Abstract
ObjectiveTo discover genetic determinants of Parkinson disease (PD) motor subtypes, including tremor dominant (TD) and postural instability/gait difficulty (PIGD) forms.MethodsIn 3,212 PD cases of European ancestry, we performed a genome-wide association study (GWAS) examining 2 complementary outcome traits derived from the Unified Parkinson's Disease Rating Scale, including dichotomous motor subtype (TD vs PIGD) or a continuous tremor/PIGD score ratio. Logistic or linear regression models were adjusted for sex, age at onset, disease duration, and 5 ancestry principal components, followed by meta-analysis.ResultsAmong 71 established PD risk variants, we detected multiple suggestive associations with PD motor subtype, including GPNMB (rs199351, psubtype = 0.01, pratio = 0.03), SH3GL2 (rs10756907, psubtype = 0.02, pratio = 0.01), HIP1R (rs10847864, psubtype = 0.02), RIT2 (rs12456492, psubtype = 0.02), and FBRSL1 (rs11610045, psubtype = 0.02). A PD genetic risk score integrating all 71 PD risk variants was also associated with subtype ratio (p = 0.026, ß = -0.04, 95% confidence interval = -0.07-0). Based on top results of our GWAS, we identify a novel suggestive association at the STK32B locus (rs2301857, pratio = 6.6 × 10-7), which harbors an independent risk allele for essential tremor.ConclusionsMultiple PD risk alleles may also modify clinical manifestations to influence PD motor subtype. The discovery of a novel variant at STK32B suggests a possible overlap between genetic risk for essential tremor and tremor-dominant PD.
| Original language | English |
|---|---|
| Article number | e557 |
| Journal | Neurology: Genetics |
| Volume | 7 |
| Issue number | 2 |
| DOIs | |
| State | Published - Apr 28 2021 |
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In: Neurology: Genetics, Vol. 7, No. 2, e557, 28.04.2021.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Genome-Wide Association Study Meta-Analysis for Parkinson Disease Motor Subtypes
AU - Alfradique-Dunham, Isabel
AU - Al-Ouran, Rami
AU - Von Coelln, Rainer
AU - Blauwendraat, Cornelis
AU - Hill, Emily
AU - Luo, Lan
AU - Stillwell, Amanda
AU - Young, Emily
AU - Kaw, Anita
AU - Tan, Manuela
AU - Liao, Calwing
AU - Hernandez, Dena
AU - Pihlstrom, Lasse
AU - Grosset, Donald
AU - Shulman, Lisa M.
AU - Liu, Zhandong
AU - Rouleau, Guy A.
AU - Nalls, Mike
AU - Singleton, Andrew B.
AU - Morris, Huw
AU - Jankovic, Joseph
AU - Shulman, Joshua M.
N1 - Funding Information: The authors thank all the subjects who donated their time and biological samples to be a part of this study. They thank J. Marinus and J.J. Van Hilten for use of the PROPARK cohort data and for feedback on the manuscript. The International Parkinson Disease Genomics Consortium (IPDGC, pdgenetics.org/partners ) is supported in part by the Intramural Research Programs of the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute on Aging (NIA), and the National Institute of Environmental Health Sciences both part of the National Institutes of Health, Department of Health and Human Services; project numbers 1ZIA-NS003154, Z01-AG000949-02, and Z01-ES101986. In addition this work was supported by the Department of Defense (award W81XWH-09-2-0128) and The Michael J. Fox Foundation for Parkinsons Research. This work was supported by National Institutes of Health grants R01NS037167, R01CA141668, and P50NS071674, American Parkinson Disease Association (APDA); Barnes Jewish Hospital Foundation; and Greater St. Louis Chapter of the APDA. The KORA (Cooperative Research in the Region of Augsburg) research platform was started and financed by the Forschungszentrum für Umwelt und Gesundheit, which is funded by the German Federal Ministry of Education, Science, Research, and Technology and by the State of Bavaria. This study was also funded by the German Federal Ministry of Education and Research (BMBF) under the funding code 031A430A, the EU Joint Programme – Neurodegenerative Diseases Research (JPND) project under the aegis of JPND -www.jpnd.eu-through Germany, BMBF, funding code 01ED1406 and iMed - the Helmholtz Initiative on Personalized Medicine. This study is funded by the German National Foundation grant (DFG SH599/6-1) (grant to M.S.), Michael J. Fox Foundation, and MSA Coalition, USA (to M.S.). The French GWAS work was supported by the French National Agency of Research (ANR-08-MNP-012). This study was also funded by France-Parkinson Association, Fondation de France, the French program Investissements davenir funding (ANR-10-IAIHU-06), and a grant from Assistance Publique-Hôpitaux de Paris (PHRC, AOR-08010) for the French clinical data. This study was also sponsored by the Landspitali University Hospital Research Fund (grant to SSv); Icelandic Research Council (grant to SSv); and European Community Framework Programme 7, People Programme, and IAPP on novel genetic and phenotypic markers of Parkinsons disease and Essential Tremor (MarkMD), contract number PIAP-GA-2008- 230596 MarkMD (to HP and JHu). Institutional research funding IUT20-46 was received of the Estonian Ministry of Education and Research (SK). The McGill study was funded by the Michael J. Fox Foundation and the Canadian Consortium on Neurodegeneration in Aging (CCNA). Mayo Clinic is an American Parkinson Disease Association (APDA) Mayo Clinic Information and Referral Center, an APDA Center for Advanced Research and the Mayo Clinic Lewy Body Dementia Association (LBDA) Research Center of Excellence. OAR is supported by the National Institutes of Health (NIH; R01 NS78086; U54 NS100693, U54 NS110435), the US Department of Defense (W81XWH-17-1-0249), The Little Family Foundation, The Mayo Clinic Functional Genomics of LBD Program the Mayo Clinic Center for Individualized Medicine, and the Michael J. Fox Foundation. Z. K. Wszolek is supported by the NIH, Mayo Clinic Center for Regenerative Medicine, The Sol Goldman Charitable Trust, and Donald G. and Jodi P. Heeringa, the Haworth Family Professorship in Neurodegenerative Diseases fund, and by the Albertson Parkinson's Research Foundation. This study used the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD ( biowulf.nih.gov ), and DNA panels, samples, and clinical data from the National Institute of Neurological Disorders and Stroke Human Genetics Resource Center DNA and Cell Line Repository. People who contributed samples are acknowledged in descriptions of every panel on the repository website. The authors thank the French Parkinsons Disease Genetics Study Group and the Drug Interaction with genes (DIGPD) study group: Y. Agid, M. Anheim, F. Artaud, A-M. Bonnet, C. Bonnet, F. Bourdain, J.-P. Brandel, C. Brefel-Courbon, M. Borg, A. Brice, E. Broussolle, F. Cormier-Dequaire, J.-C. Corvol, P. Damier, B. Debilly, B. Degos, P. Derkinderen, A. Destée, A. Dürr, F. Durif, A. Elbaz, D. Grabli, A. Hartmann, S. Klebe, P. Krack, J. Kraemmer, S. Leder, S. Lesage, R. Levy, E. Lohmann, L. Lacomblez, G. Mangone, L.-L. Mariani, A.-R. Marques, M. Martinez, V. Mesnage, J. Muellner, F. Ory-Magne, F. Pico, V. Planté-Bordeneuve, P. Pollak, O. Rascol, K. Tahiri, F. Tison, C. Tranchant, E. Roze, M. Tir, M. Vérin, F. Viallet, M. Vidailhet, and A. You. The authors also thank the members of the French 3C Consortium: A Alpérovitch, C Berr, C Tzourio, and P Amouyel for allowing us to use part of the 3C cohort and D Zelenika for support in generating the genome-wide molecular data. The authors thank P. Tienari (Molecular Neurology Programme, Biomedicum, University of Helsinki), T. Peuralinna (Department of Neurology, Helsinki University Central Hospital), L. Myllykangas (Folkhalsan Institute of Genetics and Department of Pathology, University of Helsinki), and R. Sulkava (Department of Public Health and General Practice Division of Geriatrics, University of Eastern Finland) for the Finnish controls (Vantaa85 + GWAS data). The authors used genome-wide association data generated by the Wellcome Trust Case-Control Consortium 2 (WTCCC2) from UK patients with Parkinsons disease and UK control individuals from the 1958 Birth Cohort and National Blood Service. Genotyping of UK replication cases on ImmunoChip was part of the WTCCC2 project, which was funded by the Wellcome Trust (083948/Z/07/Z). UK population control data were made available through WTCCC1. This study was supported by the Medical Research Council and Wellcome Trust disease centre (grant WT089698/Z/09/Z to NW, JHa, and ASc). As with previous IPDGC efforts, this study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the data is available from wtccc.org.uk . Funding for the project was provided by the Wellcome Trust under award 076113, 085475 and 090355. This study was also supported by Parkinsons UK (grants 8047 and J-0804) and the Medical Research Council (G0700943 and G1100643). Sequencing and genotyping performed in McGill University was supported by grants from the Michael J. Fox Foundation, the Canadian Consortium on Neurodegeneration in Aging (CCNA), the Canada First Research Excellence Fund (CFREF), awarded to McGill University for the Healthy Brains for Healthy Lives (HBHL) program and Parkinsons Society Canada. The authors thank Jeffrey Barrett and Jason Downing (Illumina Inc) for assistance with the design of the ImmunoChip and NeuroX arrays. DNA extraction work that was performed in the United Kingdom was undertaken at University College London Hospitals, University College London, who received a proportion of funding from the Department of Healths National Institute for Health Research Biomedical Research Centres funding. This study was supported in part by the Wellcome Trust/Medical Research Council Joint Call in Neurodegeneration award (WT089698) to the Parkinsons Disease Consortium (UKPDC), whose members are from the UCL Institute of Neurology, University of Sheffield, and the Medical Research Council Protein Phosphorylation Unit at the University of Dundee. The authors thank the Quebec Parkinsons Network ( rpq-qpn.org ) and its members. This work was supported by the Medical Research Council grant MR/N026004/1. The Braineac project was supported by the MRC through the MRC Sudden Death Brain Bank Grant (MR/G0901254) to J.H. P.A.L. was supported by the MRC (grants MR/N026004/1 and MR/L010933/1) and Michael J. Fox Foundation for Parkinsons Research. M.A. Nalls participation is supported by a consulting contract between Data Tecnica International and the National Institute on Aging, NIH, Bethesda, MD, USA. Funding Information: This research was supported in part by the Intramural research Program of the NIH, National Institute on Aging and the Parkinsons UK (Tracking Parkinsons study J-1101, G-1107, H-1703), and the Medical Research Council (G1100643). G.A.R. receives support from a Canadian Institutes of Health Foundation Grant, and C.L. is funded by the Vanier Graduate Scholarship. D.G. receives funding from Parkinsons UK, the UK National Institute for Health Research, and Glasgow University. J.M.S. was supported by the Huffington Foundation, McGee Foundation, Jan and Dan Duncan Neurological Research Institute at Texas Childrens Hospital, and a Career Award for Medical Scientists from the Burroughs Wellcome Fund. Additional International PD Genomics Consortium funding sources are listed in the Acknowledgments. Publisher Copyright: © American Academy of Neurology.
PY - 2021/4/28
Y1 - 2021/4/28
N2 - ObjectiveTo discover genetic determinants of Parkinson disease (PD) motor subtypes, including tremor dominant (TD) and postural instability/gait difficulty (PIGD) forms.MethodsIn 3,212 PD cases of European ancestry, we performed a genome-wide association study (GWAS) examining 2 complementary outcome traits derived from the Unified Parkinson's Disease Rating Scale, including dichotomous motor subtype (TD vs PIGD) or a continuous tremor/PIGD score ratio. Logistic or linear regression models were adjusted for sex, age at onset, disease duration, and 5 ancestry principal components, followed by meta-analysis.ResultsAmong 71 established PD risk variants, we detected multiple suggestive associations with PD motor subtype, including GPNMB (rs199351, psubtype = 0.01, pratio = 0.03), SH3GL2 (rs10756907, psubtype = 0.02, pratio = 0.01), HIP1R (rs10847864, psubtype = 0.02), RIT2 (rs12456492, psubtype = 0.02), and FBRSL1 (rs11610045, psubtype = 0.02). A PD genetic risk score integrating all 71 PD risk variants was also associated with subtype ratio (p = 0.026, ß = -0.04, 95% confidence interval = -0.07-0). Based on top results of our GWAS, we identify a novel suggestive association at the STK32B locus (rs2301857, pratio = 6.6 × 10-7), which harbors an independent risk allele for essential tremor.ConclusionsMultiple PD risk alleles may also modify clinical manifestations to influence PD motor subtype. The discovery of a novel variant at STK32B suggests a possible overlap between genetic risk for essential tremor and tremor-dominant PD.
AB - ObjectiveTo discover genetic determinants of Parkinson disease (PD) motor subtypes, including tremor dominant (TD) and postural instability/gait difficulty (PIGD) forms.MethodsIn 3,212 PD cases of European ancestry, we performed a genome-wide association study (GWAS) examining 2 complementary outcome traits derived from the Unified Parkinson's Disease Rating Scale, including dichotomous motor subtype (TD vs PIGD) or a continuous tremor/PIGD score ratio. Logistic or linear regression models were adjusted for sex, age at onset, disease duration, and 5 ancestry principal components, followed by meta-analysis.ResultsAmong 71 established PD risk variants, we detected multiple suggestive associations with PD motor subtype, including GPNMB (rs199351, psubtype = 0.01, pratio = 0.03), SH3GL2 (rs10756907, psubtype = 0.02, pratio = 0.01), HIP1R (rs10847864, psubtype = 0.02), RIT2 (rs12456492, psubtype = 0.02), and FBRSL1 (rs11610045, psubtype = 0.02). A PD genetic risk score integrating all 71 PD risk variants was also associated with subtype ratio (p = 0.026, ß = -0.04, 95% confidence interval = -0.07-0). Based on top results of our GWAS, we identify a novel suggestive association at the STK32B locus (rs2301857, pratio = 6.6 × 10-7), which harbors an independent risk allele for essential tremor.ConclusionsMultiple PD risk alleles may also modify clinical manifestations to influence PD motor subtype. The discovery of a novel variant at STK32B suggests a possible overlap between genetic risk for essential tremor and tremor-dominant PD.
UR - http://www.scopus.com/inward/record.url?scp=85116732513&partnerID=8YFLogxK
U2 - 10.1212/NXG.0000000000000557
DO - 10.1212/NXG.0000000000000557
M3 - Article
AN - SCOPUS:85116732513
SN - 2376-7839
VL - 7
JO - Neurology: Genetics
JF - Neurology: Genetics
IS - 2
M1 - e557
ER -