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17q21.31 Sub-Haplotypes Underlying H1-Associated Risk for Parkinson's Disease and Progressive Supranuclear Palsy Converge on Altered Glial Regulation

98 Pages Posted: 15 Jan 2020 Sneak Peek Status: Under Review

See all articles by Kathryn Bowles

Kathryn Bowles

Icahn School of Medicine at Mount Sinai - Nash Department of Neuroscience

Derian A. Pugh

Icahn School of Medicine at Mount Sinai - Nash Department of Neuroscience

Kurt Farrell

Icahn School of Medicine at Mount Sinai - Nash Department of Neuroscience

Natalia Han

Icahn School of Medicine at Mount Sinai - Nash Department of Neuroscience

Julia TCW

Icahn School of Medicine at Mount Sinai - Nash Department of Neuroscience; Icahn School of Medicine at Mount Sinai - Ronald M. Loeb Center for Alzheimer's Disease

Y. Liu

Icahn School of Medicine at Mount Sinai - Nash Department of Neuroscience

Shiang An Liang

University of California, Irvine - Institute for Memory Impairments and Neurological Disorders

Lu Qian

Icahn School of Medicine at Mount Sinai - Nash Department of Neuroscience; Icahn School of Medicine at Mount Sinai - Ronald M. Loeb Center for Alzheimer's Disease

Jaroslav Bendl

Icahn School of Medicine - Pamela Sklar Division of Psychiatric Genomics

John F. Fullard

Icahn School of Medicine - Pamela Sklar Division of Psychiatric Genomics

Alan E. Renton

Icahn School of Medicine at Mount Sinai - Nash Department of Neuroscience

Alicia Casella

Icahn School of Medicine at Mount Sinai - Department of Pathology

Megan A. Iida

Icahn School of Medicine at Mount Sinai - Department of Pathology

Sara Bandres-Ciga

National Institutes of Health - Laboratory of Neurogenetics

Ziv Gan-Or

McGill University - Department of Human Genetics

Peter Heutink

German Center for Neurodegenerative Diseases (DZNE)

Ari Siitonen

University of Oulu - Institute of Clinical Medicine

Sarah Bertelsen

Icahn School of Medicine at Mount Sinai - Nash Department of Neuroscience

Celeste M. Karch

Washington University in St. Louis - Department of Psychiatry

Steven J. Frucht

New York University (NYU) - Fresco Institute for Parkinson’s and Movement Disorders

Brian H. Kopell

Icahn School of Medicine at Mount Sinai - Department of Neurosurgery

Inga Peter

Icahn School of Medicine at Mount Sinai - Icahn Institute for Data Science and Genomic Technology

You Jeong Park

Icahn School of Medicine at Mount Sinai - Department of Neurosurgery

PK Crane

University of Washington - Department of Medicine

John SK Kauwe

Brigham Young University - Department of Biology

Kevin L. Boehme

Brigham Young University - Department of Biology

Guenter U. Hoglinger

Hannover Medical School - Department of Neurology

PART Working Group

International Parkinson’s Disease Genomics Consortium (IPDGC)

Progressive Supranuclear Palsy Genetics Consortium

Alexander Charney

Icahn School of Medicine at Mount Sinai - Nash Department of Neuroscience

Panagiotis Roussos

Icahn School of Medicine at Mount Sinai - Nash Department of Neuroscience

JC Wang

Icahn School of Medicine at Mount Sinai - Nash Department of Neuroscience

Wayne W. Poon

University of California, Irvine - Institute for Memory Impairments and Neurological Disorders

Towfique Raj

Icahn School of Medicine at Mount Sinai - Nash Department of Neuroscience

John F. Crary

Icahn School of Medicine at Mount Sinai - Nash Department of Neuroscience

Alison M. Goate

Icahn School of Medicine at Mount Sinai - Nash Department of Neuroscience; Icahn School of Medicine at Mount Sinai - Ronald M. Loeb Center for Alzheimer's Disease; Icahn School of Medicine at Mount Sinai - Department of Genetics and Genomic Sciences

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Abstract

Parkinson’s disease (PD) and progressive supranuclear palsy (PSP) are clinically similar neurodegenerative movement disorders that display unique neuropathological features (i.e. Lewy body pathology and Tau pathology, respectively). While each disorder has distinct clinical and genetic risk factors, both are associated with the MAPT 17q.21.31 locus H1 haplotype. This suggests a pleiotropic effect of this genomic region. To better understand the genetic contribution of this region to these diseases, we fine-mapped the apparent pleiotropy of this locus. Our study indicates that PD and PSP are associated with different sub-haplotypes of the H1 clade. PD-associated sub-haplotypes were associated with altered LRRC37A copy number and expression, which, like other PD risk-associated genes, we hypothesize to be most relevant to astroglial function. In contrast, PSP was associated with grossly altered LD structure across the 17q21.31 locus, and risk-associated variants were found to impact chromatin structure in both neurons and microglia. We conclude that the contribution of the 17q21.31 locus to multiple disorders is a result of its structural and haplotypic complexity, which in turn impacts the regulation of multiple genes and neural cell types. This raises the possibility of novel disease-specific pathogenic mechanisms driven by 17q21.31 structural variation and altered epigenetic regulation that appear to converge on glial function and gene expression. By fine-mapping the association of H1 with PD and PSP, we have begun to untangle the apparent pleiotropy of this locus, and gain better insight into the mechanism of each disease, which will guide future functional analyses and disease models for PD and PSP.

Keywords: MAPT, 17q21.31, Haplotyples, Sub-haplotypes, parkinson's disease, Progressive supranuclear palsy, LRRC37A, Glia, Tauopathy

Suggested Citation

Bowles, Kathryn and Pugh, Derian A. and Farrell, Kurt and Han, Natalia and TCW, Julia and Liu, Y. and Liang, Shiang An and Qian, Lu and Bendl, Jaroslav and Fullard, John F. and Renton, Alan E. and Casella, Alicia and Iida, Megan A. and Bandres-Ciga, Sara and Gan-Or, Ziv and Heutink, Peter and Siitonen, Ari and Bertelsen, Sarah and Karch, Celeste M. and Frucht, Steven J. and Kopell, Brian H. and Peter, Inga and Park, You Jeong and Crane, PK and Kauwe, John SK and Boehme, Kevin L. and Hoglinger, Guenter U. and Group, PART Working and Consortium (IPDGC), International Parkinson’s Disease Genomics and Consortium, Progressive Supranuclear Palsy Genetics and Charney, Alexander and Roussos, Panagiotis and Wang, JC and Poon, Wayne W. and Raj, Towfique and Crary, John F. and Goate, Alison M., 17q21.31 Sub-Haplotypes Underlying H1-Associated Risk for Parkinson's Disease and Progressive Supranuclear Palsy Converge on Altered Glial Regulation. NEURON-D-20-00007. Available at SSRN: https://ssrn.com/abstract=3518538 or http://dx.doi.org/10.2139/ssrn.3518538
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Kathryn Bowles

Icahn School of Medicine at Mount Sinai - Nash Department of Neuroscience ( email )

New York, NY
United States

Derian A. Pugh

Icahn School of Medicine at Mount Sinai - Nash Department of Neuroscience

New York, NY
United States

Kurt Farrell

Icahn School of Medicine at Mount Sinai - Nash Department of Neuroscience

New York, NY
United States

Natalia Han

Icahn School of Medicine at Mount Sinai - Nash Department of Neuroscience

New York, NY
United States

Julia TCW

Icahn School of Medicine at Mount Sinai - Nash Department of Neuroscience ( email )

New York, NY
United States

Icahn School of Medicine at Mount Sinai - Ronald M. Loeb Center for Alzheimer's Disease ( email )

New York, NY 10029
United States

Y. Liu

Icahn School of Medicine at Mount Sinai - Nash Department of Neuroscience

New York, NY
United States

Shiang An Liang

University of California, Irvine - Institute for Memory Impairments and Neurological Disorders

Irvine, CA
United States

Lu Qian

Icahn School of Medicine at Mount Sinai - Nash Department of Neuroscience ( email )

New York, NY
United States

Icahn School of Medicine at Mount Sinai - Ronald M. Loeb Center for Alzheimer's Disease ( email )

New York, NY 10029
United States

Jaroslav Bendl

Icahn School of Medicine - Pamela Sklar Division of Psychiatric Genomics ( email )

New York City, NY
United States

John F. Fullard

Icahn School of Medicine - Pamela Sklar Division of Psychiatric Genomics

United States

Alan E. Renton

Icahn School of Medicine at Mount Sinai - Nash Department of Neuroscience

New York, NY 10029
United States

Alicia Casella

Icahn School of Medicine at Mount Sinai - Department of Pathology

United States

Megan A. Iida

Icahn School of Medicine at Mount Sinai - Department of Pathology

United States

Sara Bandres-Ciga

National Institutes of Health - Laboratory of Neurogenetics

Bethesda, MD 20892
United States

Ziv Gan-Or

McGill University - Department of Human Genetics

3640 rue University
Rm W-315, Strathcona Anatomy & Dentistry Building
Montréal, QC H3A 0C7
Canada

Peter Heutink

German Center for Neurodegenerative Diseases (DZNE)

von Siebold Strasse 3a
Goettingen, 37075
Germany

Ari Siitonen

University of Oulu - Institute of Clinical Medicine

Finland

Sarah Bertelsen

Icahn School of Medicine at Mount Sinai - Nash Department of Neuroscience

New York, NY
United States

Celeste M. Karch

Washington University in St. Louis - Department of Psychiatry

660 S. Euclid Avenue
St. Louis, MO 63110
United States

Steven J. Frucht

New York University (NYU) - Fresco Institute for Parkinson’s and Movement Disorders

United States

Brian H. Kopell

Icahn School of Medicine at Mount Sinai - Department of Neurosurgery

United States

Inga Peter

Icahn School of Medicine at Mount Sinai - Icahn Institute for Data Science and Genomic Technology

United States

You Jeong Park

Icahn School of Medicine at Mount Sinai - Department of Neurosurgery

United States

PK Crane

University of Washington - Department of Medicine

Box 356340
1925 N.E. Pacific Street
Seattle, WA 98195-6340
United States

John SK Kauwe

Brigham Young University - Department of Biology

Provo, UT
United States

Kevin L. Boehme

Brigham Young University - Department of Biology

Provo, UT
United States

Guenter U. Hoglinger

Hannover Medical School - Department of Neurology

Germany

Alexander Charney

Icahn School of Medicine at Mount Sinai - Nash Department of Neuroscience

New York, NY
United States

Panagiotis Roussos

Icahn School of Medicine at Mount Sinai - Nash Department of Neuroscience

New York, NY
United States

JC Wang

Icahn School of Medicine at Mount Sinai - Nash Department of Neuroscience

New York, NY
United States

Wayne W. Poon

University of California, Irvine - Institute for Memory Impairments and Neurological Disorders ( email )

Irvine, CA
United States

Towfique Raj

Icahn School of Medicine at Mount Sinai - Nash Department of Neuroscience

New York, NY
United States

John F. Crary

Icahn School of Medicine at Mount Sinai - Nash Department of Neuroscience

New York, NY
United States

Alison M. Goate (Contact Author)

Icahn School of Medicine at Mount Sinai - Nash Department of Neuroscience ( email )

New York, NY
United States

Icahn School of Medicine at Mount Sinai - Ronald M. Loeb Center for Alzheimer's Disease ( email )

New York, NY 10029
United States

Icahn School of Medicine at Mount Sinai - Department of Genetics and Genomic Sciences ( email )

1425 Madison Avenue
New York, NY 10029
United States

No contact information is available for PART Working Group
No contact information is available for International Parkinson’s Disease Genomics Consortium (IPDGC)
No contact information is available for Progressive Supranuclear Palsy Genetics Consortium

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