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

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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.

Electronic supplementary material

The online version of this article (10.1186/s13024-018-0270-8) contains supplementary material, which is available to authorized users.

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Most cited references 17

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Regulation of bone development and extracellular matrix protein genes by RUNX2.

Toshihisa Komori (2010)

RUNX2 is a multifunctional transcription factor that controls skeletal development by regulating the differentiation of chondrocytes and osteoblasts and the expression of many extracellular matrix protein genes during chondrocyte and osteoblast differentiation. This transcription factor plays a major role at the late stage of chondrocyte differentiation: it is required for chondrocyte maturation and regulates Col10a1 expression in hypertrophic chondrocytes and the expression of Spp1, Ibsp, and Mmp13 in terminal hypertrophic chondrocytes. It is essential for the commitment of pluripotent mesenchymal cells to the osteoblast lineage. During osteoblast differentiation, RUNX2 upregulates the expression of bone matrix protein genes including Col1a1, Spp1, Ibsp, Bglap, and Fn1 in vitro and activates many promoters including those of Col1a1, Col1a2, Spp1, Bglap, and Mmp13. However, overexpression of Runx2 inhibits osteoblast maturation and reduces Col1a1 and Bglap expression. The inhibition of RUNX2 in mature osteoblasts does not reduce the expression of Col1a1 and Bglap in mice. Thus, RUNX2 directs pluripotent mesenchymal cells to the osteoblast lineage, triggers the expression of major bone matrix protein genes, and keeps the osteoblasts in an immature stage, but does not play a major role in the maintenance of the expression of Col1a1 or Bglap in mature osteoblasts. During bone development, RUNX2 induces osteoblast differentiation and increases the number of immature osteoblasts, which form immature bone, whereas Runx2 expression has to be downregulated for differentiation into mature osteoblasts, which form mature bone. During dentinogenesis, Runx2 expression is downregulated, and RUNX2 inhibits the terminal differentiation of odontoblasts.

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Matthew Freedman, David Reich, Kathryn Penney … (2004)

Population stratification refers to differences in allele frequencies between cases and controls due to systematic differences in ancestry rather than association of genes with disease. It has been proposed that false positive associations due to stratification can be controlled by genotyping a few dozen unlinked genetic markers. To assess stratification empirically, we analyzed data from 11 case-control and case-cohort association studies. We did not detect statistically significant evidence for stratification but did observe that assessments based on a few dozen markers lack power to rule out moderate levels of stratification that could cause false positive associations in studies designed to detect modest genetic risk factors. After increasing the number of markers and samples in a case-cohort study (the design most immune to stratification), we found that stratification was in fact present. Our results suggest that modest amounts of stratification can exist even in well designed studies.

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Author and article information

Contributors

Jason A. Chen: jasonchen@mednet.ucla.edu

Zhongbo Chen: zhongbo@cantab.net

Hyejung Won: wonhyejung87@gmail.com

Alden Y. Huang: alden.huang@gmail.com

Jennifer K. Lowe: JKLowe@mednet.ucla.edu

Kevin Wojta: Kevin.wojta@gmail.com

Jennifer S. Yokoyama: Jennifer.yokoyama@ucsf.edu

Gilbert Bensimon: gilbert.bensimon@psl.aphp.fr

P. Nigel Leigh: P.Leigh@bsms.ac.uk

Christine Payan: Christine.payan@aphp.fr

Aleksey Shatunov: aleksey.shatunov@kcl.ac.uk

Ashley R. Jones: ashley.r.jones@kcl.ac.uk

Cathryn M. Lewis: cathryn.lewis@kcl.ac.uk

Panagiotis Deloukas: p.deloukas@qmul.ac.uk

Philippe Amouyel: philippe.amouyel@pasteur-lille.fr

Christophe Tzourio: christophe.tzourio@u-bordeaux.fr

Jean-Francois Dartigues: jean-francois.dartigues@isped.u-bordeaux2.fr

Albert Ludolph: albert.ludolph@rku.de

Adam L. Boxer: adam.boxer@ucsf.edu

Jeff M. Bronstein: JBronste@mednet.ucla.edu

Ammar Al-Chalabi: ammar.al-chalabi@kcl.ac.uk

Daniel H. Geschwind: dhg@mednet.ucla.edu

Giovanni Coppola:

ORCID: http://orcid.org/0000-0003-2105-1061

gcoppola@ucla.edu

Journal

Journal ID (nlm-ta): Mol Neurodegener

Journal ID (iso-abbrev): Mol Neurodegener

Title: Molecular Neurodegeneration

Publisher: BioMed Central (London )

ISSN (Electronic): 1750-1326

Publication date (Electronic): 8 August 2018

Publication date PMC-release: 8 August 2018

Publication date Collection: 2018

Volume: 13

Electronic Location Identifier: 41

Affiliations

[1 ]ISNI 0000 0000 9632 6718, GRID grid.19006.3e, Interdepartmental Program in Bioinformatics, University of California, ; Los Angeles, CA 90095 USA

[2 ]ISNI 0000 0001 2322 6764, GRID grid.13097.3c, Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, King’s College London, ; London, SE5 9RX UK

[3 ]ISNI 0000 0000 9632 6718, GRID grid.19006.3e, Program in Neurogenetics, Department of Neurology and Department of Human Genetics, David Geffen School of Medicine at UCLA, ; Los Angeles, CA 90095 USA

[4 ]ISNI 0000 0000 9632 6718, GRID grid.19006.3e, Semel Institute for Neuroscience and Human Behavior, University of California, ; Los Angeles, CA 90095 USA

[5 ]ISNI 0000 0001 2297 6811, GRID grid.266102.1, Memory and Aging Center, Department of Neurology, , University of California, ; San Francisco, CA 94158 USA

[6 ]ISNI 0000 0004 0593 8241, GRID grid.411165.6, BESPIM, CHU-Nîmes, ; Nîmes, France

[7 ]ISNI 0000 0001 2150 9058, GRID grid.411439.a, Dept Pharmacologie Clinique, Pitié-Salpêtrière Hospital, AP-PH, ; Paris, France

[8 ]ISNI 0000 0001 2165 487X, GRID grid.46900.3b, Pharmacology UPMC-Paris VI, Universite Paris-Sorbonne, ; Paris, France

[9 ]ISNI 0000 0004 1936 7590, GRID grid.12082.39, Trafford Centre for Biomedical Research, Brighton and Sussex Medical School, , University of Sussex, ; Falmer, Brighton, UK

[10 ]ISNI 0000 0001 2322 6764, GRID grid.13097.3c, 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 ]ISNI 0000 0001 2171 1133, GRID grid.4868.2, 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 ]ISNI 0000 0004 0471 8845, GRID grid.410463.4, 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 ]ISNI 0000 0001 2106 639X, GRID grid.412041.2, Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, ; UMR 1219, CHU Bordeaux, F-33000 Bordeaux, France

[14 ]ISNI 0000 0004 1936 9748, GRID grid.6582.9, Department of Neurology, , University of Ulm, Oberer Eselsberg, ; Ulm, Germany

[15 ]ISNI 0000 0000 9632 6718, GRID grid.19006.3e, 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

Author information

Giovanni Coppola http://orcid.org/0000-0003-2105-1061

Article

Publisher ID: 270

DOI: 10.1186/s13024-018-0270-8

PMC ID: 6083608

PubMed ID: 30089514

SO-VID: 90329f61-a9f2-494a-b74e-ef33e34b2a2c

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 16 May 2018

Date accepted : 29 June 2018

Funding

Funded by: National Institute of Neurological Disorders and Stroke (US)

Award ID: F31 NS084556

Award Recipient : Jason A. Chen

Custom metadata

ScienceOpen disciplines: Neurosciences

Keywords: genome-wide association study,progressive supranuclear palsy,neurodegeneration

Data availability:

ScienceOpen disciplines: Neurosciences

Keywords: genome-wide association study, progressive supranuclear palsy, neurodegeneration

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

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Abstract

Background

Methods

Results

Conclusions

Electronic supplementary material

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Neuronal Signaling

Most cited references 17

Regulation of bone development and extracellular matrix protein genes by RUNX2.

Meta-analysis methods for genome-wide association studies and beyond.

Assessing the impact of population stratification on genetic association studies.

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