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

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Abstract

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.

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Most cited references 18

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β2-Adrenoreceptor is a regulator of the α-synuclein gene driving risk of Parkinson’s disease

Yang K Xiang, Elizabeth Long, Ming Jin … (2017)

Copy number mutations implicate excess production of α-synuclein as a possibly causative factor in Parkinson's disease (PD). Using an unbiased screen targeting endogenous gene expression, we discovered that the β2-adrenoreceptor (β2AR) is a regulator of the α-synuclein gene (SNCA). β2AR ligands modulate SNCA transcription through histone 3 lysine 27 acetylation of its promoter and enhancers. Over 11 years of follow-up in 4 million Norwegians, the β2AR agonist salbutamol, a brain-penetrant asthma medication, was associated with reduced risk of developing PD (rate ratio, 0.66; 95% confidence interval, 0.58 to 0.76). Conversely, a β2AR antagonist correlated with increased risk. β2AR activation protected model mice and patient-derived cells. Thus, β2AR is linked to transcription of α-synuclein and risk of PD in a ligand-specific fashion and constitutes a potential target for therapies.

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Association of GBA Mutations and the E326K Polymorphism With Motor and Cognitive Progression in Parkinson Disease.

Marie Davis, Catherine Johnson, James Leverenz … (2016)

Parkinson disease (PD) is heterogeneous in symptom manifestation and rate of progression. Identifying factors that influence disease progression could provide mechanistic insight, improve prognostic accuracy, and elucidate novel therapeutic targets.

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APOE, MAPT, and SNCA genes and cognitive performance in Parkinson disease.

Tsai-Shu Hu, Marnie L. Peterson, João F. Mata … (2014)

Cognitive impairment is a common and disabling problem in Parkinson disease (PD) that is not well understood and is difficult to treat. Identification of genetic variants that influence the rate of cognitive decline or pattern of early cognitive deficits in PD might provide a clearer understanding of the etiopathogenesis of this important nonmotor feature. To determine whether common variation in the APOE, MAPT, and SNCA genes is associated with cognitive performance in patients with PD. We studied 1079 PD patients from 6 academic centers in the United States who underwent assessments of memory (Hopkins Verbal Learning Test-Revised [HVLT-R]), attention and executive function (Letter-Number Sequencing Test and Trail Making Test), language processing (semantic and phonemic verbal fluency tests), visuospatial skills (Benton Judgment of Line Orientation test), and global cognitive function (Montreal Cognitive Assessment). Participants underwent genotyping for the APOE ε2/ε3/ε4 alleles, MAPT H1/H2 haplotypes, and SNCA rs356219. We used linear regression to test for association between genotype and baseline cognitive performance with adjustment for age, sex, years of education, disease duration, and site. We used a Bonferroni correction to adjust for the 9 comparisons that were performed for each gene. Nine variables derived from 7 psychometric tests. The APOE ε4 allele was associated with lower performance on the HVLT-R Total Recall (P = 6.7 × 10(-6); corrected P [Pc] = 6.0 × 10(-5)), Delayed Recall (P = .001; Pc = .009), and Recognition Discrimination Index (P = .004; Pc = .04); a semantic verbal fluency test (P = .002; Pc = .02); the Letter-Number Sequencing Test (P = 1 × 10(-5); Pc = 9 × 10(-5)); and Trail Making Test B minus Trail Making Test A (P = .002; Pc = .02). In a subset of 645 patients without dementia, the APOE ε4 allele was associated with lower scores on the HVLT-R Total Recall (P = .005; Pc = .045) and the semantic verbal fluency (P = .005; Pc = .045) measures. Variants of MAPT and SNCA were not associated with scores on any tests. Our data indicate that the APOE ε4 allele is an important predictor of cognitive function in PD across multiple domains. Among PD patients without dementia, the APOE ε4 allele was only associated with lower performance on word list learning and semantic verbal fluency, a pattern more typical of the cognitive deficits seen in early Alzheimer disease than PD.

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Author and article information

Journal

Title: Movement Disorders

Abbreviated Title: Mov Disord

Publisher: Wiley

ISSN (Print): 0885-3185

ISSN (Electronic): 1531-8257

Publication date Created: September 10 2019

Publication date Created: December 2019

Publication date (Electronic): September 10 2019

Publication date (Print): December 2019

Volume: 34

Issue: 12

Pages: 1839-1850

Affiliations

[1 ]Laboratory of Neurogenetics, National Institute on AgingNational Institutes of Health, Bethesda Maryland USA

[2 ]Data Tecnica International Glen Echo Maryland USA

[3 ]School of MedicineSun Yat‐sen University Guangzhou Guangdong China

[4 ]Advanced Center for Parkinson's Disease ResearchBrigham and Women's Hospital and Harvard Medical School Boston Massachusetts USA

[5 ]Precision Neurology Program, Harvard Medical SchoolBrigham and Women's Hospital Boston Massachusetts USA

[6 ]The Norwegian Centre for Movement DisordersStavanger University Hospital Stavanger Norway

[7 ]Department of Chemistry, Bioscience and Environmental EngineeringUniversity in Stavanger Stavanger Norway

[8 ]Assistance‐Publique Hôpitaux de Paris, ICM, INSERM UMRS 1127, CNRS 7225, ICM, Department of Neurology and CIC NeurosciencesPitié‐Salpêtrière Hospital Paris France

[9 ]Department of NeurologyOslo University Hospital Oslo Norway

[10 ]Radboud University Medical CentreDonders 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 NeurologyUniversity of Pennsylvania Philadelphia Pennsylvania USA

[14 ]Department of Biostatistics and Computational BiologyUniversity of Rochester Rochester New York USA

[15 ]Department of Computer ScienceUniversity of Illinois Urbana‐Champaign Champaign Illinois USA

[16 ]Department of Neurology, Center for Health + TechnologyUniversity of Rochester Rochester New York USA

[17 ]Department of Clinical NeurosciencesUniversity of Cambridge, John van Geest Centre for Brain Repair Cambridge United Kingdom

[18 ]Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease ResearchParelman School of Medicine at the University of Pennsylvania Philadelphia Pennsylvania USA

[19 ]Laboratory of Epidemiology and Population Sciences, National Institute on AgingNational 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 NeurologyStavanger University Hospital Stavanger Norway

[26 ]Preventive Neurology Unit, Wolfson Institute of Preventive MedicineQueen Mary University of London London United Kingdom

[27 ]Department of Clinical and Movement NeurosciencesUCL Institute of Neurology London United Kingdom

[28 ]Department of NeurologyHaukeland University Hospital Bergen Norway

[29 ]University of Bergen Bergen Norway

[30 ]Department of NeurologyNottingham University NHS Trust Nottingham United Kingdom

[31 ]Centre for Clinical Brain SciencesUniversity of Edinburgh Edinburgh Scotland

[32 ]Anne Rowling Regenerative Neurology ClinicUniversity of Edinburgh Edinburgh Scotland

[33 ]Usher Institute of Population Health Sciences and InformaticsUniversity of Edinburgh Edinburgh Scotland

[34 ]Department of Medical and Molecular GeneticsIndiana University Indianapolis Indiana USA

[35 ]Department of NeurologyBeth Israel Deaconess Medical Center Boston Massachusetts USA

[36 ]Harvard Medical School Boston Massachusetts USA

[37 ]NORMENT, Institute of Clinical MedicineUniversity of Oslo Oslo Norway Norway

[38 ]Division of Mental Health and AddictionOslo University Hospital Oslo Norway Norway

[39 ]Voyager Therapeutics Cambridge Massachusetts USA

[40 ]Department of NeurologyUniversity of Rochester School of Medicine Rochester New York USA

[41 ]Institute of Clinical MedicineUniversity of Oslo Oslo Norway

[42 ]German Center for Neurodegenerative Diseases‐Tubingen Tuebingen Germany

[43 ]HIH Tuebingen Tubingen Tuebingen Germany

[44 ]Department of PsychiatryUniversity of Pennsylvania School of Medicine Philadelphia Pennsylvania USA

[45 ]Department of Veterans Affairs Philadelphia Pennsylvania USA

[46 ]Department of Clinical NeurosciencesUniversity of Cambridge Cambridge United Kingdom

[47 ]Department of NeurologyLeiden University Medical Center Leiden The Netherlands

Article

DOI: 10.1002/mds.27845

PMC ID: 7017876

PubMed ID: 31505070

SO-VID: 8cf3371d-8d28-489d-a19b-7a5df2e1c513

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http://onlinelibrary.wiley.com/termsAndConditions#vor

http://doi.wiley.com/10.1002/tdm_license_1.1

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

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Abstract

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Journal of Circulating Biomarkers

Most cited references 18

β2-Adrenoreceptor is a regulator of the α-synuclein gene driving risk of Parkinson’s disease

Association of GBA Mutations and the E326K Polymorphism With Motor and Cognitive Progression in Parkinson Disease.

APOE, MAPT, and SNCA genes and cognitive performance in Parkinson disease.

Author and article information

Journal

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Article

History

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Cited by 56

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