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 Bronstein; Ammar Al-Chalabi; Daniel H Geschwind; Giovanni Coppola

doi:10.1186/s13024-018-0270-8

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

Mol Neurodegener. 2018 Aug 8;13(1):41. doi: 10.1186/s13024-018-0270-8.

Authors

Jason A Chen¹, Zhongbo Chen², Hyejung Won³, Alden Y Huang¹, Jennifer K Lowe³, Kevin Wojta⁴, Jennifer S Yokoyama⁵, Gilbert Bensimon^{6

7

8}, P Nigel Leigh⁹, Christine Payan^{6

7}, Aleksey Shatunov², Ashley R Jones², Cathryn M Lewis¹⁰, Panagiotis Deloukas¹¹, Philippe Amouyel¹², Christophe Tzourio¹³, Jean-Francois Dartigues¹³, Albert Ludolph¹⁴, Adam L Boxer⁵, Jeff M Bronstein³, Ammar Al-Chalabi², Daniel H Geschwind^{1

3}, Giovanni Coppola^{15

16

17

18}

Affiliations

¹ Interdepartmental Program in Bioinformatics, University of California, Los Angeles, CA, 90095, USA.
² Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, King's College London, London, SE5 9RX, UK.
³ Program in Neurogenetics, Department of Neurology and Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA.
⁴ Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, 90095, USA.
⁵ Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, 94158, USA.
⁶ BESPIM, CHU-Nîmes, Nîmes, France.
⁷ Dept Pharmacologie Clinique, Pitié-Salpêtrière Hospital, AP-PH, Paris, France.
⁸ Pharmacology UPMC-Paris VI, Universite Paris-Sorbonne, Paris, France.
⁹ Trafford Centre for Biomedical Research, Brighton and Sussex Medical School, University of Sussex, Falmer, Brighton, UK.
¹⁰ Medical Research Council Social, Genetic and Developmental Psychiatry Centre, and Department of Medical and Molecular Genetics, King's College London, London, SE5 8AF, UK.
¹¹ William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
¹² Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Risk Factor and molecular determinants of aging diseases, Labex-Distalz, F-59000, Lille, France.
¹³ Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219, CHU Bordeaux, F-33000 Bordeaux, France.
¹⁴ Department of Neurology, University of Ulm, Oberer Eselsberg, Ulm, Germany.
¹⁵ Interdepartmental Program in Bioinformatics, University of California, Los Angeles, CA, 90095, USA. gcoppola@ucla.edu.
¹⁶ Program in Neurogenetics, Department of Neurology and Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA. gcoppola@ucla.edu.
¹⁷ Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, 90095, USA. gcoppola@ucla.edu.
¹⁸ Departments of Psychiatry and Neurology, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E Young Dr. South, Gonda Bldg, Rm 1524, Los Angeles, CA, 90095, USA. gcoppola@ucla.edu.

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.

Keywords: Genome-wide association study; Neurodegeneration; Progressive supranuclear palsy.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Female
Genetic Predisposition to Disease / genetics*
Genome-Wide Association Study
Genotype
Humans
Male
Neurodegenerative Diseases / genetics*
Polymorphism, Single Nucleotide
Supranuclear Palsy, Progressive / genetics*

Abstract

Publication types

MeSH terms

Grants and funding