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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

KR Bowles, DA Pugh, K Farrell, N Han, J TCW, Y Liu, SA Liang, L Qian, J Bendl, JF Fullard, AE Renton, A Casella, MA Iida, S Bandres-Ciga, Z Gan-Or, P Heutink, A Siitonen, S Bertelsen, View ORCID ProfileCM Karch, SJ Frucht, BH Kopell, I Peter, YJ Park, PK Crane, JSK Kauwe, KL Boehme, GU Höglinger, PART working group, International Parkinson’s Disease Genomics Consortium (IPDGC), Progressive Supranuclear Palsy Genetics Consortium, View ORCID ProfileA Charney, P Roussos, JC Wang, WW Poon, T Raj, JF Crary, View ORCID ProfileAM Goate
doi: https://doi.org/10.1101/860668
KR Bowles
1Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
2Ronald M. Loeb Center for Alzheimer’s disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
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DA Pugh
1Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
2Ronald M. Loeb Center for Alzheimer’s disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
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K Farrell
1Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
2Ronald M. Loeb Center for Alzheimer’s disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
3Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
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N Han
1Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
2Ronald M. Loeb Center for Alzheimer’s disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
3Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
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J TCW
1Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
2Ronald M. Loeb Center for Alzheimer’s disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
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Y Liu
1Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
2Ronald M. Loeb Center for Alzheimer’s disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
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SA Liang
4Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, United States of America
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L Qian
1Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
2Ronald M. Loeb Center for Alzheimer’s disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
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J Bendl
5Pamela Sklar Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine, New York, NY, United States of America
6Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
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JF Fullard
5Pamela Sklar Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine, New York, NY, United States of America
6Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
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AE Renton
1Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
2Ronald M. Loeb Center for Alzheimer’s disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
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A Casella
3Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
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MA Iida
3Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
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S Bandres-Ciga
7Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America
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Z Gan-Or
8Department of Human Genetics, McGill University, Montréal, Québec, Canada
9Montreal Neurological Institute, McGill University, Montréal, Québec, Canada
10Department of Neurology and Neurosurgery, McGill University, Montréal, Québec, Canada
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P Heutink
11Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
12German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
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A Siitonen
13Institute of Clinical Medicine, Department of Neurology, University of Oulu, Oulu, Finland
14Department of Neurology and Medical Research Center, Oulu University Hospital, Oulu, Finland.
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S Bertelsen
1Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
2Ronald M. Loeb Center for Alzheimer’s disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
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CM Karch
15Department of Psychiatry, Washington University in St Louis, St. Louis, MO, United States of America
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  • ORCID record for CM Karch
SJ Frucht
16Fresco Institute for Parkinson’s and Movement Disorders, Department of Neurology, New York University Langone, New York, NY, United States of America
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BH Kopell
17Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
18Center for Neuromodulation, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
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I Peter
6Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
19Institute for Exposomic Research, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
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YJ Park
17Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
20Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
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PK Crane
21Department of Medicine, University of Washington, Seattle, WA, United States of America
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JSK Kauwe
22Department of Biology, Brigham Young University, Provo, UT, United States of America
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KL Boehme
22Department of Biology, Brigham Young University, Provo, UT, United States of America
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GU Höglinger
23Department of Neurology, Hannover Medical School, Hannover, Germany
24Department of Neurology, Technical University, Munich, Germany
25Department of Translational Neurodegeneration, German Centre for Neurodegenerative Diseases (DZNE), Munich, Germany
26Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
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A Charney
1Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
6Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
17Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
20Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
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P Roussos
1Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
5Pamela Sklar Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine, New York, NY, United States of America
6Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
30Mental Illness Research, Education and Clinical Centers, VISN 2, JJ Peters VA Medical Center, Bronx, New York, NY, United States of America
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JC Wang
1Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
2Ronald M. Loeb Center for Alzheimer’s disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
6Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
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WW Poon
4Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, United States of America
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T Raj
1Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
2Ronald M. Loeb Center for Alzheimer’s disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
6Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
31Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
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JF Crary
1Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
2Ronald M. Loeb Center for Alzheimer’s disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
3Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
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AM Goate
1Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
2Ronald M. Loeb Center for Alzheimer’s disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
6Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
31Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
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  • ORCID record for AM Goate
  • For correspondence: alison.goate@mssm.edu
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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.

Footnotes

  • ↵27 Primary Age-Related Tauopathy (PART) working group and other contributing brain bank authors & affiliations in Supplementary material 1

  • ↵28 IPDGC authors and affiliations in Supplementary material 2

  • ↵29 PSP Genetics Consortium authors and affiliations in Supplementary material 3

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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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
KR Bowles, DA Pugh, K Farrell, N Han, J TCW, Y Liu, SA Liang, L Qian, J Bendl, JF Fullard, AE Renton, A Casella, MA Iida, S Bandres-Ciga, Z Gan-Or, P Heutink, A Siitonen, S Bertelsen, CM Karch, SJ Frucht, BH Kopell, I Peter, YJ Park, PK Crane, JSK Kauwe, KL Boehme, GU Höglinger, PART working group, International Parkinson’s Disease Genomics Consortium (IPDGC), Progressive Supranuclear Palsy Genetics Consortium, A Charney, P Roussos, JC Wang, WW Poon, T Raj, JF Crary, AM Goate
bioRxiv 860668; doi: https://doi.org/10.1101/860668
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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
KR Bowles, DA Pugh, K Farrell, N Han, J TCW, Y Liu, SA Liang, L Qian, J Bendl, JF Fullard, AE Renton, A Casella, MA Iida, S Bandres-Ciga, Z Gan-Or, P Heutink, A Siitonen, S Bertelsen, CM Karch, SJ Frucht, BH Kopell, I Peter, YJ Park, PK Crane, JSK Kauwe, KL Boehme, GU Höglinger, PART working group, International Parkinson’s Disease Genomics Consortium (IPDGC), Progressive Supranuclear Palsy Genetics Consortium, A Charney, P Roussos, JC Wang, WW Poon, T Raj, JF Crary, AM Goate
bioRxiv 860668; doi: https://doi.org/10.1101/860668

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