Joint genome-wide association study of progressive supranuclear palsy identifies novel susceptibility loci and genetic correlation to neurodegenerative diseases

Chen, Jason A, Chen, Zhongbo, Won, Hyejung, Huang, Alden Y, Lowe, Jennifer K, Wojita, Kevin, Yokoyama, Jennifer S, Bensimon, Gilbert, Leigh, P Nigel, Payan, Christine, Shatunov, Aleksey, Jones, Ashley R, Lewis, Cathryn M, Deloukas, Panagiotis, Amouyel, Philippe, Tzourio, Christophe, Dartigues, Jean-Francois, Ludolph, Albert, Boxer, Adam L, Bronstein, Jeff M, Al-Chalabi, Ammar, Geschwind, Daniel H and Coppola, Giovanni (2018) Joint genome-wide association study of progressive supranuclear palsy identifies novel susceptibility loci and genetic correlation to neurodegenerative diseases. Molecular Neurodegeneration, 13 (41). pp. 1-11. ISSN 1750-1326

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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.

Item Type: Article
Keywords: Genomewide association study; Progressive supranuclear palsy; Neurodegeneration
Schools and Departments: Brighton and Sussex Medical School > Neuroscience
Subjects: R Medicine > RC Internal medicine > RC0321 Neurosciences. Biological psychiatry. Neuropsychiatry > RC0346 Neurology. Diseases of the nervous system Including speech disorders
Depositing User: Patricia Butler
Date Deposited: 24 Jul 2018 12:29
Last Modified: 02 Jul 2019 14:05
URI: http://sro.sussex.ac.uk/id/eprint/77357

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