Two recent studies suggested that the APOE ε4 haplotype was associated with increased α-synuclein pathology in cell and mouse models. Genetic variants in the SNCA region have strong association with Parkinson's disease (PD), dementia with Lewy bodies (DLB) and idiopathic REM sleep behaviour disorder (iRBD), while APOE is a genetic risk determinant for only DLB. To determine if genetic-level interactions between SNCA and APOE exists that can explain the protein-level association, we investigated the genotypic interaction of APOE and SNCA in cohorts of PD, DLB and iRBD. We analysed genome-wide association study (GWAS) data from 5229 PD patients and 5480 controls, 2610 DLB patients and 1920 controls, and 1055 iRBD patients and 3667 controls. We used logistic regression interaction models across all three cohorts independently between the (i) top GWAS signals of SNCA single nucleotide polymorphisms (SNPs) and APOE haplotypes and (ii) SNP×SNP and three-way SNP interaction across the entire coding region plus 200 kb flanking each gene. No significant interactions were found to be associated with any of the synucleinopathies after correction for multiple testing. Our results do not support a role for genetic interactions between APOE and SNCA across PD, DLB and iRBD. Since the tested genetic variants affect the expression and function of these proteins, it is likely that any interactions between them do not affect the risk of PD, DLB and iRBD.

Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge MA 02142 USA

Centre d'Études Avancées en Médecine du Sommeil Hôpital du Sacré Cœur de Montréal Montreal Quebec Canada H4J 1C5

CHU Sainte Justine University of Montreal Montreal Quebec Canada H3T 1C5

Clinical Neurology Unit Department of Head and Neck University Hospital of Udine Udine 33100 Italy

Department of Biomedical and Neuromotor Sciences Alma Mater Studiorum University of Bologna Bologna 40126 Italy

Department of Clinical Neurophysiology and Sleep Center University of Lille Nord de France Centre Hospitalier Universitaire Lille Lille 59045 France

Department of Engineering and Medicine of Innovation University of Verona Verona 37134 Italy

Department of Human Genetics McGill University Montreal Quebec Canada H3A 1Y2

Department of Medical Sciences and Public Health Sleep Disorder Research Center University of Cagliari Cagliari 09042 Italy

Department of Medicine University of Udine Udine 121 08 Italy

Department of Neurological Sciences Università Vita Salute San Raffaele Milan 20132 Italy

Department of Neurology and Centre of Clinical Neuroscience 1st Faculty of Medicine and General University Hospital Charles University Prague 121 08 Czech Republic

Department of Neurology and Clinical Research Institute for Neuroscience Johannes Kepler University Linz Linz 4020 Austria

Department of Neurology and Neurosurgery McGill University Montreal Quebec Canada H3A 2B4

Department of Neurology Johns Hopkins University School of Medicine Baltimore MD 21287 USA

Department of Neurology Mayo Clinic Rochester MN 55905 USA

Department of Neurology Philipps University Marburg Marburg 35032 Germany

Department of Neurology Sint Dimpna Regional Hospital Geel 2440 Belgium

Department of Neurology University Hospital Antwerp Edegem Antwerp 2650 Belgium

Department of Neurology University Medical Center Göttingen Göttingen 37075 Germany

Department of Neurosciences Université de Montréal Montreal Quebec Canada H3C 3J7

Department of Psychiatry Université de Montréal Montreal Quebec Canada H3T 1J4

Department of Psychology Université du Québec à Montréal Montreal Quebec Canada H2X 3JB

EuroMov Research Laboratory University of Montpellier Montpellier 34090 France

IRCCS Institute of Neurological Sciences of Bologna Bologna 40139 Italy

Laboratory for Sleep Disorders Sint Dimpna Regional Hospital Geel 2440 Belgium

Montreal Neurological Institute McGill University Montreal Quebec Canada H3A 1A1

National Reference Center for Narcolepsy Sleep Unit Department of Neurology Gui de Chauliac Hospital Centre Hospitalier Universitaire Montpellier University of Montpellier INSERM U1061 Montpellier 34090 France

Neurodegenerative Diseases Research Section National Institute of Neurological Disorders and Stroke Bethesda MD 20892 USA

Nuffield Department of Clinical Neurosciences University of Oxford Oxford OX3 9DU UK

Oxford Parkinson's Disease Centre University of Oxford Oxford OX1 3QX UK

Paracelsus Elena Klinik Kassel 34128 Germany

Sleep and Neurology Unit Beau Soleil Clinic Montpellier 34070 France

Sleep Disorder Unit Carémeau Hospital Centre Hospitalier Universitaire Nîmes Nîmes 30029 France

Sleep Disorders Clinic Department of Neurology Medical University of Innsbruck Innsbruck 6020 Austria

Sleep Disorders Unit Pitié Salpêtrière Hospital Centre de Recherche de l'Institut du Cerveau et de la Moelle Épinière and Sorbonne Universités Paris 75013 France

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