A multi-centre clinico-genetic analysis of the VPS35 gene in Parkinson disease indicates reduced penetrance for disease-associated variants
Identifieur interne : 000A21 ( Pmc/Corpus ); précédent : 000A20; suivant : 000A22A multi-centre clinico-genetic analysis of the VPS35 gene in Parkinson disease indicates reduced penetrance for disease-associated variants
Auteurs : Manu Sharma ; John P A. Ioannidis ; Jan O. Aasly ; Grazia Annesi ; Alexis Brice ; Lars Bertram ; Maria Bozi ; Maria Barcikowska ; David Crosiers ; Carl E. Clarke ; Maurizio F. Facheris ; Matthew Farrer ; Gaetan Garraux ; Suzana Gispert ; Georg Auburger ; Carles Vilari O-Güell ; Georgios M. Hadjigeorgiou ; Andrew A. Hicks ; Nobutaka Hattori ; Beom S. Jeon ; Zygmunt Jamrozik ; Anna Krygowska-Wajs ; Suzanne Lesage ; Christina M. Lill ; Juei-Jueng Lin ; Timothy Lynch ; Peter Lichtner ; Anthony E. Lang ; Cecile Libioulle ; Miho Murata ; Vincent Mok ; Barbara Jasinska-Myga ; George D. Mellick ; Karen E. Morrison ; Thomas Meitnger ; Alexander Zimprich ; Grzegorz Opala ; Peter P. Pramstaller ; Irene Pichler ; Sung Sup Park ; Aldo Quattrone ; Ekaterina Rogaeva ; Owen A. Ross ; Leonidas Stefanis ; Joanne D. Stockton ; Wataru Satake ; Peter A. Silburn ; Tim M. Strom ; Jessie Theuns ; Eng- King Tan ; Tatsushi Toda ; Hiroyuki Tomiyama ; Ryan J. Uitti ; Christine Van Broeckhoven ; Karin Wirdefeldt ; Zbigniew Wszolek ; Georgia Xiromerisiou ; Harumi S. Yomono ; Kuo-Chu Yueh ; Yi Zhao ; Thomas Gasser ; Demetrius Maraganore ; Rejko KrügerSource :
- Journal of Medical Genetics [ 0022-2593 ] ; 2012.
Abstract
Two recent studies identified a mutation (p.Asp620Asn) in the vacuolar protein sorting 35 gene as a cause for an autosomal dominant form of Parkinson disease . Although additional missense variants were described, their pathogenic role yet remains inconclusive.
We performed the largest multi-center study to ascertain the frequency and pathogenicity of the reported vacuolar protein sorting 35 gene variants in more than 15,000 individuals worldwide. p.Asp620Asn was detected in 5 familial and 2 sporadic PD cases and not in healthy controls, p.Leu774Met in 6 cases and 1 control, p.Gly51Ser in 3 cases and 2 controls. Overall analyses did not reveal any significant increased risk for p.Leu774Met and p.Gly51Ser in our cohort.
Our study apart from identifying the p.Asp620Asn variant in familial cases also identified it in idiopathic Parkinson disease cases, and thus provides genetic evidence for a role of p.Asp620Asn in Parkinson disease in different populations worldwide.
Url:
DOI: 10.1136/jmedgenet-2012-101155
PubMed: 23125461
PubMed Central: 3488700
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PMC:3488700Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">A multi-centre clinico-genetic analysis of the VPS35 gene in Parkinson disease indicates reduced penetrance for disease-associated variants</title><author><name sortKey="Sharma, Manu" sort="Sharma, Manu" uniqKey="Sharma M" first="Manu" last="Sharma">Manu Sharma</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Ioannidis, John P A" sort="Ioannidis, John P A" uniqKey="Ioannidis J" first="John P A" last="Ioannidis">John P A. Ioannidis</name><affiliation><nlm:aff id="af2">Stanford Prevention Research Center, Department of Medicine and Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California, USA</nlm:aff></affiliation></author><author><name sortKey="Aasly, Jan O" sort="Aasly, Jan O" uniqKey="Aasly J" first="Jan O" last="Aasly">Jan O. Aasly</name><affiliation><nlm:aff id="af3">Department of Neurology, St Olavs Hospital and NTNU Trondheim, Trondheim, Norway</nlm:aff></affiliation></author><author><name sortKey="Annesi, Grazia" sort="Annesi, Grazia" uniqKey="Annesi G" first="Grazia" last="Annesi">Grazia Annesi</name><affiliation><nlm:aff id="af4">Institute of Neurology, Department of Medical Sciences , University Magna Graecia, Catanzaro; Neuroimaging Research Unit, National Research Council, Catanzaro, Italy</nlm:aff></affiliation></author><author><name sortKey="Brice, Alexis" sort="Brice, Alexis" uniqKey="Brice A" first="Alexis" last="Brice">Alexis Brice</name><affiliation><nlm:aff id="af5">INSERM, UMR_S975, Université Pierre et Marie Curie-Paris, CNRS, UMR 7225, AP-HP, Pitié-Salpêtriére Hospital</nlm:aff></affiliation><affiliation><nlm:aff id="af6">Cnrs, UMR 7225, Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="af7">AP-HP, Hôpital Pitié-Salpêtiére, Department of Genetics and Cytogenetics, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Bertram, Lars" sort="Bertram, Lars" uniqKey="Bertram L" first="Lars" last="Bertram">Lars Bertram</name><affiliation><nlm:aff id="af8">Neuropsychiatric Genetics Group, Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.</nlm:aff></affiliation></author><author><name sortKey="Bozi, Maria" sort="Bozi, Maria" uniqKey="Bozi M" first="Maria" last="Bozi">Maria Bozi</name><affiliation><nlm:aff id="af9">General Hospital of Syros, Syros, Greece</nlm:aff></affiliation><affiliation><nlm:aff>NONE</nlm:aff></affiliation><affiliation><nlm:aff id="af11">2nd Neurology Clinic, University of Athens, ‘Attikon’ Hospital, Athens, Greece</nlm:aff></affiliation></author><author><name sortKey="Barcikowska, Maria" sort="Barcikowska, Maria" uniqKey="Barcikowska M" first="Maria" last="Barcikowska">Maria Barcikowska</name><affiliation><nlm:aff id="af12">Department of Neurodegenerative Disorders, Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland</nlm:aff></affiliation></author><author><name sortKey="Crosiers, David" sort="Crosiers, David" uniqKey="Crosiers D" first="David" last="Crosiers">David Crosiers</name><affiliation><nlm:aff id="af13">Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium</nlm:aff></affiliation><affiliation><nlm:aff id="af14">Institute Born-Bunge, University of Antwerp, Antwerp, Belgium</nlm:aff></affiliation><affiliation><nlm:aff id="af15">Department of Neurology, Antwerp University Hospital, Antwerp, Belgium.</nlm:aff></affiliation></author><author><name sortKey="Clarke, Carl E" sort="Clarke, Carl E" uniqKey="Clarke C" first="Carl E" last="Clarke">Carl E. Clarke</name><affiliation><nlm:aff id="af16">School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, City Hospital, Birmingham, UK</nlm:aff></affiliation></author><author><name sortKey="Facheris, Maurizio F" sort="Facheris, Maurizio F" uniqKey="Facheris M" first="Maurizio F" last="Facheris">Maurizio F. Facheris</name><affiliation><nlm:aff id="af17">Centre for Biomedicine, European Academy Bozen/Bolzano, Itlay, Affiliated institute of the University of Lübeck, Lübeck, German</nlm:aff></affiliation></author><author><name sortKey="Farrer, Matthew" sort="Farrer, Matthew" uniqKey="Farrer M" first="Matthew" last="Farrer">Matthew Farrer</name><affiliation><nlm:aff id="af18">Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada</nlm:aff></affiliation></author><author><name sortKey="Garraux, Gaetan" sort="Garraux, Gaetan" uniqKey="Garraux G" first="Gaetan" last="Garraux">Gaetan Garraux</name><affiliation><nlm:aff id="af19">Human Genetic Centre, University Hospital of Liége, Liége, Belgium and Department of Neurology, General Central Hospital, Bolzano, Itlay</nlm:aff></affiliation></author><author><name sortKey="Gispert, Suzana" sort="Gispert, Suzana" uniqKey="Gispert S" first="Suzana" last="Gispert">Suzana Gispert</name><affiliation><nlm:aff id="af20">Department of Neurology, Goethe University Frankfurt am Main, Frankfurt, Germany</nlm:aff></affiliation></author><author><name sortKey="Auburger, Georg" sort="Auburger, Georg" uniqKey="Auburger G" first="Georg" last="Auburger">Georg Auburger</name><affiliation><nlm:aff id="af19">Human Genetic Centre, University Hospital of Liége, Liége, Belgium and Department of Neurology, General Central Hospital, Bolzano, Itlay</nlm:aff></affiliation></author><author><name sortKey="Vilari O Guell, Carles" sort="Vilari O Guell, Carles" uniqKey="Vilari O Guell C" first="Carles" last="Vilari O-Güell">Carles Vilari O-Güell</name><affiliation><nlm:aff id="af18">Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada</nlm:aff></affiliation></author><author><name sortKey="Hadjigeorgiou, Georgios M" sort="Hadjigeorgiou, Georgios M" uniqKey="Hadjigeorgiou G" first="Georgios M" last="Hadjigeorgiou">Georgios M. Hadjigeorgiou</name><affiliation><nlm:aff id="af21">Department of Neurology, University of Thessaly and Institute of Biomedical Research and Technology, CERETETH, Larissa, Greece</nlm:aff></affiliation></author><author><name sortKey="Hicks, Andrew A" sort="Hicks, Andrew A" uniqKey="Hicks A" first="Andrew A" last="Hicks">Andrew A. Hicks</name><affiliation><nlm:aff id="af17">Centre for Biomedicine, European Academy Bozen/Bolzano, Itlay, Affiliated institute of the University of Lübeck, Lübeck, German</nlm:aff></affiliation></author><author><name sortKey="Hattori, Nobutaka" sort="Hattori, Nobutaka" uniqKey="Hattori N" first="Nobutaka" last="Hattori">Nobutaka Hattori</name><affiliation><nlm:aff id="af22">Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan</nlm:aff></affiliation></author><author><name sortKey="Jeon, Beom S" sort="Jeon, Beom S" uniqKey="Jeon B" first="Beom S" last="Jeon">Beom S. Jeon</name><affiliation><nlm:aff id="af23">Department of Neurology, Seoul National University Hospital, Seoul, Korea</nlm:aff></affiliation></author><author><name sortKey="Jamrozik, Zygmunt" sort="Jamrozik, Zygmunt" uniqKey="Jamrozik Z" first="Zygmunt" last="Jamrozik">Zygmunt Jamrozik</name><affiliation><nlm:aff id="af24">Department of Neurology, Medical University of Warsaw, Warsaw, Poland</nlm:aff></affiliation></author><author><name sortKey="Krygowska Wajs, Anna" sort="Krygowska Wajs, Anna" uniqKey="Krygowska Wajs A" first="Anna" last="Krygowska-Wajs">Anna Krygowska-Wajs</name><affiliation><nlm:aff id="af25">Department of Neurology, Jagiellonian University, Krakow, Poland</nlm:aff></affiliation></author><author><name sortKey="Lesage, Suzanne" sort="Lesage, Suzanne" uniqKey="Lesage S" first="Suzanne" last="Lesage">Suzanne Lesage</name><affiliation><nlm:aff id="af5">INSERM, UMR_S975, Université Pierre et Marie Curie-Paris, CNRS, UMR 7225, AP-HP, Pitié-Salpêtriére Hospital</nlm:aff></affiliation><affiliation><nlm:aff id="af6">Cnrs, UMR 7225, Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="af7">AP-HP, Hôpital Pitié-Salpêtiére, Department of Genetics and Cytogenetics, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Lill, Christina M" sort="Lill, Christina M" uniqKey="Lill C" first="Christina M" last="Lill">Christina M. Lill</name><affiliation><nlm:aff id="af9">General Hospital of Syros, Syros, Greece</nlm:aff></affiliation><affiliation><nlm:aff id="af26">Department of Neurology, Johannes Gutenberg University, Mainz, Germany</nlm:aff></affiliation></author><author><name sortKey="Lin, Juei Jueng" sort="Lin, Juei Jueng" uniqKey="Lin J" first="Juei-Jueng" last="Lin">Juei-Jueng Lin</name><affiliation><nlm:aff id="af27">Department of Neurology, Chushang Show-Chwan Hospital, Nantou and Chung-Shan Medical University Hospital, Taichung, Taiwan</nlm:aff></affiliation></author><author><name sortKey="Lynch, Timothy" sort="Lynch, Timothy" uniqKey="Lynch T" first="Timothy" last="Lynch">Timothy Lynch</name><affiliation><nlm:aff id="af28">The Dublin Neurological Institute at the Mater Misericordiae University Hospital, and Conway Institute, University College Dublin, Dublin, Ireland</nlm:aff></affiliation></author><author><name sortKey="Lichtner, Peter" sort="Lichtner, Peter" uniqKey="Lichtner P" first="Peter" last="Lichtner">Peter Lichtner</name><affiliation><nlm:aff id="af29">Helmholtz Zentrum München, German Research Centre for Environmental Health (Gmbh), Neuherberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Lang, Anthony E" sort="Lang, Anthony E" uniqKey="Lang A" first="Anthony E" last="Lang">Anthony E. Lang</name><affiliation><nlm:aff id="af30">Movement Disorders Centre, and the Edmond J Safra Program in Parkinson's Disease, Toronto Western Hospital, University of Toronto, Toronto, Canada</nlm:aff></affiliation></author><author><name sortKey="Libioulle, Cecile" sort="Libioulle, Cecile" uniqKey="Libioulle C" first="Cecile" last="Libioulle">Cecile Libioulle</name><affiliation><nlm:aff id="af18">Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada</nlm:aff></affiliation></author><author><name sortKey="Murata, Miho" sort="Murata, Miho" uniqKey="Murata M" first="Miho" last="Murata">Miho Murata</name><affiliation><nlm:aff id="af31">Department of Neurology, National Center Hospital of Neurology and Psychiatry, Tokyo, Japan</nlm:aff></affiliation></author><author><name sortKey="Mok, Vincent" sort="Mok, Vincent" uniqKey="Mok V" first="Vincent" last="Mok">Vincent Mok</name><affiliation><nlm:aff id="af32">Department of Medicine and Therapeutics, Prince of Wales Hospital,The Chinese University of Hong Kong, Shatin, Hong Kong</nlm:aff></affiliation></author><author><name sortKey="Jasinska Myga, Barbara" sort="Jasinska Myga, Barbara" uniqKey="Jasinska Myga B" first="Barbara" last="Jasinska-Myga">Barbara Jasinska-Myga</name><affiliation><nlm:aff id="af33">Department of Neurology, Medical University of Silesia, Katowice, Poland</nlm:aff></affiliation></author><author><name sortKey="Mellick, George D" sort="Mellick, George D" uniqKey="Mellick G" first="George D" last="Mellick">George D. Mellick</name><affiliation><nlm:aff id="af34">Eskitis Institute for Cell and Molecular Therapies, Griffith University, Brisbane, Australia</nlm:aff></affiliation></author><author><name sortKey="Morrison, Karen E" sort="Morrison, Karen E" uniqKey="Morrison K" first="Karen E" last="Morrison">Karen E. Morrison</name><affiliation><nlm:aff id="af17">Centre for Biomedicine, European Academy Bozen/Bolzano, Itlay, Affiliated institute of the University of Lübeck, Lübeck, German</nlm:aff></affiliation><affiliation><nlm:aff id="af35">Neurosciences Department, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK</nlm:aff></affiliation></author><author><name sortKey="Meitnger, Thomas" sort="Meitnger, Thomas" uniqKey="Meitnger T" first="Thomas" last="Meitnger">Thomas Meitnger</name><affiliation><nlm:aff id="af36">German Research Center for Environmental Health, Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="af37">Institute of Human Genetics, Technische Universität München, Munich, Germany</nlm:aff></affiliation></author><author><name sortKey="Zimprich, Alexander" sort="Zimprich, Alexander" uniqKey="Zimprich A" first="Alexander" last="Zimprich">Alexander Zimprich</name><affiliation><nlm:aff id="af38">Department of Neurology, Medizinische Universität Wien, Vienna, Austria</nlm:aff></affiliation></author><author><name sortKey="Opala, Grzegorz" sort="Opala, Grzegorz" uniqKey="Opala G" first="Grzegorz" last="Opala">Grzegorz Opala</name><affiliation><nlm:aff id="af36">German Research Center for Environmental Health, Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Pramstaller, Peter P" sort="Pramstaller, Peter P" uniqKey="Pramstaller P" first="Peter P" last="Pramstaller">Peter P. Pramstaller</name><affiliation><nlm:aff id="af19">Human Genetic Centre, University Hospital of Liége, Liége, Belgium and Department of Neurology, General Central Hospital, Bolzano, Itlay</nlm:aff></affiliation></author><author><name sortKey="Pichler, Irene" sort="Pichler, Irene" uniqKey="Pichler I" first="Irene" last="Pichler">Irene Pichler</name><affiliation><nlm:aff id="af19">Human Genetic Centre, University Hospital of Liége, Liége, Belgium and Department of Neurology, General Central Hospital, Bolzano, Itlay</nlm:aff></affiliation></author><author><name sortKey="Park, Sung Sup" sort="Park, Sung Sup" uniqKey="Park S" first="Sung Sup" last="Park">Sung Sup Park</name><affiliation><nlm:aff id="af26">Department of Neurology, Johannes Gutenberg University, Mainz, Germany</nlm:aff></affiliation></author><author><name sortKey="Quattrone, Aldo" sort="Quattrone, Aldo" uniqKey="Quattrone A" first="Aldo" last="Quattrone">Aldo Quattrone</name><affiliation><nlm:aff id="af4">Institute of Neurology, Department of Medical Sciences , University Magna Graecia, Catanzaro; Neuroimaging Research Unit, National Research Council, Catanzaro, Italy</nlm:aff></affiliation></author><author><name sortKey="Rogaeva, Ekaterina" sort="Rogaeva, Ekaterina" uniqKey="Rogaeva E" first="Ekaterina" last="Rogaeva">Ekaterina Rogaeva</name><affiliation><nlm:aff id="af39">Tanz Centre for Research in Neurodegenerative Diseases, Department of Medicine, University of Toronto, Toronto, Canada</nlm:aff></affiliation></author><author><name sortKey="Ross, Owen A" sort="Ross, Owen A" uniqKey="Ross O" first="Owen A." last="Ross">Owen A. Ross</name><affiliation><nlm:aff id="af40">Department of Neuroscience, Mayo Clinic, Jacksonville, Florida</nlm:aff></affiliation></author><author><name sortKey="Stefanis, Leonidas" sort="Stefanis, Leonidas" uniqKey="Stefanis L" first="Leonidas" last="Stefanis">Leonidas Stefanis</name><affiliation><nlm:aff id="af11">2nd Neurology Clinic, University of Athens, ‘Attikon’ Hospital, Athens, Greece</nlm:aff></affiliation><affiliation><nlm:aff id="af41">Divisions of Basic Neurosciences & Cell Biology, Biomedical Research Foundation of Academy of Athens, Athens, Greece</nlm:aff></affiliation></author><author><name sortKey="Stockton, Joanne D" sort="Stockton, Joanne D" uniqKey="Stockton J" first="Joanne D" last="Stockton">Joanne D. Stockton</name><affiliation><nlm:aff id="af35">Neurosciences Department, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK</nlm:aff></affiliation></author><author><name sortKey="Satake, Wataru" sort="Satake, Wataru" uniqKey="Satake W" first="Wataru" last="Satake">Wataru Satake</name><affiliation><nlm:aff id="af42">Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, Japan</nlm:aff></affiliation></author><author><name sortKey="Silburn, Peter A" sort="Silburn, Peter A" uniqKey="Silburn P" first="Peter A" last="Silburn">Peter A. Silburn</name><affiliation><nlm:aff id="af43">University of Queensland Centre for Clinical Research, Herston, Australia</nlm:aff></affiliation></author><author><name sortKey="Strom, Tim M" sort="Strom, Tim M" uniqKey="Strom T" first="Tim M" last="Strom">Tim M. Strom</name><affiliation><nlm:aff id="af37">Institute of Human Genetics, Technische Universität München, Munich, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="af39">Tanz Centre for Research in Neurodegenerative Diseases, Department of Medicine, University of Toronto, Toronto, Canada</nlm:aff></affiliation></author><author><name sortKey="Theuns, Jessie" sort="Theuns, Jessie" uniqKey="Theuns J" first="Jessie" last="Theuns">Jessie Theuns</name><affiliation><nlm:aff id="af14">Institute Born-Bunge, University of Antwerp, Antwerp, Belgium</nlm:aff></affiliation><affiliation><nlm:aff id="af15">Department of Neurology, Antwerp University Hospital, Antwerp, Belgium.</nlm:aff></affiliation></author><author><name sortKey="Tan, Eng King" sort="Tan, Eng King" uniqKey="Tan E" first="Eng- King" last="Tan">Eng- King Tan</name><affiliation><nlm:aff id="af44">Department of Neurology, Singapore General Hospital, National Neuroscience Institute, Singapore</nlm:aff></affiliation></author><author><name sortKey="Toda, Tatsushi" sort="Toda, Tatsushi" uniqKey="Toda T" first="Tatsushi" last="Toda">Tatsushi Toda</name><affiliation><nlm:aff id="af42">Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, Japan</nlm:aff></affiliation></author><author><name sortKey="Tomiyama, Hiroyuki" sort="Tomiyama, Hiroyuki" uniqKey="Tomiyama H" first="Hiroyuki" last="Tomiyama">Hiroyuki Tomiyama</name><affiliation><nlm:aff id="af22">Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan</nlm:aff></affiliation></author><author><name sortKey="Uitti, Ryan J" sort="Uitti, Ryan J" uniqKey="Uitti R" first="Ryan J" last="Uitti">Ryan J. Uitti</name><affiliation><nlm:aff id="af45">Department of Neurology, Mayo Clinic Jacksonville, USA</nlm:aff></affiliation></author><author><name sortKey="Van Broeckhoven, Christine" sort="Van Broeckhoven, Christine" uniqKey="Van Broeckhoven C" first="Christine" last="Van Broeckhoven">Christine Van Broeckhoven</name><affiliation><nlm:aff id="af14">Institute Born-Bunge, University of Antwerp, Antwerp, Belgium</nlm:aff></affiliation><affiliation><nlm:aff id="af15">Department of Neurology, Antwerp University Hospital, Antwerp, Belgium.</nlm:aff></affiliation></author><author><name sortKey="Wirdefeldt, Karin" sort="Wirdefeldt, Karin" uniqKey="Wirdefeldt K" first="Karin" last="Wirdefeldt">Karin Wirdefeldt</name><affiliation><nlm:aff id="af46">Epidemiology and Biostatistics and Department of Clinical Neuroscience, Karolinska Institutet</nlm:aff></affiliation></author><author><name sortKey="Wszolek, Zbigniew" sort="Wszolek, Zbigniew" uniqKey="Wszolek Z" first="Zbigniew" last="Wszolek">Zbigniew Wszolek</name><affiliation><nlm:aff id="af45">Department of Neurology, Mayo Clinic Jacksonville, USA</nlm:aff></affiliation></author><author><name sortKey="Xiromerisiou, Georgia" sort="Xiromerisiou, Georgia" uniqKey="Xiromerisiou G" first="Georgia" last="Xiromerisiou">Georgia Xiromerisiou</name><affiliation><nlm:aff id="af21">Department of Neurology, University of Thessaly and Institute of Biomedical Research and Technology, CERETETH, Larissa, Greece</nlm:aff></affiliation></author><author><name sortKey="Yomono, Harumi S" sort="Yomono, Harumi S" uniqKey="Yomono H" first="Harumi S" last="Yomono">Harumi S. Yomono</name><affiliation><nlm:aff id="af47">Department of Neurology, National Hospital Organization Tokyo Hospital, Tokyo, Japan</nlm:aff></affiliation></author><author><name sortKey="Yueh, Kuo Chu" sort="Yueh, Kuo Chu" uniqKey="Yueh K" first="Kuo-Chu" last="Yueh">Kuo-Chu Yueh</name><affiliation><nlm:aff id="af27">Department of Neurology, Chushang Show-Chwan Hospital, Nantou and Chung-Shan Medical University Hospital, Taichung, Taiwan</nlm:aff></affiliation></author><author><name sortKey="Zhao, Yi" sort="Zhao, Yi" uniqKey="Zhao Y" first="Yi" last="Zhao">Yi Zhao</name></author><author><name sortKey="Gasser, Thomas" sort="Gasser, Thomas" uniqKey="Gasser T" first="Thomas" last="Gasser">Thomas Gasser</name><affiliation><nlm:aff id="af1">Department of Neurodegenerative diseases, Hertie-Institute for Clinical Brain Research and DZNE- German Center for Neurodegenerative Diseases, Tübingen</nlm:aff></affiliation></author><author><name sortKey="Maraganore, Demetrius" sort="Maraganore, Demetrius" uniqKey="Maraganore D" first="Demetrius" last="Maraganore">Demetrius Maraganore</name><affiliation><nlm:aff id="af48">Department of Neurology, NorthShore University HealthSystem, Chicago, USA</nlm:aff></affiliation></author><author><name sortKey="Kruger, Rejko" sort="Kruger, Rejko" uniqKey="Kruger R" first="Rejko" last="Krüger">Rejko Krüger</name><affiliation><nlm:aff id="af1">Department of Neurodegenerative diseases, Hertie-Institute for Clinical Brain Research and DZNE- German Center for Neurodegenerative Diseases, Tübingen</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">23125461</idno><idno type="pmc">3488700</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3488700</idno><idno type="RBID">PMC:3488700</idno><idno type="doi">10.1136/jmedgenet-2012-101155</idno><date when="2012">2012</date><idno type="wicri:Area/Pmc/Corpus">000A21</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000A21</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">A multi-centre clinico-genetic analysis of the VPS35 gene in Parkinson disease indicates reduced penetrance for disease-associated variants</title><author><name sortKey="Sharma, Manu" sort="Sharma, Manu" uniqKey="Sharma M" first="Manu" last="Sharma">Manu Sharma</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Ioannidis, John P A" sort="Ioannidis, John P A" uniqKey="Ioannidis J" first="John P A" last="Ioannidis">John P A. Ioannidis</name><affiliation><nlm:aff id="af2">Stanford Prevention Research Center, Department of Medicine and Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California, USA</nlm:aff></affiliation></author><author><name sortKey="Aasly, Jan O" sort="Aasly, Jan O" uniqKey="Aasly J" first="Jan O" last="Aasly">Jan O. Aasly</name><affiliation><nlm:aff id="af3">Department of Neurology, St Olavs Hospital and NTNU Trondheim, Trondheim, Norway</nlm:aff></affiliation></author><author><name sortKey="Annesi, Grazia" sort="Annesi, Grazia" uniqKey="Annesi G" first="Grazia" last="Annesi">Grazia Annesi</name><affiliation><nlm:aff id="af4">Institute of Neurology, Department of Medical Sciences , University Magna Graecia, Catanzaro; Neuroimaging Research Unit, National Research Council, Catanzaro, Italy</nlm:aff></affiliation></author><author><name sortKey="Brice, Alexis" sort="Brice, Alexis" uniqKey="Brice A" first="Alexis" last="Brice">Alexis Brice</name><affiliation><nlm:aff id="af5">INSERM, UMR_S975, Université Pierre et Marie Curie-Paris, CNRS, UMR 7225, AP-HP, Pitié-Salpêtriére Hospital</nlm:aff></affiliation><affiliation><nlm:aff id="af6">Cnrs, UMR 7225, Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="af7">AP-HP, Hôpital Pitié-Salpêtiére, Department of Genetics and Cytogenetics, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Bertram, Lars" sort="Bertram, Lars" uniqKey="Bertram L" first="Lars" last="Bertram">Lars Bertram</name><affiliation><nlm:aff id="af8">Neuropsychiatric Genetics Group, Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.</nlm:aff></affiliation></author><author><name sortKey="Bozi, Maria" sort="Bozi, Maria" uniqKey="Bozi M" first="Maria" last="Bozi">Maria Bozi</name><affiliation><nlm:aff id="af9">General Hospital of Syros, Syros, Greece</nlm:aff></affiliation><affiliation><nlm:aff>NONE</nlm:aff></affiliation><affiliation><nlm:aff id="af11">2nd Neurology Clinic, University of Athens, ‘Attikon’ Hospital, Athens, Greece</nlm:aff></affiliation></author><author><name sortKey="Barcikowska, Maria" sort="Barcikowska, Maria" uniqKey="Barcikowska M" first="Maria" last="Barcikowska">Maria Barcikowska</name><affiliation><nlm:aff id="af12">Department of Neurodegenerative Disorders, Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland</nlm:aff></affiliation></author><author><name sortKey="Crosiers, David" sort="Crosiers, David" uniqKey="Crosiers D" first="David" last="Crosiers">David Crosiers</name><affiliation><nlm:aff id="af13">Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium</nlm:aff></affiliation><affiliation><nlm:aff id="af14">Institute Born-Bunge, University of Antwerp, Antwerp, Belgium</nlm:aff></affiliation><affiliation><nlm:aff id="af15">Department of Neurology, Antwerp University Hospital, Antwerp, Belgium.</nlm:aff></affiliation></author><author><name sortKey="Clarke, Carl E" sort="Clarke, Carl E" uniqKey="Clarke C" first="Carl E" last="Clarke">Carl E. Clarke</name><affiliation><nlm:aff id="af16">School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, City Hospital, Birmingham, UK</nlm:aff></affiliation></author><author><name sortKey="Facheris, Maurizio F" sort="Facheris, Maurizio F" uniqKey="Facheris M" first="Maurizio F" last="Facheris">Maurizio F. Facheris</name><affiliation><nlm:aff id="af17">Centre for Biomedicine, European Academy Bozen/Bolzano, Itlay, Affiliated institute of the University of Lübeck, Lübeck, German</nlm:aff></affiliation></author><author><name sortKey="Farrer, Matthew" sort="Farrer, Matthew" uniqKey="Farrer M" first="Matthew" last="Farrer">Matthew Farrer</name><affiliation><nlm:aff id="af18">Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada</nlm:aff></affiliation></author><author><name sortKey="Garraux, Gaetan" sort="Garraux, Gaetan" uniqKey="Garraux G" first="Gaetan" last="Garraux">Gaetan Garraux</name><affiliation><nlm:aff id="af19">Human Genetic Centre, University Hospital of Liége, Liége, Belgium and Department of Neurology, General Central Hospital, Bolzano, Itlay</nlm:aff></affiliation></author><author><name sortKey="Gispert, Suzana" sort="Gispert, Suzana" uniqKey="Gispert S" first="Suzana" last="Gispert">Suzana Gispert</name><affiliation><nlm:aff id="af20">Department of Neurology, Goethe University Frankfurt am Main, Frankfurt, Germany</nlm:aff></affiliation></author><author><name sortKey="Auburger, Georg" sort="Auburger, Georg" uniqKey="Auburger G" first="Georg" last="Auburger">Georg Auburger</name><affiliation><nlm:aff id="af19">Human Genetic Centre, University Hospital of Liége, Liége, Belgium and Department of Neurology, General Central Hospital, Bolzano, Itlay</nlm:aff></affiliation></author><author><name sortKey="Vilari O Guell, Carles" sort="Vilari O Guell, Carles" uniqKey="Vilari O Guell C" first="Carles" last="Vilari O-Güell">Carles Vilari O-Güell</name><affiliation><nlm:aff id="af18">Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada</nlm:aff></affiliation></author><author><name sortKey="Hadjigeorgiou, Georgios M" sort="Hadjigeorgiou, Georgios M" uniqKey="Hadjigeorgiou G" first="Georgios M" last="Hadjigeorgiou">Georgios M. Hadjigeorgiou</name><affiliation><nlm:aff id="af21">Department of Neurology, University of Thessaly and Institute of Biomedical Research and Technology, CERETETH, Larissa, Greece</nlm:aff></affiliation></author><author><name sortKey="Hicks, Andrew A" sort="Hicks, Andrew A" uniqKey="Hicks A" first="Andrew A" last="Hicks">Andrew A. Hicks</name><affiliation><nlm:aff id="af17">Centre for Biomedicine, European Academy Bozen/Bolzano, Itlay, Affiliated institute of the University of Lübeck, Lübeck, German</nlm:aff></affiliation></author><author><name sortKey="Hattori, Nobutaka" sort="Hattori, Nobutaka" uniqKey="Hattori N" first="Nobutaka" last="Hattori">Nobutaka Hattori</name><affiliation><nlm:aff id="af22">Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan</nlm:aff></affiliation></author><author><name sortKey="Jeon, Beom S" sort="Jeon, Beom S" uniqKey="Jeon B" first="Beom S" last="Jeon">Beom S. Jeon</name><affiliation><nlm:aff id="af23">Department of Neurology, Seoul National University Hospital, Seoul, Korea</nlm:aff></affiliation></author><author><name sortKey="Jamrozik, Zygmunt" sort="Jamrozik, Zygmunt" uniqKey="Jamrozik Z" first="Zygmunt" last="Jamrozik">Zygmunt Jamrozik</name><affiliation><nlm:aff id="af24">Department of Neurology, Medical University of Warsaw, Warsaw, Poland</nlm:aff></affiliation></author><author><name sortKey="Krygowska Wajs, Anna" sort="Krygowska Wajs, Anna" uniqKey="Krygowska Wajs A" first="Anna" last="Krygowska-Wajs">Anna Krygowska-Wajs</name><affiliation><nlm:aff id="af25">Department of Neurology, Jagiellonian University, Krakow, Poland</nlm:aff></affiliation></author><author><name sortKey="Lesage, Suzanne" sort="Lesage, Suzanne" uniqKey="Lesage S" first="Suzanne" last="Lesage">Suzanne Lesage</name><affiliation><nlm:aff id="af5">INSERM, UMR_S975, Université Pierre et Marie Curie-Paris, CNRS, UMR 7225, AP-HP, Pitié-Salpêtriére Hospital</nlm:aff></affiliation><affiliation><nlm:aff id="af6">Cnrs, UMR 7225, Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="af7">AP-HP, Hôpital Pitié-Salpêtiére, Department of Genetics and Cytogenetics, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Lill, Christina M" sort="Lill, Christina M" uniqKey="Lill C" first="Christina M" last="Lill">Christina M. Lill</name><affiliation><nlm:aff id="af9">General Hospital of Syros, Syros, Greece</nlm:aff></affiliation><affiliation><nlm:aff id="af26">Department of Neurology, Johannes Gutenberg University, Mainz, Germany</nlm:aff></affiliation></author><author><name sortKey="Lin, Juei Jueng" sort="Lin, Juei Jueng" uniqKey="Lin J" first="Juei-Jueng" last="Lin">Juei-Jueng Lin</name><affiliation><nlm:aff id="af27">Department of Neurology, Chushang Show-Chwan Hospital, Nantou and Chung-Shan Medical University Hospital, Taichung, Taiwan</nlm:aff></affiliation></author><author><name sortKey="Lynch, Timothy" sort="Lynch, Timothy" uniqKey="Lynch T" first="Timothy" last="Lynch">Timothy Lynch</name><affiliation><nlm:aff id="af28">The Dublin Neurological Institute at the Mater Misericordiae University Hospital, and Conway Institute, University College Dublin, Dublin, Ireland</nlm:aff></affiliation></author><author><name sortKey="Lichtner, Peter" sort="Lichtner, Peter" uniqKey="Lichtner P" first="Peter" last="Lichtner">Peter Lichtner</name><affiliation><nlm:aff id="af29">Helmholtz Zentrum München, German Research Centre for Environmental Health (Gmbh), Neuherberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Lang, Anthony E" sort="Lang, Anthony E" uniqKey="Lang A" first="Anthony E" last="Lang">Anthony E. Lang</name><affiliation><nlm:aff id="af30">Movement Disorders Centre, and the Edmond J Safra Program in Parkinson's Disease, Toronto Western Hospital, University of Toronto, Toronto, Canada</nlm:aff></affiliation></author><author><name sortKey="Libioulle, Cecile" sort="Libioulle, Cecile" uniqKey="Libioulle C" first="Cecile" last="Libioulle">Cecile Libioulle</name><affiliation><nlm:aff id="af18">Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada</nlm:aff></affiliation></author><author><name sortKey="Murata, Miho" sort="Murata, Miho" uniqKey="Murata M" first="Miho" last="Murata">Miho Murata</name><affiliation><nlm:aff id="af31">Department of Neurology, National Center Hospital of Neurology and Psychiatry, Tokyo, Japan</nlm:aff></affiliation></author><author><name sortKey="Mok, Vincent" sort="Mok, Vincent" uniqKey="Mok V" first="Vincent" last="Mok">Vincent Mok</name><affiliation><nlm:aff id="af32">Department of Medicine and Therapeutics, Prince of Wales Hospital,The Chinese University of Hong Kong, Shatin, Hong Kong</nlm:aff></affiliation></author><author><name sortKey="Jasinska Myga, Barbara" sort="Jasinska Myga, Barbara" uniqKey="Jasinska Myga B" first="Barbara" last="Jasinska-Myga">Barbara Jasinska-Myga</name><affiliation><nlm:aff id="af33">Department of Neurology, Medical University of Silesia, Katowice, Poland</nlm:aff></affiliation></author><author><name sortKey="Mellick, George D" sort="Mellick, George D" uniqKey="Mellick G" first="George D" last="Mellick">George D. Mellick</name><affiliation><nlm:aff id="af34">Eskitis Institute for Cell and Molecular Therapies, Griffith University, Brisbane, Australia</nlm:aff></affiliation></author><author><name sortKey="Morrison, Karen E" sort="Morrison, Karen E" uniqKey="Morrison K" first="Karen E" last="Morrison">Karen E. Morrison</name><affiliation><nlm:aff id="af17">Centre for Biomedicine, European Academy Bozen/Bolzano, Itlay, Affiliated institute of the University of Lübeck, Lübeck, German</nlm:aff></affiliation><affiliation><nlm:aff id="af35">Neurosciences Department, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK</nlm:aff></affiliation></author><author><name sortKey="Meitnger, Thomas" sort="Meitnger, Thomas" uniqKey="Meitnger T" first="Thomas" last="Meitnger">Thomas Meitnger</name><affiliation><nlm:aff id="af36">German Research Center for Environmental Health, Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="af37">Institute of Human Genetics, Technische Universität München, Munich, Germany</nlm:aff></affiliation></author><author><name sortKey="Zimprich, Alexander" sort="Zimprich, Alexander" uniqKey="Zimprich A" first="Alexander" last="Zimprich">Alexander Zimprich</name><affiliation><nlm:aff id="af38">Department of Neurology, Medizinische Universität Wien, Vienna, Austria</nlm:aff></affiliation></author><author><name sortKey="Opala, Grzegorz" sort="Opala, Grzegorz" uniqKey="Opala G" first="Grzegorz" last="Opala">Grzegorz Opala</name><affiliation><nlm:aff id="af36">German Research Center for Environmental Health, Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Pramstaller, Peter P" sort="Pramstaller, Peter P" uniqKey="Pramstaller P" first="Peter P" last="Pramstaller">Peter P. Pramstaller</name><affiliation><nlm:aff id="af19">Human Genetic Centre, University Hospital of Liége, Liége, Belgium and Department of Neurology, General Central Hospital, Bolzano, Itlay</nlm:aff></affiliation></author><author><name sortKey="Pichler, Irene" sort="Pichler, Irene" uniqKey="Pichler I" first="Irene" last="Pichler">Irene Pichler</name><affiliation><nlm:aff id="af19">Human Genetic Centre, University Hospital of Liége, Liége, Belgium and Department of Neurology, General Central Hospital, Bolzano, Itlay</nlm:aff></affiliation></author><author><name sortKey="Park, Sung Sup" sort="Park, Sung Sup" uniqKey="Park S" first="Sung Sup" last="Park">Sung Sup Park</name><affiliation><nlm:aff id="af26">Department of Neurology, Johannes Gutenberg University, Mainz, Germany</nlm:aff></affiliation></author><author><name sortKey="Quattrone, Aldo" sort="Quattrone, Aldo" uniqKey="Quattrone A" first="Aldo" last="Quattrone">Aldo Quattrone</name><affiliation><nlm:aff id="af4">Institute of Neurology, Department of Medical Sciences , University Magna Graecia, Catanzaro; Neuroimaging Research Unit, National Research Council, Catanzaro, Italy</nlm:aff></affiliation></author><author><name sortKey="Rogaeva, Ekaterina" sort="Rogaeva, Ekaterina" uniqKey="Rogaeva E" first="Ekaterina" last="Rogaeva">Ekaterina Rogaeva</name><affiliation><nlm:aff id="af39">Tanz Centre for Research in Neurodegenerative Diseases, Department of Medicine, University of Toronto, Toronto, Canada</nlm:aff></affiliation></author><author><name sortKey="Ross, Owen A" sort="Ross, Owen A" uniqKey="Ross O" first="Owen A." last="Ross">Owen A. Ross</name><affiliation><nlm:aff id="af40">Department of Neuroscience, Mayo Clinic, Jacksonville, Florida</nlm:aff></affiliation></author><author><name sortKey="Stefanis, Leonidas" sort="Stefanis, Leonidas" uniqKey="Stefanis L" first="Leonidas" last="Stefanis">Leonidas Stefanis</name><affiliation><nlm:aff id="af11">2nd Neurology Clinic, University of Athens, ‘Attikon’ Hospital, Athens, Greece</nlm:aff></affiliation><affiliation><nlm:aff id="af41">Divisions of Basic Neurosciences & Cell Biology, Biomedical Research Foundation of Academy of Athens, Athens, Greece</nlm:aff></affiliation></author><author><name sortKey="Stockton, Joanne D" sort="Stockton, Joanne D" uniqKey="Stockton J" first="Joanne D" last="Stockton">Joanne D. Stockton</name><affiliation><nlm:aff id="af35">Neurosciences Department, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK</nlm:aff></affiliation></author><author><name sortKey="Satake, Wataru" sort="Satake, Wataru" uniqKey="Satake W" first="Wataru" last="Satake">Wataru Satake</name><affiliation><nlm:aff id="af42">Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, Japan</nlm:aff></affiliation></author><author><name sortKey="Silburn, Peter A" sort="Silburn, Peter A" uniqKey="Silburn P" first="Peter A" last="Silburn">Peter A. Silburn</name><affiliation><nlm:aff id="af43">University of Queensland Centre for Clinical Research, Herston, Australia</nlm:aff></affiliation></author><author><name sortKey="Strom, Tim M" sort="Strom, Tim M" uniqKey="Strom T" first="Tim M" last="Strom">Tim M. Strom</name><affiliation><nlm:aff id="af37">Institute of Human Genetics, Technische Universität München, Munich, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="af39">Tanz Centre for Research in Neurodegenerative Diseases, Department of Medicine, University of Toronto, Toronto, Canada</nlm:aff></affiliation></author><author><name sortKey="Theuns, Jessie" sort="Theuns, Jessie" uniqKey="Theuns J" first="Jessie" last="Theuns">Jessie Theuns</name><affiliation><nlm:aff id="af14">Institute Born-Bunge, University of Antwerp, Antwerp, Belgium</nlm:aff></affiliation><affiliation><nlm:aff id="af15">Department of Neurology, Antwerp University Hospital, Antwerp, Belgium.</nlm:aff></affiliation></author><author><name sortKey="Tan, Eng King" sort="Tan, Eng King" uniqKey="Tan E" first="Eng- King" last="Tan">Eng- King Tan</name><affiliation><nlm:aff id="af44">Department of Neurology, Singapore General Hospital, National Neuroscience Institute, Singapore</nlm:aff></affiliation></author><author><name sortKey="Toda, Tatsushi" sort="Toda, Tatsushi" uniqKey="Toda T" first="Tatsushi" last="Toda">Tatsushi Toda</name><affiliation><nlm:aff id="af42">Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, Japan</nlm:aff></affiliation></author><author><name sortKey="Tomiyama, Hiroyuki" sort="Tomiyama, Hiroyuki" uniqKey="Tomiyama H" first="Hiroyuki" last="Tomiyama">Hiroyuki Tomiyama</name><affiliation><nlm:aff id="af22">Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan</nlm:aff></affiliation></author><author><name sortKey="Uitti, Ryan J" sort="Uitti, Ryan J" uniqKey="Uitti R" first="Ryan J" last="Uitti">Ryan J. Uitti</name><affiliation><nlm:aff id="af45">Department of Neurology, Mayo Clinic Jacksonville, USA</nlm:aff></affiliation></author><author><name sortKey="Van Broeckhoven, Christine" sort="Van Broeckhoven, Christine" uniqKey="Van Broeckhoven C" first="Christine" last="Van Broeckhoven">Christine Van Broeckhoven</name><affiliation><nlm:aff id="af14">Institute Born-Bunge, University of Antwerp, Antwerp, Belgium</nlm:aff></affiliation><affiliation><nlm:aff id="af15">Department of Neurology, Antwerp University Hospital, Antwerp, Belgium.</nlm:aff></affiliation></author><author><name sortKey="Wirdefeldt, Karin" sort="Wirdefeldt, Karin" uniqKey="Wirdefeldt K" first="Karin" last="Wirdefeldt">Karin Wirdefeldt</name><affiliation><nlm:aff id="af46">Epidemiology and Biostatistics and Department of Clinical Neuroscience, Karolinska Institutet</nlm:aff></affiliation></author><author><name sortKey="Wszolek, Zbigniew" sort="Wszolek, Zbigniew" uniqKey="Wszolek Z" first="Zbigniew" last="Wszolek">Zbigniew Wszolek</name><affiliation><nlm:aff id="af45">Department of Neurology, Mayo Clinic Jacksonville, USA</nlm:aff></affiliation></author><author><name sortKey="Xiromerisiou, Georgia" sort="Xiromerisiou, Georgia" uniqKey="Xiromerisiou G" first="Georgia" last="Xiromerisiou">Georgia Xiromerisiou</name><affiliation><nlm:aff id="af21">Department of Neurology, University of Thessaly and Institute of Biomedical Research and Technology, CERETETH, Larissa, Greece</nlm:aff></affiliation></author><author><name sortKey="Yomono, Harumi S" sort="Yomono, Harumi S" uniqKey="Yomono H" first="Harumi S" last="Yomono">Harumi S. Yomono</name><affiliation><nlm:aff id="af47">Department of Neurology, National Hospital Organization Tokyo Hospital, Tokyo, Japan</nlm:aff></affiliation></author><author><name sortKey="Yueh, Kuo Chu" sort="Yueh, Kuo Chu" uniqKey="Yueh K" first="Kuo-Chu" last="Yueh">Kuo-Chu Yueh</name><affiliation><nlm:aff id="af27">Department of Neurology, Chushang Show-Chwan Hospital, Nantou and Chung-Shan Medical University Hospital, Taichung, Taiwan</nlm:aff></affiliation></author><author><name sortKey="Zhao, Yi" sort="Zhao, Yi" uniqKey="Zhao Y" first="Yi" last="Zhao">Yi Zhao</name></author><author><name sortKey="Gasser, Thomas" sort="Gasser, Thomas" uniqKey="Gasser T" first="Thomas" last="Gasser">Thomas Gasser</name><affiliation><nlm:aff id="af1">Department of Neurodegenerative diseases, Hertie-Institute for Clinical Brain Research and DZNE- German Center for Neurodegenerative Diseases, Tübingen</nlm:aff></affiliation></author><author><name sortKey="Maraganore, Demetrius" sort="Maraganore, Demetrius" uniqKey="Maraganore D" first="Demetrius" last="Maraganore">Demetrius Maraganore</name><affiliation><nlm:aff id="af48">Department of Neurology, NorthShore University HealthSystem, Chicago, USA</nlm:aff></affiliation></author><author><name sortKey="Kruger, Rejko" sort="Kruger, Rejko" uniqKey="Kruger R" first="Rejko" last="Krüger">Rejko Krüger</name><affiliation><nlm:aff id="af1">Department of Neurodegenerative diseases, Hertie-Institute for Clinical Brain Research and DZNE- German Center for Neurodegenerative Diseases, Tübingen</nlm:aff></affiliation></author></analytic><series><title level="j">Journal of Medical Genetics</title><idno type="ISSN">0022-2593</idno><idno type="eISSN">1468-6244</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background</title><p>Two recent studies identified a mutation (p.Asp620Asn) in the vacuolar protein sorting 35 gene as a cause for an autosomal dominant form of Parkinson disease . Although additional missense variants were described, their pathogenic role yet remains inconclusive.</p></sec><sec><title>Methods and results</title><p>We performed the largest multi-center study to ascertain the frequency and pathogenicity of the reported vacuolar protein sorting 35 gene variants in more than 15,000 individuals worldwide. p.Asp620Asn was detected in 5 familial and 2 sporadic PD cases and not in healthy controls, p.Leu774Met in 6 cases and 1 control, p.Gly51Ser in 3 cases and 2 controls. Overall analyses did not reveal any significant increased risk for p.Leu774Met and p.Gly51Ser in our cohort.</p></sec><sec><title>Conclusions</title><p>Our study apart from identifying the p.Asp620Asn variant in familial cases also identified it in idiopathic Parkinson disease cases, and thus provides genetic evidence for a role of p.Asp620Asn in Parkinson disease in different populations worldwide.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Ioannidis, Jp" uniqKey="Ioannidis J">JP Ioannidis</name></author><author><name sortKey="Thomas, G" uniqKey="Thomas G">G Thomas</name></author><author><name sortKey="Daly, Mj" uniqKey="Daly M">MJ Daly</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Singleton, Ab" uniqKey="Singleton A">AB Singleton</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zimprich, A" uniqKey="Zimprich A">A 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article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">J Med Genet</journal-id><journal-id journal-id-type="iso-abbrev">J. Med. Genet</journal-id><journal-id journal-id-type="hwp">jmedgenet</journal-id><journal-id journal-id-type="publisher-id">jmg</journal-id><journal-title-group><journal-title>Journal of Medical Genetics</journal-title></journal-title-group><issn pub-type="ppub">0022-2593</issn><issn pub-type="epub">1468-6244</issn><publisher><publisher-name>BMJ Publishing Group</publisher-name><publisher-loc>BMA House, Tavistock Square, London, WC1H 9JR</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">23125461</article-id><article-id pub-id-type="pmc">3488700</article-id><article-id pub-id-type="publisher-id">jmedgenet-2012-101155</article-id><article-id pub-id-type="doi">10.1136/jmedgenet-2012-101155</article-id><article-categories><subj-group subj-group-type="hwp-journal-coll"><subject>1506</subject></subj-group><subj-group subj-group-type="heading"><subject>Genotype-Phenotype Correlations</subject></subj-group><series-title>Short report</series-title></article-categories><title-group><article-title>A multi-centre clinico-genetic analysis of the VPS35 gene in Parkinson disease indicates reduced penetrance for disease-associated variants</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Sharma</surname><given-names>Manu</given-names></name><xref ref-type="aff" rid="af1">1CA</xref></contrib><contrib contrib-type="author"><name><surname>Ioannidis</surname><given-names>John P A</given-names></name><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Aasly</surname><given-names>Jan O</given-names></name><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>Annesi</surname><given-names>Grazia</given-names></name><xref ref-type="aff" rid="af4">4</xref></contrib><contrib contrib-type="author"><name><surname>Brice</surname><given-names>Alexis</given-names></name><xref ref-type="aff" 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rid="af42">42</xref></contrib><contrib contrib-type="author"><name><surname>Silburn</surname><given-names>Peter A</given-names></name><xref ref-type="aff" rid="af43">43</xref></contrib><contrib contrib-type="author"><name><surname>Strom</surname><given-names>Tim M</given-names></name><xref ref-type="aff" rid="af37">37</xref><xref ref-type="aff" rid="af39">39</xref></contrib><contrib contrib-type="author"><name><surname>Theuns</surname><given-names>Jessie</given-names></name><xref ref-type="aff" rid="af14">14</xref><xref ref-type="aff" rid="af15">15</xref></contrib><contrib contrib-type="author"><name><surname>Tan</surname><given-names>Eng- King</given-names></name><xref ref-type="aff" rid="af44">44</xref></contrib><contrib contrib-type="author"><name><surname>Toda</surname><given-names>Tatsushi</given-names></name><xref ref-type="aff" rid="af42">42</xref></contrib><contrib contrib-type="author"><name><surname>Tomiyama</surname><given-names>Hiroyuki</given-names></name><xref ref-type="aff" rid="af22">22</xref></contrib><contrib contrib-type="author"><name><surname>Uitti</surname><given-names>Ryan J</given-names></name><xref ref-type="aff" rid="af45">45</xref></contrib><contrib contrib-type="author"><name><surname>Van Broeckhoven</surname><given-names>Christine</given-names></name><xref ref-type="aff" rid="af14">14</xref><xref ref-type="aff" rid="af15">15</xref></contrib><contrib contrib-type="author"><name><surname>Wirdefeldt</surname><given-names>Karin</given-names></name><xref ref-type="aff" rid="af46">46</xref></contrib><contrib contrib-type="author"><name><surname>Wszolek</surname><given-names>Zbigniew</given-names></name><xref ref-type="aff" rid="af45">45</xref></contrib><contrib contrib-type="author"><name><surname>Xiromerisiou</surname><given-names>Georgia</given-names></name><xref ref-type="aff" rid="af21">21</xref></contrib><contrib contrib-type="author"><name><surname>Yomono</surname><given-names>Harumi S</given-names></name><xref ref-type="aff" rid="af47">47</xref></contrib><contrib contrib-type="author"><name><surname>Yueh</surname><given-names>Kuo-Chu</given-names></name><xref ref-type="aff" rid="af27">27</xref></contrib><contrib contrib-type="author"><name><surname>Zhao</surname><given-names>Yi</given-names></name></contrib><contrib contrib-type="author"><name><surname>Gasser</surname><given-names>Thomas</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Maraganore</surname><given-names>Demetrius</given-names></name><xref ref-type="aff" rid="af48">48</xref></contrib><contrib contrib-type="author"><name><surname>Krüger</surname><given-names>Rejko</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><collab>on behalf of GEOPD consortium</collab></contrib></contrib-group><aff id="af1"><label>1</label>Department of Neurodegenerative diseases, Hertie-Institute for Clinical Brain Research and DZNE- German Center for Neurodegenerative Diseases, Tübingen</aff><aff id="af2"><label>2</label>Stanford Prevention Research Center, Department of Medicine and Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California, USA</aff><aff id="af3"><label>3</label>Department of Neurology, St Olavs Hospital and NTNU Trondheim, Trondheim, Norway</aff><aff id="af4"><label>4</label>Institute of Neurology, Department of Medical Sciences , University Magna Graecia, Catanzaro; Neuroimaging Research Unit, National Research Council, Catanzaro, Italy</aff><aff id="af5"><label>5</label>INSERM, UMR_S975, Université Pierre et Marie Curie-Paris, CNRS, UMR 7225, AP-HP, Pitié-Salpêtriére Hospital</aff><aff id="af6"><label>6</label>Cnrs, UMR 7225, Paris, France</aff><aff id="af7"><label>7</label>AP-HP, Hôpital Pitié-Salpêtiére, Department of Genetics and Cytogenetics, Paris, France</aff><aff id="af8"><label>8</label>Neuropsychiatric Genetics Group, Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.</aff><aff id="af9"><label>9</label>General Hospital of Syros, Syros, Greece</aff><aff id="af10"><label>10</label>‘Hygeia’ Hospital, Clinic of Neurodegenerative Disorders, Athens, Greece</aff><aff id="af11"><label>11</label>2nd Neurology Clinic, University of Athens, ‘Attikon’ Hospital, Athens, Greece</aff><aff id="af12"><label>12</label>Department of Neurodegenerative Disorders, Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland</aff><aff id="af13"><label>13</label>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium</aff><aff id="af14"><label>14</label>Institute Born-Bunge, University of Antwerp, Antwerp, Belgium</aff><aff id="af15"><label>15</label>Department of Neurology, Antwerp University Hospital, Antwerp, Belgium.</aff><aff id="af16"><label>16</label>School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, City Hospital, Birmingham, UK</aff><aff id="af17"><label>17</label>Centre for Biomedicine, European Academy Bozen/Bolzano, Itlay, Affiliated institute of the University of Lübeck, Lübeck, German</aff><aff id="af18"><label>18</label>Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada</aff><aff id="af19"><label>19</label>Human Genetic Centre, University Hospital of Liége, Liége, Belgium and Department of Neurology, General Central Hospital, Bolzano, Itlay</aff><aff id="af20"><label>20</label>Department of Neurology, Goethe University Frankfurt am Main, Frankfurt, Germany</aff><aff id="af21"><label>21</label>Department of Neurology, University of Thessaly and Institute of Biomedical Research and Technology, CERETETH, Larissa, Greece</aff><aff id="af22"><label>22</label>Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan</aff><aff id="af23"><label>23</label>Department of Neurology, Seoul National University Hospital, Seoul, Korea</aff><aff id="af24"><label>24</label>Department of Neurology, Medical University of Warsaw, Warsaw, Poland</aff><aff id="af25"><label>25</label>Department of Neurology, Jagiellonian University, Krakow, Poland</aff><aff id="af26"><label>26</label>Department of Neurology, Johannes Gutenberg University, Mainz, Germany</aff><aff id="af27"><label>27</label>Department of Neurology, Chushang Show-Chwan Hospital, Nantou and Chung-Shan Medical University Hospital, Taichung, Taiwan</aff><aff id="af28"><label>28</label>The Dublin Neurological Institute at the Mater Misericordiae University Hospital, and Conway Institute, University College Dublin, Dublin, Ireland</aff><aff id="af29"><label>29</label>Helmholtz Zentrum München, German Research Centre for Environmental Health (Gmbh), Neuherberg, Germany</aff><aff id="af30"><label>30</label>Movement Disorders Centre, and the Edmond J Safra Program in Parkinson's Disease, Toronto Western Hospital, University of Toronto, Toronto, Canada</aff><aff id="af31"><label>31</label>Department of Neurology, National Center Hospital of Neurology and Psychiatry, Tokyo, Japan</aff><aff id="af32"><label>32</label>Department of Medicine and Therapeutics, Prince of Wales Hospital,The Chinese University of Hong Kong, Shatin, Hong Kong</aff><aff id="af33"><label>33</label>Department of Neurology, Medical University of Silesia, Katowice, Poland</aff><aff id="af34"><label>34</label>Eskitis Institute for Cell and Molecular Therapies, Griffith University, Brisbane, Australia</aff><aff id="af35"><label>35</label>Neurosciences Department, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK</aff><aff id="af36"><label>36</label>German Research Center for Environmental Health, Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany</aff><aff id="af37"><label>37</label>Institute of Human Genetics, Technische Universität München, Munich, Germany</aff><aff id="af38"><label>38</label>Department of Neurology, Medizinische Universität Wien, Vienna, Austria</aff><aff id="af39"><label>39</label>Tanz Centre for Research in Neurodegenerative Diseases, Department of Medicine, University of Toronto, Toronto, Canada</aff><aff id="af40"><label>40</label>Department of Neuroscience, Mayo Clinic, Jacksonville, Florida</aff><aff id="af41"><label>41</label>Divisions of Basic Neurosciences & Cell Biology, Biomedical Research Foundation of Academy of Athens, Athens, Greece</aff><aff id="af42"><label>42</label>Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, Japan</aff><aff id="af43"><label>43</label>University of Queensland Centre for Clinical Research, Herston, Australia</aff><aff id="af44"><label>44</label>Department of Neurology, Singapore General Hospital, National Neuroscience Institute, Singapore</aff><aff id="af45"><label>45</label>Department of Neurology, Mayo Clinic Jacksonville, USA</aff><aff id="af46"><label>46</label>Epidemiology and Biostatistics and Department of Clinical Neuroscience, Karolinska Institutet</aff><aff id="af47"><label>47</label>Department of Neurology, National Hospital Organization Tokyo Hospital, Tokyo, Japan</aff><aff id="af48"><label>48</label>Department of Neurology, NorthShore University HealthSystem, Chicago, USA</aff><author-notes><corresp><label>Correspondence to</label> Dr Manu Sharma, Department. of Neurodegenerative diseases, Hertie-Institute for Clinical Brain Research and DZNE- German Center for Neurodegenerative Diseases, Tübingen, Hoppe-Seyler-Str. 3, Tübingen 72076, Germany; <email>manu.sharma@uni-tuebingen.de</email></corresp></author-notes><pub-date pub-type="ppub"><month>11</month><year>2012</year></pub-date><volume>49</volume><issue>11</issue><fpage>721</fpage><lpage>726</lpage><history><date date-type="received"><day>6</day><month>7</month><year>2012</year></date><date date-type="rev-recd"><day>5</day><month>9</month><year>2012</year></date><date date-type="accepted"><day>7</day><month>9</month><year>2012</year></date></history><permissions><copyright-statement>Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions</copyright-statement><copyright-year>2012</copyright-year><license license-type="open-access"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc/3.0/">http://creativecommons.org/licenses/by-nc/3.0/</ext-link> and <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc/3.0/legalcode">http://creativecommons.org/licenses/by-nc/3.0/legalcode</ext-link></license-p></license></permissions><self-uri xlink:title="pdf" xlink:type="simple" xlink:href="jmedgenet-2012-101155.pdf"></self-uri><abstract><sec><title>Background</title><p>Two recent studies identified a mutation (p.Asp620Asn) in the vacuolar protein sorting 35 gene as a cause for an autosomal dominant form of Parkinson disease . Although additional missense variants were described, their pathogenic role yet remains inconclusive.</p></sec><sec><title>Methods and results</title><p>We performed the largest multi-center study to ascertain the frequency and pathogenicity of the reported vacuolar protein sorting 35 gene variants in more than 15,000 individuals worldwide. p.Asp620Asn was detected in 5 familial and 2 sporadic PD cases and not in healthy controls, p.Leu774Met in 6 cases and 1 control, p.Gly51Ser in 3 cases and 2 controls. Overall analyses did not reveal any significant increased risk for p.Leu774Met and p.Gly51Ser in our cohort.</p></sec><sec><title>Conclusions</title><p>Our study apart from identifying the p.Asp620Asn variant in familial cases also identified it in idiopathic Parkinson disease cases, and thus provides genetic evidence for a role of p.Asp620Asn in Parkinson disease in different populations worldwide.</p></sec></abstract><kwd-group><kwd>Parkinson-s disease</kwd><kwd>Genome-wide</kwd><kwd>Genetics</kwd><kwd>Genetic epidemiology</kwd><kwd>Complex traits</kwd></kwd-group><custom-meta-group><custom-meta><meta-name>special-feature</meta-name><meta-value>unlocked</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec id="s1"><title>Introduction</title><p>There is increasing interest to try to identify uncommon and rare genetic variants that increase the risk of common diseases and that are difficult to identify using traditional genome-wide association studies (GWAS) approaches.<xref ref-type="bibr" rid="R1">1</xref> Rare variants which are not mapped by GWAS can be identified by using next generation sequencing, that is, exome sequencing in large families with multiple affected individuals.<xref ref-type="bibr" rid="R2">2</xref> Exome sequencing is now routinely used to identify rare mutations in familial forms of disease in diverse phenotypes.<xref ref-type="bibr" rid="R2">2</xref></p><p>Two recent studies independently performed exome sequencing in large families of Caucasian descent, and identified a mutation in the vacuolar protein sorting 35 (VPS35) gene as a possible cause for an autosomal dominant form of Parkinson disease (PD).<xref ref-type="bibr" rid="R3">3</xref><xref ref-type="bibr" rid="R4">4</xref> In addition, several non-synonymous base exchanges were identified, but their involvement in disease pathogenesis remains inconclusive. Furthermore, recently published studies provided conflicting results regarding the role of VPS35 in PD.<xref ref-type="bibr" rid="R5 R6 R7 R8">5–8</xref> Here, we performed a large multi-centre study to determine the frequency and pathogenicity of VPS35 variants in PD in diverse populations worldwide.</p></sec><sec sec-type="methods" id="s2"><title>Methods</title><sec id="s2a"><title>Consortium</title><p>Investigators from the Genetic Epidemiology of Parkinson disease Consortium were invited to participate in this study. A total of 23 sites representing 19 countries from four continents agreed to contribute DNA samples and clinical data for a total of 15 383 individuals (8870 cases and 6513 controls). Control individuals underwent neurological examination and were excluded from the study whenever there was clinical evidence for any extrapyramidal disorder.</p></sec><sec id="s2b"><title>Genotyping</title><p>We selected seven non-synonymous variants exactly as they were proposed.<xref ref-type="bibr" rid="R3">3</xref> In addition, we selected tag single nucleotide polymorphisms (SNPs) (HapMap Rel 28 phase II+III, Aug10, National Centre for Biotechnology Information. B36 dbSNP b126; <ext-link ext-link-type="uri" xlink:href="http://www.hapmap.org">http://www.hapmap.org</ext-link>) that cover the common genetic variants in the VPS35 gene using an r<sup>2</sup> threshold of 0.8–1.0 to select tag SNPs for VPS35 gene. Using this strategy, we were able to capture 23 SNPs in a 40 kb region, including VPS35 (‘chr16:46 693 589–46 723 144 based on hg 19’). Therefore, in total, 10 SNPs located in the VPS35 were genotyped (including seven rare non-synonymous and three common variants). Genotyping was performed by a central genotyping core. Genotyping was performed using a matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry on a MassArray system (Sequenom, San Diego, California, USA). Cleaned extension products were analysed by a mass spectrometer (Bruker Daltronic, Billerica, MA, USA) and peaks were identified using the MassArray Typer 4.0.2.5 software (Sequenom). Assays were designed by the AssayDesigner software 4.0 (Sequenom) with the default parameters for the iPLEX Gold chemistry and the Human GenoTyping Tools ProxSNP and PreXTEND (Sequenom). All variants were genotyped in one multiplex assay. The average call rate of the variants was >97%. The local Ethics Committee approved the study. All participants gave signed informed consent.</p></sec><sec id="s2c"><title>Statistical analysis</title><p>Logistic regression was used to test the association between VPS35 and PD in our overall cohort. For common variants (minor allele frequency >5%), we synthesised the effect estimates using fixed and random effects models. Fixed effect models assume that the genetic effect is the same in populations from different sites and that observed differences are due to chance alone. For associations showing between-study heterogeneity, fixed effect estimates yield narrower CIs and smaller p values as compared with random effects models, which incorporate between-study heterogeneity.<xref ref-type="bibr" rid="R9">9</xref><xref ref-type="bibr" rid="R10">10</xref> Random effects models allow the genetic effects might be different due to genuine heterogeneity that may exist across different sites. Random effects calculations take into account the estimated between-study heterogeneity. Cochran's Q test of homogeneity and the I<sup>2</sup> metric were used to evaluate the between-site heterogeneity. The I<sup>2</sup> metric ranges from 0% to 100% and measures the proportion of variability that is beyond chance. Typically, estimates of I<sup>2</sup><25% are considered to reflect little or no heterogeneity, 25%–50% moderate heterogeneity, 50%–75% large heterogeneity and >75% very large heterogeneity. The overall main analysis considered all sites and populations irrespective of ancestry. For variants with minor allele frequency <1%, an exact test was used to compare the frequency differences between cases and controls combining data across all 21 sites.</p></sec></sec><sec sec-type="results" id="s3"><title>Results</title><sec id="s3a"><title>Characteristics of sites and overall database</title><p>Overall, 23 sites contributed a total of 8870 cases and 6513 controls. Characteristics of all participating sites are shown in <xref ref-type="table" rid="JMEDGENET2012101155TB1">table 1</xref>. Most sites contributed participants of Caucasian ancestry (N=19); four sites included participants of Asian ancestry. The proportion of men and women ranged from 42% to 58% across different participating sites (<xref ref-type="table" rid="JMEDGENET2012101155TB1">table 1</xref>). The median age at onset of PD in our studied population was 61 years.</p><table-wrap id="JMEDGENET2012101155TB1" position="float"><label>Table 1</label><caption><p>Description of datasets contributed by each study site</p></caption><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" span="1"></col><col align="left" span="1"></col><col align="char" char="." span="1"></col><col align="char" char="." span="1"></col><col align="char" char="." span="1"></col><col align="char" char="(" span="1"></col><col align="char" char="(" span="1"></col><col align="char" char="." span="1"></col><col align="char" char="." span="1"></col><col align="left" span="1"></col></colgroup><thead valign="bottom"><tr><th align="left" rowspan="1" colspan="1">Site</th><th align="left" rowspan="1" colspan="1">Country</th><th align="left" rowspan="1" colspan="1">N</th><th align="left" rowspan="1" colspan="1">Case</th><th align="left" rowspan="1" colspan="1">Control</th><th align="left" rowspan="1" colspan="1">Male (%)</th><th align="left" rowspan="1" colspan="1">Female (%)</th><th align="left" rowspan="1" colspan="1">Mean AAO</th><th align="left" rowspan="1" colspan="1">Mean Age at study</th><th align="left" rowspan="1" colspan="1">Diagnostic criteria</th></tr></thead><tbody><tr><td rowspan="1" colspan="1">Annesi</td><td rowspan="1" colspan="1">Italy</td><td rowspan="1" colspan="1">394</td><td rowspan="1" colspan="1">197</td><td rowspan="1" colspan="1">197</td><td rowspan="1" colspan="1">204 (51.7%)</td><td rowspan="1" colspan="1">190 (48.2%)</td><td rowspan="1" colspan="1">61.5</td><td rowspan="1" colspan="1">63.7</td><td rowspan="1" colspan="1">UKPDBB</td></tr><tr><td rowspan="1" colspan="1">Brice</td><td rowspan="1" colspan="1">France</td><td rowspan="1" colspan="1">505</td><td rowspan="1" colspan="1">272</td><td rowspan="1" colspan="1">233</td><td rowspan="1" colspan="1">302 (59.8%)</td><td rowspan="1" colspan="1">203 (40.1%)</td><td rowspan="1" colspan="1">47.6</td><td rowspan="1" colspan="1">57.8</td><td rowspan="1" colspan="1">UKPDBB</td></tr><tr><td rowspan="1" colspan="1">Bozi</td><td rowspan="1" colspan="1">Greece</td><td rowspan="1" colspan="1">222</td><td rowspan="1" colspan="1">114</td><td rowspan="1" colspan="1">108</td><td rowspan="1" colspan="1">107 (48.1%)</td><td rowspan="1" colspan="1">115 (51.8%)</td><td rowspan="1" colspan="1">69.9</td><td rowspan="1" colspan="1">74.5</td><td rowspan="1" colspan="1">UKPDBB</td></tr><tr><td rowspan="1" colspan="1">Wszolek</td><td rowspan="1" colspan="1">USA</td><td rowspan="1" colspan="1">1518</td><td rowspan="1" colspan="1">692</td><td rowspan="1" colspan="1">826</td><td rowspan="1" colspan="1">794 (52.3%)</td><td rowspan="1" colspan="1">724 (47.6%)</td><td rowspan="1" colspan="1">64.4</td><td rowspan="1" colspan="1">71.7</td><td rowspan="1" colspan="1">UKPDBB</td></tr><tr><td rowspan="1" colspan="1">Garraux</td><td rowspan="1" colspan="1">Belgium</td><td rowspan="1" colspan="1">82</td><td rowspan="1" colspan="1">68</td><td rowspan="1" colspan="1">14</td><td rowspan="1" colspan="1">45 (54.8)</td><td rowspan="1" colspan="1">37 (45.1%)</td><td rowspan="1" colspan="1">62.1</td><td rowspan="1" colspan="1">69.6</td><td rowspan="1" colspan="1">UKPDBB</td></tr><tr><td rowspan="1" colspan="1">Hadjigeorgiou</td><td rowspan="1" colspan="1">Greece</td><td rowspan="1" colspan="1">714</td><td rowspan="1" colspan="1">357</td><td rowspan="1" colspan="1">357</td><td rowspan="1" colspan="1">379 (53.0%)</td><td rowspan="1" colspan="1">335 (46.9%)</td><td rowspan="1" colspan="1">63.4</td><td rowspan="1" colspan="1">63.7</td><td rowspan="1" colspan="1">UKPDBB</td></tr><tr><td rowspan="1" colspan="1">Jeon</td><td rowspan="1" colspan="1">Korea</td><td rowspan="1" colspan="1">749</td><td rowspan="1" colspan="1">408</td><td rowspan="1" colspan="1">341</td><td rowspan="1" colspan="1">314 (41.9%)</td><td rowspan="1" colspan="1">435 (58.0%)</td><td rowspan="1" colspan="1">57.6</td><td rowspan="1" colspan="1">NA</td><td rowspan="1" colspan="1">UKPDBB</td></tr><tr><td rowspan="1" colspan="1">Opala</td><td rowspan="1" colspan="1">Poland</td><td rowspan="1" colspan="1">629</td><td rowspan="1" colspan="1">352</td><td rowspan="1" colspan="1">277</td><td rowspan="1" colspan="1">340 (54.0%)</td><td rowspan="1" colspan="1">288 (45.7%)</td><td rowspan="1" colspan="1">50.2</td><td rowspan="1" colspan="1">68.1</td><td rowspan="1" colspan="1">UKPDBB</td></tr><tr><td rowspan="1" colspan="1">Lynch</td><td rowspan="1" colspan="1">Ireland</td><td rowspan="1" colspan="1">740</td><td rowspan="1" colspan="1">368</td><td rowspan="1" colspan="1">372</td><td rowspan="1" colspan="1">340 (45.9%)</td><td rowspan="1" colspan="1">400 (54.0%)</td><td rowspan="1" colspan="1">50.5</td><td rowspan="1" colspan="1">70.7</td><td rowspan="1" colspan="1">UKPDBB</td></tr><tr><td rowspan="1" colspan="1">Lin</td><td rowspan="1" colspan="1">Taiwan</td><td rowspan="1" colspan="1">320</td><td rowspan="1" colspan="1">160</td><td rowspan="1" colspan="1">160</td><td rowspan="1" colspan="1">160 (50%)</td><td rowspan="1" colspan="1">160 (50%)</td><td rowspan="1" colspan="1">62.0</td><td rowspan="1" colspan="1">70.8</td><td rowspan="1" colspan="1">UKPDBB</td></tr><tr><td rowspan="1" colspan="1">Facheris</td><td rowspan="1" colspan="1">Italy</td><td rowspan="1" colspan="1">181</td><td rowspan="1" colspan="1">114</td><td rowspan="1" colspan="1">67</td><td rowspan="1" colspan="1">86 (47.5%)</td><td rowspan="1" colspan="1">95 (52.4%)</td><td rowspan="1" colspan="1">63.0</td><td rowspan="1" colspan="1">NA</td><td rowspan="1" colspan="1">UKPDBB</td></tr><tr><td rowspan="1" colspan="1">Maraganore</td><td rowspan="1" colspan="1">USA</td><td rowspan="1" colspan="1">1024</td><td rowspan="1" colspan="1">801</td><td rowspan="1" colspan="1">223</td><td rowspan="1" colspan="1">600 (58.5%)</td><td rowspan="1" colspan="1">361 (35.3%)</td><td rowspan="1" colspan="1">59</td><td rowspan="1" colspan="1">74.7</td><td rowspan="1" colspan="1">Bower</td></tr><tr><td rowspan="1" colspan="1">Mellick</td><td rowspan="1" colspan="1">Australia</td><td rowspan="1" colspan="1">2024</td><td rowspan="1" colspan="1">1012</td><td rowspan="1" colspan="1">1012</td><td rowspan="1" colspan="1">1042 (51.4%)</td><td rowspan="1" colspan="1">981 (48.4%)</td><td rowspan="1" colspan="1">59</td><td rowspan="1" colspan="1">72.2</td><td rowspan="1" colspan="1">Bower</td></tr><tr><td rowspan="1" colspan="1">Morrison</td><td rowspan="1" colspan="1">England</td><td rowspan="1" colspan="1">1120</td><td rowspan="1" colspan="1">766</td><td rowspan="1" colspan="1">354</td><td rowspan="1" colspan="1">606 (54.1%)</td><td rowspan="1" colspan="1">514 (45.8%)</td><td rowspan="1" colspan="1">66.1</td><td rowspan="1" colspan="1">NA</td><td rowspan="1" colspan="1">UKPDBB</td></tr><tr><td rowspan="1" colspan="1">Mok</td><td rowspan="1" colspan="1">China</td><td rowspan="1" colspan="1">436</td><td rowspan="1" colspan="1">260</td><td rowspan="1" colspan="1">176</td><td rowspan="1" colspan="1"> 264 (60.5%)</td><td rowspan="1" colspan="1">170 (38.9%)</td><td rowspan="1" colspan="1">NA</td><td rowspan="1" colspan="1">63.5</td><td rowspan="1" colspan="1">UKPDBB</td></tr><tr><td rowspan="1" colspan="1">Aasly</td><td rowspan="1" colspan="1">Norway</td><td rowspan="1" colspan="1">1278</td><td rowspan="1" colspan="1">656</td><td rowspan="1" colspan="1">622</td><td rowspan="1" colspan="1">721 (56.4%)</td><td rowspan="1" colspan="1">557 (43.5%)</td><td rowspan="1" colspan="1">58.8</td><td rowspan="1" colspan="1">72.9</td><td rowspan="1" colspan="1">UKPDBB</td></tr><tr><td rowspan="1" colspan="1">Wirdefeldt</td><td rowspan="1" colspan="1">Sweden</td><td rowspan="1" colspan="1">299</td><td rowspan="1" colspan="1">83</td><td rowspan="1" colspan="1">216</td><td rowspan="1" colspan="1">147 (49.1%)</td><td rowspan="1" colspan="1">152 (50.8%)</td><td rowspan="1" colspan="1">65.8</td><td rowspan="1" colspan="1">71.4</td><td rowspan="1" colspan="1">Gelb</td></tr><tr><td rowspan="1" colspan="1">Van Broeckhoven</td><td rowspan="1" colspan="1">Belgium</td><td rowspan="1" colspan="1">1010</td><td rowspan="1" colspan="1">501</td><td rowspan="1" colspan="1">509</td><td rowspan="1" colspan="1">500 (49.5%)</td><td rowspan="1" colspan="1">509 (50.3%)</td><td rowspan="1" colspan="1">60.5</td><td rowspan="1" colspan="1">66.3</td><td rowspan="1" colspan="1">Pals/Gelb</td></tr><tr><td rowspan="1" colspan="1">Rogaeva</td><td rowspan="1" colspan="1">Canada</td><td rowspan="1" colspan="1">560</td><td rowspan="1" colspan="1">387</td><td rowspan="1" colspan="1">173</td><td rowspan="1" colspan="1">303 (54.1%)</td><td rowspan="1" colspan="1">257 (45.8%)</td><td rowspan="1" colspan="1">49.7</td><td rowspan="1" colspan="1">64.2</td><td rowspan="1" colspan="1">UKPDBB</td></tr><tr><td rowspan="1" colspan="1">Tan</td><td rowspan="1" colspan="1">Singapore</td><td rowspan="1" colspan="1">391</td><td rowspan="1" colspan="1">194</td><td rowspan="1" colspan="1">197</td><td rowspan="1" colspan="1">244 (62.4%)</td><td rowspan="1" colspan="1">147 (37.5%)</td><td rowspan="1" colspan="1">59.7</td><td rowspan="1" colspan="1">54.0</td><td rowspan="1" colspan="1">UKPDBB</td></tr><tr><td rowspan="1" colspan="1">Hattori</td><td rowspan="1" colspan="1">Japan</td><td rowspan="1" colspan="1">121</td><td rowspan="1" colspan="1">121</td><td rowspan="1" colspan="1">0</td><td rowspan="1" colspan="1">62 (51.2%)</td><td rowspan="1" colspan="1">59 (48.7%)</td><td rowspan="1" colspan="1">NA</td><td rowspan="1" colspan="1">NA</td><td rowspan="1" colspan="1">UKPDBB</td></tr><tr><td rowspan="1" colspan="1">Gasser/Sharma</td><td rowspan="1" colspan="1">Germany</td><td rowspan="1" colspan="1">760</td><td rowspan="1" colspan="1">760</td><td rowspan="1" colspan="1">0</td><td rowspan="1" colspan="1">479 (63.3%)</td><td rowspan="1" colspan="1">281 (36.9%)</td><td rowspan="1" colspan="1">58.9</td><td rowspan="1" colspan="1">NA</td><td rowspan="1" colspan="1">UKPDBB</td></tr><tr><td rowspan="1" colspan="1">Toda</td><td rowspan="1" colspan="1">Japan</td><td rowspan="1" colspan="1">306</td><td rowspan="1" colspan="1">227</td><td rowspan="1" colspan="1">79</td><td rowspan="1" colspan="1">161 (52.6%)</td><td rowspan="1" colspan="1">145 (47.3%)</td><td rowspan="1" colspan="1">57.8</td><td rowspan="1" colspan="1">65.1</td><td rowspan="1" colspan="1">UKPDBB</td></tr><tr><td rowspan="1" colspan="1">Total</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"><bold>15</bold> <bold>383</bold></td><td rowspan="1" colspan="1"><bold>8870</bold></td><td rowspan="1" colspan="1"><bold>6513</bold></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">59.5</td><td rowspan="1" colspan="1">67.6</td><td rowspan="1" colspan="1"></td></tr></tbody></table><table-wrap-foot><fn><p>AAO, Age at onset; NA: Not applicable.</p></fn></table-wrap-foot></table-wrap></sec><sec id="s3b"><title>Rare variants</title><p>Overall, we observed p.Asp620Asn in seven cases, p.Leu774Met in six cases and one control, p.Gly51Ser in three cases and two controls. Details per site are shown in <xref ref-type="table" rid="JMEDGENET2012101155TB2">table 2</xref>. The controls subjects carrying p.Leu774Met (P-13) and p.Gly51Ser (P-2 and P-16) at the time of study sampling were 81, 84 and 76 years, respectively. In Caucasian populations, the number of carriers in cases and controls for the three variants were 5 versus 0 (pAsp620Asn), 4 versus 1 (pLeu774Met) and 3 versus 1 (p.Gly51Ser), respectively. In Asian descent populations, the respective numbers were 2 versus 0 (p.Asp620Asn), 2 versus 0 (p.Leu774Met) and 0 versus 1 (p.Gly51Ser). Most interestingly, two out of seven patients carrying the p.Asp620Asn variant presented without any family history for PD. This represents the first evidence for reduced penetrance of the respective variant initially attributed to autosomal dominant familial PD. We did not observe any carriers for one variant (p.Arg524Trp) in our cohort. Two non-synonymous variants (p.Met57Ile, p.Thr82Arg) failed genotyping. By collapsing the rare variants across different sites, we did not observe statistically significant increased risk for p.Leu774Met and p.Gly51Ser in our cohort (see online supplementary table S1).</p><table-wrap id="JMEDGENET2012101155TB2" position="float"><label>Table 2</label><caption><p>Clinical description of carriers of non-synonymous variants of vacuolar protein sorting 35 gene</p></caption><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" span="1"></col><col align="left" span="1"></col><col align="left" span="1"></col><col align="left" span="1"></col><col align="left" span="1"></col><col align="left" span="1"></col><col align="left" span="1"></col><col align="left" span="1"></col><col align="left" span="1"></col><col align="left" span="1"></col><col align="left" span="1"></col><col align="left" span="1"></col></colgroup><thead valign="bottom"><tr><th align="left" rowspan="1" colspan="1">Id</th><th align="left" rowspan="1" colspan="1">Ethnicity</th><th align="left" rowspan="1" colspan="1">Rare variant</th><th align="left" rowspan="1" colspan="1">Age at onset</th><th align="left" rowspan="1" colspan="1">Clinical signs</th><th align="left" rowspan="1" colspan="1">Bradykinesia</th><th align="left" rowspan="1" colspan="1">Rigidity</th><th align="left" rowspan="1" colspan="1">Tremor</th><th align="left" rowspan="1" colspan="1">Postural instability</th><th align="left" rowspan="1" colspan="1">L-dopa responsive</th><th align="left" rowspan="1" colspan="1">Non-motor symptoms</th><th align="left" rowspan="1" colspan="1">Family history</th></tr></thead><tbody><tr><td rowspan="1" colspan="1">P-1</td><td rowspan="1" colspan="1">Caucasian</td><td rowspan="1" colspan="1">p.Asp620Asn</td><td rowspan="1" colspan="1">59</td><td rowspan="1" colspan="1">Classical PD</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">Negative</td><td rowspan="1" colspan="1">Negative</td></tr><tr><td rowspan="1" colspan="1">P-2</td><td rowspan="1" colspan="1">Caucasian</td><td rowspan="1" colspan="1">p.Gly51Ser</td><td rowspan="1" colspan="1">NA</td><td rowspan="1" colspan="1">Control</td><td rowspan="1" colspan="1">−</td><td rowspan="1" colspan="1">−</td><td rowspan="1" colspan="1">−</td><td rowspan="1" colspan="1">−</td><td rowspan="1" colspan="1">−</td><td rowspan="1" colspan="1">Negative</td><td rowspan="1" colspan="1">Negative</td></tr><tr><td rowspan="1" colspan="1">P-3</td><td rowspan="1" colspan="1">Caucasian</td><td rowspan="1" colspan="1">p.Gly51Ser</td><td rowspan="1" colspan="1">NAV</td><td rowspan="1" colspan="1">Classical PD</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">Dementia, visual hallucinations</td><td rowspan="1" colspan="1">Negative</td></tr><tr><td rowspan="1" colspan="1">P-4</td><td rowspan="1" colspan="1">Caucasian</td><td rowspan="1" colspan="1">p.Gly51Ser</td><td rowspan="1" colspan="1">55</td><td rowspan="1" colspan="1">Classical PD</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">Negative</td><td rowspan="1" colspan="1">Negative</td></tr><tr><td rowspan="1" colspan="1">P-5</td><td rowspan="1" colspan="1">Caucasian</td><td rowspan="1" colspan="1">p.Gly51Ser</td><td rowspan="1" colspan="1">49</td><td rowspan="1" colspan="1">Classical PD</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">Negative</td><td rowspan="1" colspan="1">Negative</td></tr><tr><td rowspan="1" colspan="1">P-6</td><td rowspan="1" colspan="1">Caucasian</td><td rowspan="1" colspan="1">p.Asp620Asn</td><td rowspan="1" colspan="1">37</td><td rowspan="1" colspan="1">Classical PD</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">Negative</td><td rowspan="1" colspan="1">Positive</td></tr><tr><td rowspan="1" colspan="1">P-7</td><td rowspan="1" colspan="1">Caucasian</td><td rowspan="1" colspan="1">p.Asp620Asn</td><td rowspan="1" colspan="1">59</td><td rowspan="1" colspan="1">Classical PD</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">Negative</td><td rowspan="1" colspan="1">Positive</td></tr><tr><td rowspan="1" colspan="1">P-8</td><td rowspan="1" colspan="1">Caucasian</td><td rowspan="1" colspan="1">p.Asp620Asn</td><td rowspan="1" colspan="1">55</td><td rowspan="1" colspan="1">Classical PD</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">Negative</td><td rowspan="1" colspan="1">Positive</td></tr><tr><td rowspan="1" colspan="1">P-9</td><td rowspan="1" colspan="1">Caucasian</td><td rowspan="1" colspan="1">p.Asp620Asn</td><td rowspan="1" colspan="1">66</td><td rowspan="1" colspan="1">Classical PD</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">Negative</td><td rowspan="1" colspan="1">Positive</td></tr><tr><td rowspan="1" colspan="1">P-10</td><td rowspan="1" colspan="1">Caucasian</td><td rowspan="1" colspan="1">p.Leu774Met</td><td rowspan="1" colspan="1">41</td><td rowspan="1" colspan="1">Classical PD</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">Negative</td><td rowspan="1" colspan="1">Positive</td></tr><tr><td rowspan="1" colspan="1">P-11</td><td rowspan="1" colspan="1">Caucasian</td><td rowspan="1" colspan="1">p.Leu774Met</td><td rowspan="1" colspan="1">65</td><td rowspan="1" colspan="1">Classical PD</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">Negative</td><td rowspan="1" colspan="1">Positive</td></tr><tr><td rowspan="1" colspan="1">P-12</td><td rowspan="1" colspan="1">Caucasian</td><td rowspan="1" colspan="1">p.Leu774Met</td><td rowspan="1" colspan="1">65</td><td rowspan="1" colspan="1">Classical PD</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">Disturbance of gait and balance</td><td rowspan="1" colspan="1">Positive</td></tr><tr><td rowspan="1" colspan="1">P-13</td><td rowspan="1" colspan="1">Caucasian</td><td rowspan="1" colspan="1">p.Leu774Met</td><td rowspan="1" colspan="1">NA</td><td rowspan="1" colspan="1">Control</td><td rowspan="1" colspan="1">−</td><td rowspan="1" colspan="1">−</td><td rowspan="1" colspan="1">−</td><td rowspan="1" colspan="1">−</td><td rowspan="1" colspan="1">NA</td><td rowspan="1" colspan="1">-</td><td rowspan="1" colspan="1">Negative</td></tr><tr><td rowspan="1" colspan="1">P-14</td><td rowspan="1" colspan="1">Caucasian</td><td rowspan="1" colspan="1">p.Leu774Met</td><td rowspan="1" colspan="1">44</td><td rowspan="1" colspan="1">Classical PD</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+ Rest 1st sx</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">Autonomic dysfunction</td><td rowspan="1" colspan="1">Positive</td></tr><tr><td rowspan="1" colspan="1">P-15</td><td rowspan="1" colspan="1">Asian</td><td rowspan="1" colspan="1">p.Asp620Asn,p.Leu774Met</td><td rowspan="1" colspan="1">52</td><td rowspan="1" colspan="1">Classical PD</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">Negative</td><td rowspan="1" colspan="1">Negative</td></tr><tr><td rowspan="1" colspan="1">P-16</td><td rowspan="1" colspan="1">Asian</td><td rowspan="1" colspan="1">p.Gly51Ser</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">Control</td><td rowspan="1" colspan="1">−</td><td rowspan="1" colspan="1">−</td><td rowspan="1" colspan="1">−</td><td rowspan="1" colspan="1">−</td><td rowspan="1" colspan="1">−</td><td rowspan="1" colspan="1">–</td><td rowspan="1" colspan="1">Negative</td></tr><tr><td rowspan="1" colspan="1">P-17</td><td rowspan="1" colspan="1">Asian</td><td rowspan="1" colspan="1">p.Leu774Met</td><td rowspan="1" colspan="1">75</td><td rowspan="1" colspan="1">Classical PD</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">Negative</td><td rowspan="1" colspan="1">Negative</td></tr><tr><td rowspan="1" colspan="1">P-18</td><td rowspan="1" colspan="1">Asian</td><td rowspan="1" colspan="1">p.Asp620Asn</td><td rowspan="1" colspan="1">43</td><td rowspan="1" colspan="1">Classical PD</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">+</td><td rowspan="1" colspan="1">Mild cognitive impairment</td><td rowspan="1" colspan="1">Positive</td></tr></tbody></table><table-wrap-foot><fn><p>NA, not applicable; NAV, not available; PD, Parkinson disease; +positive; −negative.</p></fn></table-wrap-foot></table-wrap></sec><sec id="s3c"><title>Overall data synthesis for common variants</title><p>Out of three tag SNPs, one SNP (rs3218745) failed genotyping. We did not observe significant association for any of common variants with PD either with either fixed effect or random effect models (see online supplementary table S2). The OR ranged from 0.96 to 0.99 and tight 95% CIs excluded modest association effects. We observed no substantial heterogeneity for the two genotyped SNPs, and also the Q test was non-statistically significant for common SNPs. Moreover, examining the Caucasian or Asian populations separately did not change our results (data not shown).</p></sec><sec id="s3d"><title>Clinical features</title><p>All PD patients who carried potential pathogenic variants (p.Asp620Asn, p.Gly51Ser, p.Leu774Met) were clinically diagnosed with PD (Online supplementary clinical analysis data). A few of these (0.2%) affected individuals also have a positive family history. Affected individuals exhibited classical symptoms of PD (resting tremor, bradykinesia, rigidity) (<xref ref-type="table" rid="JMEDGENET2012101155TB2">table 2</xref>). The clinical diagnosis of PD was made by movement disorder specialists who used UK brain bank criteria for PD. Non-motor symptoms were present in the majority of PD patients carrying a pathogenic variant (<xref ref-type="table" rid="JMEDGENET2012101155TB2">table 2</xref>). Interestingly, hallucinations and dementia were also observed in one asymptomatic carrier suggesting clinical heterogeneity associated with VPS35. The identified healthy carriers have not shown any sign of PD as yet (<xref ref-type="table" rid="JMEDGENET2012101155TB2">table 2</xref>).</p></sec></sec><sec sec-type="discussion" id="s4"><title>Discussion</title><p>We performed the first multi-centre study to define the role of the VPS35 gene (PARK17) in PD by assessing the frequency of the reported non-synonymous variants in familial and sporadic PD patients from different populations worldwide. Among 15 383 subjects genotyped, we found a pathogenic relevance for p.Asp620Asn in different populations. Most interestingly, out of seven subjects who carry p.Asp620Asn, two have a negative family history. Therefore, our results provide additional evidence that VPS35 is a rare cause of familial as well as the common sporadic form of PD. In total, about 0.4% of PD cases in diverse population were due to disease-associated variant in the VPS35 gene. Our lack of supporting the role of common variants of the VPS35 gene in PD is consistent with recently published GWAS and also meta- analyses of GWAS of PD, as none of these highlighted the role of common variability in VPS35 gene as a risk factor for PD.<xref ref-type="bibr" rid="R11 R12 R13 R14 R15">11–15</xref> The p.Asp620Asn variant is located in the C-terminal region of the VPS35 protein pointing that subtle structural changes might influence the disease pathogenesis.<xref ref-type="bibr" rid="R3">3</xref></p><p>The spectrum of proteins involved in PD aetiology has grown considerably. This includes proteins that are related to mitochondrial quality control (Parkin, PINK1 and DJ1), proteins involved in protein aggregation (SNCA) (Synuclein, MAPT) Microtubule associated protein Tau), and proteins which are involved in sorting and degradation within endocytic and autophagy pathways ((VDAC) Voltage dependent anion channel, (GBA) Glucocerebrosidase gene, VPS35).<xref ref-type="bibr" rid="R16">16</xref><xref ref-type="bibr" rid="R17">17</xref> So far, very little is known about the specific role of VPS35 in PD, except that it is hypothesised that it is involved in cargo recognition as part of a retrograde complex recycling membrane proteins from endosomes to the trans-Golgi network.<xref ref-type="bibr" rid="R3">3</xref><xref ref-type="bibr" rid="R4">4</xref> Indeed<italic>,</italic> in vitro and in vivo studies strongly implicate the role of VPS35 gene in neurodegeneration. For example, reduced levels of VPS35 have been found in affected brain regions of Alzheimer disease (AD) patients<xref ref-type="bibr" rid="R18">18</xref> and loss of VPS35 function has been shown to increase the levels of amyloid β and cause synaptic impairment in a mouse model of AD. Furthermore, variants in another member of the VPS family and substrate of retromer complex, SORL1, have been implicated in AD.<xref ref-type="bibr" rid="R19">19</xref></p><p>In this study, we have focused only on non-synonymous variants identified by Zimprich and colleagues.<xref ref-type="bibr" rid="R3">3</xref> Of note, we confirmed the pathogenic relevance of the p.Asp620Asn variant which was identified by both studies for familial cases and in sporadic PD. Recently, published studies also identified p.Asp620Asn mutations in PD,<xref ref-type="bibr" rid="R6">6</xref><xref ref-type="bibr" rid="R20">20</xref> thus providing support to the role of p.Asp620Asn in PD. In our study, clinically, the symptomatic carriers showed a broad spectrum of clinical phenotypes ranging from typical PD to (DLB) Dementia with Lewy body, so longitudinal evaluation of carriers at risk will provide unique information on the natural course of the disease caused by VPS35. Even though our data support the role of p.Asp620Asn variant in PD, given the fact that the frequency in diverse population is far below <1%, it is likely to be a rare cause of PD worldwide. Nevertheless, sequencing of families is encouraged for identifying additional missense variants which may provide mechanistic insight into the causes of PD.</p></sec><sec sec-type="supplementary-material"><title>Supplementary Material</title><supplementary-material content-type="local-data" id="SD1"><caption><title>Web appendix</title></caption><media xlink:href="jmedgenet-2012-101155supp.pdf" xlink:type="simple" id="d34e2100" position="anchor" mimetype="application" mime-subtype="pdf"></media></supplementary-material></sec></body><back><ack><p>RS Boyle, MD (Princess Alexandra Hospital, Brisbane, Site Investigator); A Sellbach, MD (Princess Alexandra Hospital, Brisbane, Site Investigator); JD O'Sullivan, MD (Royal Brisbane and Women's Hospital Brisbane, Site Investigator); GT Sutherland, PhD (Eskitis Institute for Cell and Molecular Therapies, Griffith University, Nathan, QLD, Site Investigator); GA Siebert, MD (Eskitis Institute for Cell and Molecular Therapies, Griffith University, Nathan, QLD, Site Investigator); NNW Dissanayaka, MD (Eskitis Institute for Cell and Molecular Therapies, Griffith University, Nathan, QLD,Site Investigator); Christine Van Broeckhoven, PhD DSc (Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB; and Laboratory of Neurogenetics, Institute Born-Bunge; and University of Antwerp); Jessie Theuns, PhD (Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB; and Laboratory of Neurogenetics, Institute Born-Bunge; and University of Antwerp); David Crosiers, MD (Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB; and Laboratory of Neurobiology, Institute Born-Bunge; and University of Antwerp; and Department of Neurology, Antwerp University Hospital, Antwerp); Barbara Pickut, MD (Department of Neurology, Antwerp University Hospital, Antwerp); Sebastiaan Engelborghs, MD, PhD (Laboratory of Neurochemistry and Behaviour, Institute Born-Bunge; and University of Antwerp; and Department of Neurology and Memory Clinic, Hospital Network Antwerp, Middelheim and Hoge Beuken, Antwerp); Aline Verstraeten (Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB; and Laboratory of Neurogenetics, Institute Born-Bunge; and University of Antwerp); Peter P De Deyn, MD, PhD (Laboratory of Neurochemistry and Behaviour, Institute Born-Bunge; and University of Antwerp; and Department of Neurology and Memory Clinic, Hospital Network Antwerp, Middelheim and Hoge Beuken, Antwerp; and Department of Neurology and Alzheimer Research Center, University Medical Center Groningen, The Netherlands); Patrick Cras, MD, PhD (Laboratory of Neurobiology, Institute Born-Bunge; and University of Antwerp; Department of Neurology, Antwerp University Hospital, Antwerp). Funding: The research was in part supported by the Methusalem excellence program of the Flemish Government; a Centre of Excellence grant by the Special Research Fund of the University of Antwerp; the Research Foundation Flanders (FWO); the Agency for Innovation by Science and Technology Flanders (IWT); the Interuniversity Attraction Poles program (IAP) P6/43 of the Belgian Science Policy Office; the Belgian Parkinson Foundation; and the Foundation for Alzheimer Research (SAO/FRMA). DC is receiving a PhD fellowship of the FWO and AV of the IWT. Ekaterina Rogaeva, PhD (Tanz Centre for Research in Neurodegenerative Diseases, Department of Medicine, Division of Neurology, University of Toronto, ON, Canada, Site Investigator); Anthony E Lang, MD (Movement Disorders Centre, Toronto Western Hospital, University of Toronto, Toronto, ON, Canada, Site Investigator); Y Agid, MD (Inserm, Paris, From the French Parkinson's Disease Genetics Study Group, Site Investigator); M Anheim, MD (Inserm, Paris, From the French Parkinson's Disease Genetics Study Group, Site Investigator); A-M Bonnet, MD (Inserm, Paris, From the French Parkinson's Disease Genetics Study Group, Site Investigator); M Borg, MD (From the French Parkinson's Disease Genetics Study Group, Site Investigator); A Brice, MD (Paris, From the French Parkinson's Disease Genetics Study Group, Site Investigator); E Broussolle MD (From the French Parkinson's Disease Genetics Study Group, Site Investigator); JC Corvol MD (Inserm, Paris, From the French Parkinson's Disease Genetics Study Group, Site Investigator); P Damier, MD (From the French Parkinson's Disease Genetics Study Group, Site Investigator); A Destée, MD (From the French Parkinson's Disease Genetics Study Group, Site Investigator); A Dürr, MD (Inserm U708, Paris, From the French Parkinson's Disease Genetics Study Group, Site Investigator); F Durif, MD (From the French Parkinson's Disease Genetics Study Group, Site Investigator); S Lesage, PhD (Inserm, Paris, From the French Parkinson's Disease Genetics Study Group, Site Investigator); E Lohmann, MD (Inserm, Paris, From the French Parkinson's Disease Genetics Study Group, Site Investigator); P Pollak, MD (From the French Parkinson's Disease Genetics Study Group, Site Investigator); O Rascol, MD (From the French Parkinson's Disease Genetics Study Group, Site Investigator); F Tison, MD (From the French Parkinson's Disease Genetics Study Group, Site Investigator); C Tranchant, MD (From the French Parkinson's Disease Genetics Study Group, Site Investigator); F Viallet, MD (From the French Parkinson's Disease Genetics Study Group, Site Investigator); M Vidailhet, MD (Inserm, Paris, From the French Parkinson's Disease Genetics Study Group, Site Investigator); Christophe Tzourio, MD (Inserm U708, Paris, From the French Parkinson's Disease Genetics Study Group, Site Investigator); Philippe Amouyel, MD (Inserm U744, Lille, Site Investigator); Marie-Anne Loriot, MD (Inserm UMRS775, Paris, Site Investigator); Eugénie Mutez, MD (Inserm UMR837, Service de Neurologie et de Pathologie du Mouvement CHRU de Lille, Univ Lille Nord de France, Site Investigator); Aurélie Duflot, MD (UMR837 Inserm-Univ Lille 2, CHRU de Lille, Site Investigator); Jean-Philippe Legendre, MD (Service de Neurologie et Pathologie du Mouvement, Clinique de Neurologie du CHU de Lille, Site Investigator); Nawal Waucquier, MD (Service de Neurologie et Pathologie du Mouvement, Clinique de Neurologie du CHU de Lille, Site Investigator); Thomas Gasser MD (Department of Neurology, University Hospital Tuebingen, Site Investigator); Olaf Riess MD (Department of Neurology, University Hospital Tuebingen, Site Investigator); Christine Klein, MD (Section of Clinical and Molecular Neurogenetics at the Department of Neurology, University of Lübeck, Site Investigator); Ana Djarmati, PhD (Department of Neurology, University of Lübeck, Site Investigator); Johann Hagenah, MD (Department of Neurology, University of Lübeck, Site Investigator); Katja Lohmann, PhD (Section of Clinical and Molecular Neurogenetics at the Department of Neurology, University of Lübeck, Site Investigator); Georg Auburger, MD (Department of Neurology, Goethe University Frankfurt am Main, Germany, Site Investigator); Rüdiger Hilker, MD (Department of Neurology, Goethe University Frankfurt am Main, Germany, Site Investigator); Simone van de Loo, MD (Department of Neurology, Goethe University Frankfurt am Main, Germany, Site Investigator); Efthimios Dardiotis, MD (Department of Neurology, Faculty of Medicine, University of Thessaly and Institute of Biomedical Research & Technology, CERETETH, Larissa; Site Investigator); Vaia Tsimourtou, MD (Department of Neurology, Faculty of Medicine, University of Thessaly, Larissa, Site Investigator); Styliani Ralli, MD (Department of Neurology, Faculty of Medicine, University of Thessaly, Larissa, Site Investigator); Persa Kountra, MD (Department of Neurology, Faculty of Medicine, University of Thessaly, Larissa, Site Investigator); Gianna Patramani, MD (Department of Neurology, Faculty of Medicine, University of Thessaly, Larissa, Site Investigator); Cristina Vogiatzi, MD (Department of Neurology, Faculty of Medicine, University of Thessaly, Larissa, Site Investigator); Nobutaka Hattori, MD, PhD (Department of Neurology, Juntendo University School of Medicine, Tokyo, Site Investigator); Hiroyuki Tomiyama, MD, PhD (Department of Neurology, Juntendo University School of Medicine, Tokyo, Site Investigator); Manabu Funayama, PhD (Department of Neurology, and Research Institute for Diseases of Old Age, Graduate School of Medicine, Juntendo University, Tokyo, Site Investigator); Hiroyo Yoshino, PhD (Research Institute for Diseases of Old Age, Graduate School of Medicine, Juntendo University, Tokyo, Site Investigator); Yuanzhe Li MD,PhD Research Institute for Diseases of Old Age, Graduate School of Medicine, Juntendo University, Tokyo, Site Investigator); Yoko Imamichi (Department of Neurology, Juntendo University School of Medicine, Tokyo, Site Investigator); Tatsushi Toda, MD (Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, Japan, Site Investigator); Wataru Satake, MD, PhD (Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, Japan, Site Investigator); Tim Lynch, MD (The Dublin Neurological Institute at the Mater Misericordiae University Hospital, Clinical Investigator at the Conway Institute, University College Dublin, Ireland, Site Investigator); J Mark Gibson, MD (Department of Neurology, Royal Victoria Hospital, Belfast, Ireland, Site Investigator); Enza Maria Valente, MD, PhD (IRCCS, Casa Sollievo della Sofferenza Hospital, Mendel Institute, San Giovanni Rotondo, Site Investigator); Alessandro Ferraris, MD (IRCCS, Casa Sollievo della Sofferenza Hospital, Mendel Institute, San Giovanni Rotondo, Site Investigator); Bruno Dallapiccola, MD (Mendel Institute, Casa Sollievo della Sofferenza Hospital, Rome, Site Investigator); Tamara Ialongo, MD, PhD (Institute of Neurology, Catholic University, Rome, Site Investigator); Laura Brighina, MD, PhD (Department of Neurology, Ospedale San Gerarado, Monza, Italy, Site Investigator); Barbara Corradi, PhD (Department of Paediatrics, University of Milano-Bicocca, Monza, Site Investigator); Roberto Piolti, MD (Department of Neurology, Ospedale San Gerardo, Monza, Italy, Site Investigator); Patrizia Tarantino, PhD (Institute of Neurological Sciences, National Research Council, Site Investigator); Ferdinanda Annesi, PhD (Institute of Neurological Sciences, National Research Council, Site Investigator); Beom S Jeon, MD, PhD (Department of Neurology, Seoul National University Hospital, Site Investigator); Sung-Sup Park, MD, PhD (Department of Laboratory Medicine, Seoul National University Hospital, Site Investigator); J Aasly, MD (Department of Neurology, University of Trondheim, Norway, Site Investigator); Grzegorz Opala, MD, PhD (Department of Neurology, Aging, Degenerative and Cerebrovascular Disorders, Medical University of Silesia, Katowice; Site Investigator); Barbara Jasinska-Myga, MD, PhD (Department of Neurology, Aging, Degenerative and Cerebrovascular Disorders, Medical University of Silesia, Katowice, Site Investigator); Gabriela Klodowska-Duda, MD, PhD (Department of Neurology, Aging, Degenerative and Cerebrovascular Disorders, Medical University of Silesia, Katowice, Site Investigator); Magdalena Boczarska-Jedynak, MD, PhD (Department of Neurology, Aging, Degenerative and Cerebrovascular Disorders, Medical University of Silesia, Katowice, Site Investigator); Eng King Tan, MD, PhD (National Medical and Biomedical Research Councils, and the Duke-NUS Graduate Medical School, Singapore Millenium Foundation, Site Investigator); Andrea Carmine Belin, PhD (Department of Neuroscience, Karolinska Institutet, Stockholm, Site Investigator); Lars Olson, MD (Department of Neuroscience, Karolinska Institutet, Stockholm, Site Investigator); Dagmar Galter, PhD (Department of Neuroscience, Karolinska Institutet, Stockholm; Site Investigator); Marie Westerlund, PhD (Department of Neuroscience, Karolinska Institutet, Stockholm, Site Investigator); Olof Sydow, PhD (Department of Clinical Neuroscience, Karolinska University Hospital, Stockholm; Site Investigator); Christer Nilsson, MD, PhD (Department of Geriatric Psychiatry, Lund University; Site Investigator); Andreas Puschmann, MD (Department of Neurology, Lund University Hospital, Department of Geriatric Psychiatry, Lund University, Site Investigator); JJ Lin, MD (Department of Neurology, Cushang Show-Chwan Hospital, Taiwan, Site Investigator); Demetrius M Maraganore, MD (Department of Neurology, NorthShore Health Systems, Chicago, IL, Site Investigator); J Eric Ahlskog PhD, MD (Department of Neurology, Mayo Clinic, Rochester, MN, USA, Site Investigator); Mariza de Andrade, PhD (Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA, Site Investigator); Timothy G Lesnick, MS (Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA, Site Investigator); Walter A Rocca, MD, MPH (Departments of Neurology and Health Sciences Research, Mayo Clinic, Rochester, MN, USA, Site Investigator); Harvey Checkoway, PhD (Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, Site Investigator); Owen A Ross PhD (Division of Neuroscience, Mayo Clinic, Jacksonville, USA, Site Investigator); Zbigniew K Wszolek, MD (Department of Neurology, Mayo Clinic, Jacksonville, FL, Site Investigator); Ryan J Uitti, MD (Department of Neurology, Mayo Clinic, Jacksonville, FL, Site Investigator).</p></ack><fn-group><fn><p><bold>Contributors:</bold> All authors presented in this study made substantial contributions to: (1) conception and design, acquisition of data, or analysis and interpretation of data; (2) drafting the article or revising it critically for important intellectual content; and (3) final approval of the version to be published.</p></fn><fn><p><bold>Funding:</bold> This work was supported by Michael J Fox Foundation under the Edmond J Safra Rapid Response Innovation Award program.</p></fn><fn><p><bold>Competing interests:</bold> None.</p></fn><fn><p><bold>Provenance and peer review:</bold> None.</p></fn></fn-group><ref-list><title>References</title><ref id="R1"><label>1</label><mixed-citation publication-type="journal"><person-group 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