome-wide association study (GWAS), in total comprising 1646 cases and 10,662 controls of European ancestry. RESULTS: We identified 5 associated loci at a genome-wide significance threshold P < 5 × 10- 8, including replication of 3 loci from previous studies and 2 novel loci at 6p21.1 and 12p12.1 (near RUNX2 and SLCO1A2, respectively). At the 17q21.31 locus, stepwise regression analysis confirmed the presence of multiple independent loci (localized near MAPT and KANSL1). An additional 4 loci were highly suggestive of association (P < 1 × 10- 6). We analyzed the genetic correlation with multiple neurodegenerative diseases, and found that PSP had shared polygenic heritability with Parkinson's disease and amyotrophic lateral sclerosis. CONCLUSIONS: In total, we identified 6 additional significant or suggestive SNP associations with PSP, and discovered genetic overlap with other neurodegenerative diseases. These findings clarify the pathogenesis and genetic architecture of PSP.

Type: Article
Title: Joint Genome-wide Association Study of Progressive Supranuclear Palsy Identifies Novel Susceptibility Loci and Genetic Correlation to Neurodegenerative Diseases
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1186/s13024-018-0270-8
Publisher version: https://doi.org/10.1186/s13024-018-0270-8
Language: English
Additional information: This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Keywords: Genome-wide association study, Neurodegeneration, Progressive supranuclear palsy
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10058872
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