Genomewide association study of Parkinson's disease clinical biomarkers in 12 longitudinal patients' cohorts

Hirotaka Iwaki; Cornelis Blauwendraat; Hampton L Leonard; Jonggeol J Kim; Ganqiang Liu; Jodi Maple-Grødem; Jean-Christophe Corvol; Lasse Pihlstrøm; Marlies van Nimwegen; Samantha J Hutten; Khanh-Dung H Nguyen; Jacqueline Rick; Shirley Eberly; Faraz Faghri; Peggy Auinger; Kirsten M Scott; Ruwani Wijeyekoon; Vivianna M Van Deerlin; Dena G Hernandez; J Raphael Gibbs; International Parkinson's Disease Genomics Consortium; Kumaraswamy Naidu Chitrala; Aaron G Day-Williams; Alexis Brice; Guido Alves; Alastair J Noyce; Ole-Bjørn Tysnes; Jonathan R Evans; David P Breen; Karol Estrada; Claire E Wegel; Fabrice Danjou; David K Simon; Ole Andreassen; Bernard Ravina; Mathias Toft; Peter Heutink; Bastiaan R Bloem; Daniel Weintraub; Roger A Barker; Caroline H Williams-Gray; Bart P van de Warrenburg; Jacobus J Van Hilten; Clemens R Scherzer; Andrew B Singleton; Mike A Nalls

doi:10.1002/mds.27845

Genomewide association study of Parkinson's disease clinical biomarkers in 12 longitudinal patients' cohorts

Mov Disord. 2019 Dec;34(12):1839-1850. doi: 10.1002/mds.27845. Epub 2019 Sep 10.

Authors

Hirotaka Iwaki^{1

2}, Cornelis Blauwendraat¹, Hampton L Leonard^{1

2}, Jonggeol J Kim¹, Ganqiang Liu^{3

4

5}, Jodi Maple-Grødem^{6

7}, Jean-Christophe Corvol⁸, Lasse Pihlstrøm⁹, Marlies van Nimwegen¹⁰, Samantha J Hutten¹¹, Khanh-Dung H Nguyen¹², Jacqueline Rick¹³, Shirley Eberly¹⁴, Faraz Faghri^{1

15}, Peggy Auinger¹⁶, Kirsten M Scott¹⁷, Ruwani Wijeyekoon¹⁷, Vivianna M Van Deerlin¹⁸, Dena G Hernandez¹, J Raphael Gibbs¹; International Parkinson's Disease Genomics Consortium; Kumaraswamy Naidu Chitrala¹⁹, Aaron G Day-Williams^{20

21}, Alexis Brice^{22

23

24}, Guido Alves^{6

7

25}, Alastair J Noyce^{26

27}, Ole-Bjørn Tysnes^{28

29}, Jonathan R Evans³⁰, David P Breen^{31

32

33}, Karol Estrada¹², Claire E Wegel³⁴, Fabrice Danjou²², David K Simon^{35

36}, Ole Andreassen^{37

38}, Bernard Ravina^{39

40}, Mathias Toft^{9

41}, Peter Heutink^{42

43}, Bastiaan R Bloem¹⁰, Daniel Weintraub^{44

45}, Roger A Barker⁴⁶, Caroline H Williams-Gray⁴⁶, Bart P van de Warrenburg¹⁰, Jacobus J Van Hilten⁴⁷, Clemens R Scherzer^{4

5}, Andrew B Singleton¹, Mike A Nalls^{1

2}

Affiliations

¹ Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.
² Data Tecnica International, Glen Echo, Maryland, USA.
³ School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China.
⁴ Advanced Center for Parkinson's Disease Research, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁵ Precision Neurology Program, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts, USA.
⁶ The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway.
⁷ Department of Chemistry, Bioscience and Environmental Engineering, University in Stavanger, Stavanger, Norway.
⁸ Assistance-Publique Hôpitaux de Paris, ICM, INSERM UMRS 1127, CNRS 7225, ICM, Department of Neurology and CIC Neurosciences, Pitié-Salpêtrière Hospital, Paris, France.
⁹ Department of Neurology, Oslo University Hospital, Oslo, Norway.
¹⁰ Radboud University Medical Centre, Donders Institute for Brain, Cognition, and Behaviour; Department of Neurology, Nijmegen, The Netherlands.
¹¹ The Michael J. Fox Foundation for Parkinson's Research, New York, New York, USA.
¹² Translational Genome Sciences, Biogen, Cambridge, Massachusetts, USA.
¹³ Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹⁴ Department of Biostatistics and Computational Biology, University of Rochester, Rochester, New York, USA.
¹⁵ Department of Computer Science, University of Illinois Urbana-Champaign, Champaign, Illinois, USA.
¹⁶ Department of Neurology, Center for Health + Technology, University of Rochester, Rochester, New York, USA.
¹⁷ Department of Clinical Neurosciences, University of Cambridge, John van Geest Centre for Brain Repair, Cambridge, United Kingdom.
¹⁸ Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Parelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹⁹ Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.
²⁰ Flagship Labs 60 Inc, Cambridge, Massachusetts, USA.
²¹ Statistical Genetics, Biogen, Cambridge, Massachusetts, USA.
²² Institut du cerveau et de la moelle épinière ICM, Paris, France.
²³ Sorbonne Université SU, Paris, France.
²⁴ INSERM UMR1127, Paris, France.
²⁵ Department of Neurology, Stavanger University Hospital, Stavanger, Norway.
²⁶ Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, United Kingdom.
²⁷ Department of Clinical and Movement Neurosciences, UCL Institute of Neurology, London, United Kingdom.
²⁸ Department of Neurology, Haukeland University Hospital, Bergen, Norway.
²⁹ University of Bergen, Bergen, Norway.
³⁰ Department of Neurology, Nottingham University NHS Trust, Nottingham, United Kingdom.
³¹ Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, Scotland.
³² Anne Rowling Regenerative Neurology Clinic, University of Edinburgh, Edinburgh, Scotland.
³³ Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland.
³⁴ Department of Medical and Molecular Genetics, Indiana University, Indianapolis, Indiana, USA.
³⁵ Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
³⁶ Harvard Medical School, Boston, Massachusetts, USA.
³⁷ NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, Norway, Norway.
³⁸ Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway, Norway.
³⁹ Voyager Therapeutics, Cambridge, Massachusetts, USA.
⁴⁰ Department of Neurology, University of Rochester School of Medicine, Rochester, New York, USA.
⁴¹ Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁴² German Center for Neurodegenerative Diseases-Tubingen, Tuebingen, Germany.
⁴³ HIH Tuebingen, Tubingen, Tuebingen, Germany.
⁴⁴ Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
⁴⁵ Department of Veterans Affairs, Philadelphia, Pennsylvania, USA.
⁴⁶ Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
⁴⁷ Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.

Abstract

Background: Several reports have identified different patterns of Parkinson's disease progression in individuals carrying missense variants in GBA or LRRK2 genes. The overall contribution of genetic factors to the severity and progression of Parkinson's disease, however, has not been well studied.

Objectives: To test the association between genetic variants and the clinical features of Parkinson's disease on a genomewide scale.

Methods: We accumulated individual data from 12 longitudinal cohorts in a total of 4093 patients with 22,307 observations for a median of 3.81 years. Genomewide associations were evaluated for 25 cross-sectional and longitudinal phenotypes. Specific variants of interest, including 90 recently identified disease-risk variants, were also investigated post hoc for candidate associations with these phenotypes.

Results: Two variants were genomewide significant. Rs382940(T>A), within the intron of SLC44A1, was associated with reaching Hoehn and Yahr stage 3 or higher faster (hazard ratio 2.04 [1.58-2.62]; P value = 3.46E-8). Rs61863020(G>A), an intergenic variant and expression quantitative trait loci for α-2A adrenergic receptor, was associated with a lower prevalence of insomnia at baseline (odds ratio 0.63 [0.52-0.75]; P value = 4.74E-8). In the targeted analysis, we found 9 associations between known Parkinson's risk variants and more severe motor/cognitive symptoms. Also, we replicated previous reports of GBA coding variants (rs2230288: p.E365K; rs75548401: p.T408M) being associated with greater motor and cognitive decline over time, and an APOE E4 tagging variant (rs429358) being associated with greater cognitive deficits in patients.

Conclusions: We identified novel genetic factors associated with heterogeneity of Parkinson's disease. The results can be used for validation or hypothesis tests regarding Parkinson's disease. © 2019 International Parkinson and Movement Disorder Society.

Keywords: Apolipoprotein E; GBA; Parkinson's disease; genomewide association study.

Publication types

Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Aged, 80 and over
Antigens, CD / genetics
Biomarkers
Cognitive Dysfunction / etiology
Cognitive Dysfunction / genetics
Cognitive Dysfunction / psychology
Cohort Studies
Cross-Sectional Studies
Disease Progression
Female
Genome-Wide Association Study*
Glucosylceramidase / genetics
Humans
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics
Longitudinal Studies
Male
Middle Aged
Organic Cation Transport Proteins / genetics
Parkinson Disease / genetics*
Parkinson Disease / psychology
Phenotype
Risk Assessment

Substances

Antigens, CD
Biomarkers
Organic Cation Transport Proteins
SLC44A1 protein, human
LRRK2 protein, human
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
GBA protein, human
Glucosylceramidase

Abstract

Publication types

MeSH terms

Substances

Grants and funding