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Genome Biol. 2017 Jan 30;18(1):22. doi: 10.1186/s13059-017-1147-9.

Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing.

Collaborators (135)

Nalls MA, Plagnol V, Hernandez DG, Sharma M, Sheerin UM, Saad M, SimónSánchez J, Schulte C, Lesage S, Sveinbjörnsdóttir S, Arepalli S, Barker R, Ben-Shlomo Y, Berendse HW, Berg D, Bhatia K, de Bie RM, Biffi A, Bloem B, Bochdanovits Z, Bonin M, Bras JM, Brockmann K, Brooks J, Burn DJ, Majounie E, Lubbe S, Jansen IE, Price R, Nicolas A, Charlesworth G, Lungu C, Chen H, Chinnery PF, Chong S, Clarke CE, Cookson MR, Cooper JM, Corvol JC, Counsell C, Damier P, Dartigues JF, Deloukas P, Deuschl G, Dexter DT, van Dijk KD, Dillman A, Durif F, Dürr A, Edkins S, Evans JR, Foltynie T, Dong J, Gardner M, Gibbs JR, Goate A, Gray E, Guerreiro R, Harris C, van Hilten JJ, Hofman A, Hollenbeck A, Holton J, Hu M, Wurster I, Mätzler W, Hudson G, Hunt SE, Huttenlocher J, Illig T, Jónsson PV, Lambert JC, Langford C, Lees A, Lichtner P, Limousin P, Lopez G, Lorenz D, Lungu C, McNeill A, Moorby C, Moore M, Morris HR, Morrison KE, Escott-Price V, Mudanohwo E, O'Sullivan SS, Pearson J, Perlmutter JS, Pétursson H, Pollak P, Post B, Potter S, Ravina B, Revesz T, Riess O, Rivadeneira F, Rizzu P, Ryten M, Sawcer S, Schapira A, Scheffer H, Shaw K, Shoulson I, Shulman J, Sidransky E, Smith C, Spencer CC, Stefánsson H, Bettella F, Stockton JD, Strange A, Talbot K, Tanner CM, Tashakkori-Ghanbaria A, Tison F, Trabzuni D, Traynor BJ, Uitterlinden AG, Velseboer D, Vidailhet M, Walker R, van de Warrenburg B, Wickremaratchi M, Williams N, Williams-Gray CH, Winder-Rhodes S, Stefánsson K, Martinez M, Wood NW, Hardy J, Heutink P, Brice A, Gasser T, Singleton AB.

Author information

1
German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller-Str. 23, Tübingen, 72076, Germany.
2
Department of Clinical Genetics, VU University Medical Center, Amsterdam, 1081HZ, The Netherlands.
3
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
4
Graduate School of Cellular & Molecular Neuroscience, Tübingen, 72074, Germany.
5
European Research Institute for the Biology of Aging, University of Groningen, University Medical Centre Groningen, Groningen, 9700AD, The Netherlands.
6
Department of Clinical Neuroscience, UCL Institute of Neurology, London, UK.
7
Northwestern University Feinberg School of Medicine, Ken and Ruth Davee Department of Neurology, Chicago, IL, USA.
8
Inserm U1127, CNRS UMR7225, Sorbonne Universités, UPMC Univ Paris 06, UMR_S1127, Institut du Cerveau et de la Moelle épinière, Paris, France.
9
Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
10
Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
11
Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
12
Department of Medical & Molecular Genetics, King's College London, London, UK.
13
Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
14
Department of Neurology, Baylor College of Medicine, Houston, TX, USA.
15
Genetic Epidemiology Unit, Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
16
Assistance Publique Hôpitaux de Paris, Hôpital de la Salpêtrière, Département de Génétique et Cytogénétique, Paris, France.
17
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. Joshua.Shulman@bcm.edu.
18
Department of Neurology, Baylor College of Medicine, Houston, TX, USA. Joshua.Shulman@bcm.edu.
19
Department of Neuroscience and Program in Developmental Biology, Baylor College of Medicine, Houston, TX, USA. Joshua.Shulman@bcm.edu.
20
Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, 1250 Moursund St., N.1150, Houston, TX, 77030, USA. Joshua.Shulman@bcm.edu.
21
German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller-Str. 23, Tübingen, 72076, Germany. Peter.Heutink@dzne.de.
22
Department of Clinical Genetics, VU University Medical Center, Amsterdam, 1081HZ, The Netherlands. Peter.Heutink@dzne.de.
23
Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. Peter.Heutink@dzne.de.

Abstract

BACKGROUND:

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.

RESULTS:

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.

CONCLUSIONS:

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.

KEYWORDS:

Animal model; Functional screening; Genomics; Loss-of-function; Mitochondria; Parkin; Parkinson’s disease; Rare variants; Whole-exome sequencing; α-synuclein

PMID:
28137300
PMCID:
PMC5282828
DOI:
10.1186/s13059-017-1147-9
[Indexed for MEDLINE]
Free PMC Article

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