Genetic modifiers of risk and age at onset in GBA associated Parkinson’s disease and Lewy body dementia

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Abstract

Variation in GBA confers a spectrum of increased risk for Parkinson’s disease. Blauwendraat et al. report that an individual’s overall Parkinson’s disease genetic risk score modifies the effect of GBA variants on disease risk and age at onset. Genes implicated in lysosomal function exert the most influence on GBA-associated risk.

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Most cited references 21

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FlashPCA2: principal component analysis of biobank-scale genotype datasets.

Gad Abraham, Yixuan Qiu, Michael Inouye (2017)

Principal component analysis (PCA) is a crucial step in quality control of genomic data and a common approach for understanding population genetic structure. With the advent of large genotyping studies involving hundreds of thousands of individuals, standard approaches are no longer feasible. However, when the full decomposition is not required, substantial computational savings can be made. We present FlashPCA2, a tool that can perform partial PCA on 1 million individuals faster than competing approaches, while requiring substantially less memory.

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Parkinson's disease age at onset genome‐wide association study: Defining heritability, genetic loci, and α‐synuclein mechanisms

Cornelis Blauwendraat, Karl Heilbron, Costanza Vallerga … (2019)

Increasing evidence supports an extensive and complex genetic contribution to PD. Previous genome-wide association studies (GWAS) have shed light on the genetic basis of risk for this disease. However, the genetic determinants of PD age at onset are largely unknown.

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Large-scale screening of the Gaucher's disease-related glucocerebrosidase gene in Europeans with Parkinson's disease.

, Alexis Brice, Suzanne Lesage … (2011)

Pathogenic variants in the glucocerebrosidase gene (GBA) encoding the enzyme deficient in Gaucher's disease (GD) are associated with Parkinson's disease (PD). To investigate the sequence variants, their association with PD and the related phenotypes in a large cohort of European, mostly French, patients and controls, we sequenced all exons of GBA in 786 PD patients from 525 unrelated multiplex families, 605 patients with apparently sporadic PD and 391 ethnically matched controls. GBA mutations were significantly more frequent (odds ratio=6.98, 95% confidence interval 2.54-19.21; P=0.00002) in the PD patients (76/1130=6.7%) than in controls (4/391=1.0%) and in patients with family histories of PD (8.4%) than in isolated cases (5.3%). Twenty-eight different mutations were identified in patient and control groups, including seven novel variants. N370S and L444P accounted for 70% of all mutant alleles in the patient group. PD patients with GBA mutations more frequently had bradykinesia as the presenting symptom and levodopa-induced dyskinesias. The phenotype was similar in patients with one, two or complex GBA mutations, although the two patients with c.1263del+RecTL and N370S/RecΔ55 mutations had signs of GD. Segregation analyses in 21 multiplex families showed that 17% of the affected relatives did not carry GBA mutations found in the given family, indicating heterogeneity of the aetiology, but 46% of the unaffected relatives were GBA mutation carriers. These genotype and clinical analyses on the largest homogeneous sample of European patients studied to date confirmed that GBA mutations are the most common genetic risk factor for PD, particularly in familial forms.

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Author and article information

Journal

Title: Brain

Publisher: Oxford University Press (OUP)

ISSN (Print): 0006-8950

ISSN (Electronic): 1460-2156

Publication date Created: January 2020

Publication date Created: January 01 2020

Publication date Created: November 22 2019

Publication date Other: January 2020

Publication date (Print): January 01 2020

Publication date (Electronic): November 22 2019

Volume: 143

Issue: 1

Pages: 234-248

Affiliations

[1 ]Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA

[2 ]Department of Human Genetics, McGill University, Montreal, Quebec, Canada

[3 ]Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada

[4 ]23andMe, Inc., Mountain View, CA, USA

[5 ]Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK

[6 ]Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA

[7 ]Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, New York, NY, USA

[8 ]Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

[9 ]Department of Neurology, Sheba Medical Center, Tel Hashomer, Israel

[10 ]Movement Disorders Institute, Sheba Medical Center, Tel Hashomer, Israel

[11 ]The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer, Israel

[12 ]The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel

[13 ]Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA

[14 ]Department of Neurology, Oslo University Hospital, Oslo, Norway

[15 ]Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands

[16 ]Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany

[17 ]German Center for Neurodegenerative Diseases (DZNE), Tuebingen, Germany

[18 ]Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tubingen, Germany

[19 ]Institute of Clinical Medicine, Department of Neurology, University of Oulu, Oulu, Finland

[20 ]Department of Neurology and Medical Research Center, Oulu University Hospital, Oulu, Finland

[21 ]Department of Neurology, Helsinki University Hospital, and Molecular Neurology, Research Programs Unit, Biomedicum, University of Helsinki, Helsinki, Finland

[22 ]Neuroregeneration and Stem Cell Program, Institute for Cell Engineering, Johns Hopkins University Medical Center, Baltimore, MD, USA

[23 ]Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA

[24 ]Laboratory of Behavioral Neuroscience, National Institute on Aging, Baltimore, MD, USA

[25 ]Longitudinal Studies Section, National Institute on Aging, Baltimore, MD, USA

[26 ]Newcastle Brain Tissue Resource, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK

[27 ]Department of Pathology (Neuropathology, Johns Hopkins University Medical Center, Baltimore, MD, USA

[28 ]Department of Neurology, Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK

[29 ]Inserm U1127, Sorbonne Universités, UPMC Univ Paris 06 UMR S1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France

[30 ]Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK

[31 ]Department of Neurodegenerative Diseases, UCL Queen Square Institute of Neurology, London, UK

[32 ]Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA

[33 ]Department of Neurology, Baylor College of Medicine, Houston, USA

[34 ]Departments of Molecular and Human Genetics and Neuroscience, Baylor College of Medicine, Houston, USA

[35 ]Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, USA

[36 ]Data Tecnica International, Glen Echo, MD, USA

[37 ]Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada

Article

DOI: 10.1093/brain/awz350

PMC ID: 6935749

PubMed ID: 31755958

SO-VID: 65a77b74-c9b0-4bfa-a387-56e6d62fc9b9

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Genetic modifiers of risk and age at onset in GBA associated Parkinson’s disease and Lewy body dementia

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Most cited references 21

FlashPCA2: principal component analysis of biobank-scale genotype datasets.

Parkinson's disease age at onset genome‐wide association study: Defining heritability, genetic loci, and α‐synuclein mechanisms

Large-scale screening of the Gaucher's disease-related glucocerebrosidase gene in Europeans with Parkinson's disease.

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