. 2018 Aug 8;13(1):41.

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

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.

PMID: 30089514
PMCID: PMC6083608
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

Jason A Chen et al. Mol Neurodegener. 2018.

. 2018 Aug 8;13(1):41.

doi: 10.1186/s13024-018-0270-8.

Authors

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.

PMID: 30089514
PMCID: PMC6083608
DOI: 10.1186/s13024-018-0270-8

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.

PubMed Disclaimer

Conflict of interest statement

Written informed consent was obtained for all patients participating in the Allon Therapeutics davunetide trial and the NNIPPS trial, and IRB approval was obtained from the corresponding Institutional Review Boards. For the NNIPPS study, The protocol and amendments were reviewed and approved by the Comité de Protection des Personnes of Pitié-Salpêtrière Hospital (France), the UK Multicentre Research Ethics Committee (MREC) (UK), Ethikkommission of the University of Ulm (Germany) and by local Institutional Review Boards (Ethics Committees) where appropriate (UK, Germany). For the BBBIPPS study, the protocol and amendments were reviewed and approved by the Comité de Protection des Personnes of Pitié-Salpêtrière Hospital (France). Additional data was obtained via NIAGADS and dbGAP in accordance with data access policies. The Institutional Review Board at the University of California, Los Angeles, approved the joint study design, including review of outside consent forms.

Not applicable.

J.A.C. is founder of Verge Genomics, a biotechnology company, and holds an equity stake. P.A. is a member of the Scientific Advisory Board of Genoscreen, a biotechnology company, and Director of the Fondation Plan Alzheimer, a non-profit organization. J-F.G. has received research grant funding from Roche.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

**Fig. 1**
Genome-wide SNP association in the joint analysis. a Manhattan plot indicating the SNP association P values. The vertical axis displays the strength of association (−log10 P value) as a function of genomic position, with alternating colors for sequential chromosomes. Genome-wide significant and suggestive loci are labeled with the nearest gene symbol. The thresholds for significant (P < 5 × 10^− 8, red horizontal line) and suggestive (P < 1 × 10^− 6, blue horizontal line) associations are shown. **b-d** Quantile-quantile plots for: b all SNPs, including the strongly associated extended haplotype on chromosome 17; c SNPs excluding chromosome 17; and d SNPs excluding genome-wide significant and suggestive loci. The 95% confidence interval for the expected distribution of p-values is shaded

**Fig. 2**
Forest plots showing association across each individual cohort for selected SNPs. A total of six genome-wide significant loci were identified, with representative SNPs: a rs71920662 in 17q21.31, near *MAPT*; b rs57113693 in 1q25.3, near *STX6*; c rs10675541 in 3p22.1, near *MOBP*; d rs35740963 in 6p21.1, near *RUNX2*; and e rs7966334 in 12p12.1, near *SLCO1A2.* An additional four suggestive loci were also identified: f rs12125383 in 1q41, near *DUSP10* in an intergenic region; g rs147124286 in 12q13.13, near *SP1*; h rs2045091 in 8q24.21, near *ASAP1*; and i rs114573015 in 1p22.3, near *WDR63*. j Additionally, a previously reported GWAS SNP rs7571971 in 2p11.2, near *EIF2AK3*, was not identified as genome-wide significant in the joint analysis

**Fig. 3**
Heatmap of genetic correlation between GWAS summary statistics for neurodegenerative diseases (PSP – progressive supranuclear palsy, ALS – amyotrophic lateral sclerosis, AD – Alzheimer’s disease, bvFTD – behavioral variant frontotemporal dementia, PD – Parkinson’s disease), calculated by LDSC. GWAS for non-neurodegenerative phenotypes (SCZ – schizophrenia, BIP – bipolar disorder, height, and T2D– type 2 diabetes mellitus) are also included for comparison. In each cell, the genetic correlation coefficient (and P value in parentheses) is shown. Phenotypes that share a common polygenic background are positively correlated

See this image and copyright information in PMC

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Miscellaneous