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

Jason A. Chen, Zhongbo Chen, Hyejung Won, Alden Y. Huang, Jennifer K. Lowe, Kevin Wojta, Jennifer S. Yokoyama, Gilbert Bensimon, P. Nigel Leigh, Christine Payan, Aleksey Shatunov, Ashley R. Jones, Cathryn M. Lewis, Panagiotis Deloukas, Philippe Amouyel, Christophe Tzourio, Jean Francois Dartigues, Albert Ludolph, Adam L. Boxer, Jeff M. BronsteinAmmar Al-Chalabi, Daniel H. Geschwind, Giovanni Coppola*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

58 Citations (Scopus)
156 Downloads (Pure)

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.

Original languageEnglish
Article number41
JournalMolecular Neurodegeneration
Volume13
Issue number1
DOIs
Publication statusPublished - 8 Aug 2018

Keywords

  • Genome-wide association study
  • Neurodegeneration
  • Progressive supranuclear palsy

Fingerprint

Dive into the research topics of 'Joint genome-wide association study of progressive supranuclear palsy identifies novel susceptibility loci and genetic correlation to neurodegenerative diseases'. Together they form a unique fingerprint.

Cite this