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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.
SUBMITTER: Chen JA
PROVIDER: S-EPMC6083608 | biostudies-literature | 2018 Aug
REPOSITORIES: biostudies-literature
Chen Jason A JA Chen Zhongbo Z Won Hyejung H Huang Alden Y AY Lowe Jennifer K JK Wojta Kevin K Yokoyama Jennifer S JS Bensimon Gilbert G Leigh P Nigel PN Payan Christine C Shatunov Aleksey A Jones Ashley R AR Lewis Cathryn M CM Deloukas Panagiotis P Amouyel Philippe P Tzourio Christophe C Dartigues Jean-Francois JF Ludolph Albert A Boxer Adam L AL Bronstein Jeff M JM Al-Chalabi Ammar A Geschwind Daniel H DH Coppola Giovanni G
Molecular neurodegeneration 20180808 1
<h4>Background</h4>Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease for which the genetic contribution is incompletely understood.<h4>Methods</h4>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 ...[more]