title: Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing.
abstract: Whole-exome sequencing (WES) has been successful in identifying genes that cause familial Parkinson's disease (PD). However, until now this approach has not been deployed to study large cohorts of unrelated participants. To discover rare PD susceptibility variants, we performed WES in 1148 unrelated cases and 503 control participants. Candidate genes were subsequently validated for functions relevant to PD based on parallel RNA-interference (RNAi) screens in human cell culture and Drosophila and C. elegans models.
  
  
  
  Assuming autosomal recessive inheritance, we identify 27 genes that have homozygous or compound heterozygous loss-of-function variants in PD cases. Definitive replication and confirmation of these findings were hindered by potential heterogeneity and by the rarity of the implicated alleles. We therefore looked for potential genetic interactions with established PD mechanisms. Following RNAi-mediated knockdown, 15 of the genes modulated mitochondrial dynamics in human neuronal cultures and four candidates enhanced α-synuclein-induced neurodegeneration in Drosophila. Based on complementary analyses in independent human datasets, five functionally validated genes-GPATCH2L, UHRF1BP1L, PTPRH, ARSB, and VPS13C-also showed evidence consistent with genetic replication.
  
  
  
  By integrating human genetic and functional evidence, we identify several PD susceptibility gene candidates for further investigation. Our approach highlights a powerful experimental strategy with broad applicability for future studies of disorders with complex genetic etiologies.
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller-Str. 23, Tübingen, 72076, Germany.|Department of Clinical Genetics, VU University Medical Center, Amsterdam, 1081HZ, The Netherlands.
authors.forename: Iris E
authors.initials: IE
authors.lastname: Jansen
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Ye
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller-Str. 23, Tübingen, 72076, Germany.
authors.forename: Sasja
authors.initials: S
authors.lastname: Heetveld
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller-Str. 23, Tübingen, 72076, Germany.|Graduate School of Cellular & Molecular Neuroscience, Tübingen, 72074, Germany.
authors.forename: Marie C
authors.initials: MC
authors.lastname: Lechler
authors.affiliation: European Research Institute for the Biology of Aging, University of Groningen, University Medical Centre Groningen, Groningen, 9700AD, The Netherlands.
authors.forename: Helen
authors.initials: H
authors.lastname: Michels
authors.affiliation: European Research Institute for the Biology of Aging, University of Groningen, University Medical Centre Groningen, Groningen, 9700AD, The Netherlands.
authors.forename: Renée I
authors.initials: RI
authors.lastname: Seinstra
authors.affiliation: Department of Clinical Neuroscience, UCL Institute of Neurology, London, UK.|Northwestern University Feinberg School of Medicine, Ken and Ruth Davee Department of Neurology, Chicago, IL, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Lubbe
authors.affiliation: Inserm U1127, CNRS UMR7225, Sorbonne Universités, UPMC Univ Paris 06, UMR_S1127, Institut du Cerveau et de la Moelle épinière, Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Drouet
authors.affiliation: Inserm U1127, CNRS UMR7225, Sorbonne Universités, UPMC Univ Paris 06, UMR_S1127, Institut du Cerveau et de la Moelle épinière, Paris, France.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Lesage
authors.affiliation: Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
authors.forename: Elisa
authors.initials: E
authors.lastname: Majounie
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
authors.forename: J Raphael
authors.initials: JR
authors.lastname: Gibbs
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
authors.forename: Mike A
authors.initials: MA
authors.lastname: Nalls
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.|Department of Medical & Molecular Genetics, King's College London, London, UK.
authors.forename: Mina
authors.initials: M
authors.lastname: Ryten
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Juan A
authors.initials: JA
authors.lastname: Botia
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Jana
authors.initials: J
authors.lastname: Vandrovcova
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller-Str. 23, Tübingen, 72076, Germany.|Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Javier
authors.initials: J
authors.lastname: Simon-Sanchez
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller-Str. 23, Tübingen, 72076, Germany.
authors.forename: Melissa
authors.initials: M
authors.lastname: Castillo-Lizardo
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller-Str. 23, Tübingen, 72076, Germany.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Rizzu
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller-Str. 23, Tübingen, 72076, Germany.
authors.forename: Cornelis
authors.initials: C
authors.lastname: Blauwendraat
authors.affiliation: Department of Neurology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Amit K
authors.initials: AK
authors.lastname: Chouhan
authors.affiliation: Department of Neurology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Yarong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Neurology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Puja
authors.initials: P
authors.lastname: Yogi
authors.affiliation: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Najaf
authors.initials: N
authors.lastname: Amin
authors.affiliation: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.affiliation: Department of Clinical Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Huw R
authors.initials: HR
authors.lastname: Morris
authors.affiliation: Inserm U1127, CNRS UMR7225, Sorbonne Universités, UPMC Univ Paris 06, UMR_S1127, Institut du Cerveau et de la Moelle épinière, Paris, France.|Assistance Publique Hôpitaux de Paris, Hôpital de la Salpêtrière, Département de Génétique et Cytogénétique, Paris, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Singleton
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller-Str. 23, Tübingen, 72076, Germany.
authors.forename: Della C
authors.initials: DC
authors.lastname: David
authors.affiliation: European Research Institute for the Biology of Aging, University of Groningen, University Medical Centre Groningen, Groningen, 9700AD, The Netherlands.
authors.forename: Ellen A
authors.initials: EA
authors.lastname: Nollen
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller-Str. 23, Tübingen, 72076, Germany.
authors.forename: Shushant
authors.initials: S
authors.lastname: Jain
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. Joshua.Shulman@bcm.edu.|Department of Neurology, Baylor College of Medicine, Houston, TX, USA. Joshua.Shulman@bcm.edu.|Department of Neuroscience and Program in Developmental Biology, Baylor College of Medicine, Houston, TX, USA. Joshua.Shulman@bcm.edu.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, 1250 Moursund St., N.1150, Houston, TX, 77030, USA. Joshua.Shulman@bcm.edu.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Shulman
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller-Str. 23, Tübingen, 72076, Germany. Peter.Heutink@dzne.de.|Department of Clinical Genetics, VU University Medical Center, Amsterdam, 1081HZ, The Netherlands. Peter.Heutink@dzne.de.|Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. Peter.Heutink@dzne.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Heutink
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000235:genetics; D016022:Case-Control Studies; D002478:Cells, Cultured; D002648:Child; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000235:genetics; D059472:Exome; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008875:Middle Aged; D010300:Parkinson Disease / Q000235:genetics*; D034622:RNA Interference; D017422:Sequence Analysis, DNA / Q000379:methods*; D055815:Young Adult; D051844:alpha-Synuclein / Q000235:genetics*
chemical_list: D051844:alpha-Synuclein
keywords: Animal model; Functional screening; Genomics; Loss-of-function; Mitochondria; Parkin; Parkinson’s disease; Rare variants; Whole-exome sequencing; α-synuclein