TY - JOUR
T1 - Joint genome-wide association study of progressive supranuclear palsy identifies novel susceptibility loci and genetic correlation to neurodegenerative diseases
AU - Chen, Jason A.
AU - Chen, Zhongbo
AU - Won, Hyejung
AU - Huang, Alden Y.
AU - Lowe, Jennifer K.
AU - Wojta, Kevin
AU - Yokoyama, Jennifer S.
AU - Bensimon, Gilbert
AU - Leigh, P. Nigel
AU - Payan, Christine
AU - Shatunov, Aleksey
AU - Jones, Ashley R.
AU - Lewis, Cathryn M.
AU - Deloukas, Panagiotis
AU - Amouyel, Philippe
AU - Tzourio, Christophe
AU - Dartigues, Jean Francois
AU - Ludolph, Albert
AU - Boxer, Adam L.
AU - Bronstein, Jeff M.
AU - Al-Chalabi, Ammar
AU - Geschwind, Daniel H.
AU - Coppola, Giovanni
PY - 2018/8/8
Y1 - 2018/8/8
N2 - 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.
AB - 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.
KW - Genome-wide association study
KW - Neurodegeneration
KW - Progressive supranuclear palsy
UR - http://www.scopus.com/inward/record.url?scp=85051187037&partnerID=8YFLogxK
U2 - 10.1186/s13024-018-0270-8
DO - 10.1186/s13024-018-0270-8
M3 - Article
AN - SCOPUS:85051187037
SN - 1750-1326
VL - 13
JO - Molecular Neurodegeneration
JF - Molecular Neurodegeneration
IS - 1
M1 - 41
ER -