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An exome study of Parkinson’s disease in Sardinia, a Mediterranean genetic isolate

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Abstract

Parkinson’s disease (PD) is a common neurodegenerative disorder of complex aetiology. Rare, highly penetrant PD-causing mutations and common risk factors of small effect size have been identified in several genes/loci. However, these mutations and risk factors only explain a fraction of the disease burden, suggesting that additional, substantial genetic determinants remain to be found. Genetically isolated populations offer advantages for dissecting the genetic architecture of complex disorders, such as PD. We performed exome sequencing in 100 unrelated PD patients from Sardinia, a genetic isolate. SNPs absent from dbSNP129 and 1000 Genomes, shared by at least five patients, and of functional effects were genotyped in an independent Sardinian case-control sample (n = 500). Variants associated with PD with nominal p value <0.05 and those with odds ratio (OR) ≥3 were validated by Sanger sequencing and typed in a replication sample of 2965 patients and 2678 controls from Italy, Spain, and Portugal. We identified novel moderately rare variants in several genes, including SCAPER, HYDIN, UBE2H, EZR, MMRN2 and OGFOD1 that were specifically present in PD patients or enriched among them, nominating these as novel candidate risk genes for PD, although no variants achieved genome-wide significance after Bonferroni correction. Our results suggest that the genetic bases of PD are highly heterogeneous, with implications for the design of future large-scale exome or whole-genome analyses of this disease.

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Acknowledgments

This work was supported by BGI-Shenzhen, China, and by grants from the “Stichting ParkinsonFonds”—The Netherlands and the Netherlands Organization for Scientific Research (NWO, VIDI grant, project n. 91786395) to V.B. The samples from Milan, Italy, were obtained from the “Parkinson Institute Biobank” (http://www.parkinsonbiobank.com), member of the Telethon Network of Genetic Biobanks (project n. GTB12001) funded by TELETHON Italy and supported by the “Fondazione Grigioni per il Morbo di Parkinson”.

Ethical standards

All experiments performed in this study comply with the current laws of the countries in which they were performed.

Conflict of interest

MQ, XY, GC, SO, VMS, GJB, LO, JH, NX, JG, VR, DM, CM, MJM, PT, RS, FV, MG, GP, ME, AQ, GA, BAO, MM and JW reports no conflict of interest. LCG reports personal fees from Centro Hospitalar Lisboa Norte. JF reports personal fees from GlaxoSmithKline, Novartis, TEVA, Lundbeck, Solvay, Abbott, BIAL, Merck-Serono, Merz, Ipsen, Grunenthal, Merck Sharp and Dohme, Allergan, Centro Hospitalar Lisboa Norte, Faculdade de Medicina de Lisboa, Fundacao MSD (Portugal) and European Huntington Disease Network. SG reports grants from Italian Telethon Foundation. ET received honoraria for consultancy from Novartis, TEVA, Boehringer Ingelheim, UCB, Solvay and Lundbeck, and he received funding for research from the Spaniard Network for Research on Neurodegenerative Disorders (CIBERNED)-Instituto Carlos III (ISCIII), The Michael J. Fox Foundation for Parkinson’s Research (MJFF) and Fondo de Investigaciones Sanitarias de la Seguridad Social (FISS). VB reports personal compensation for serving as Associate Editor of Parkinsonism & Related Disorders and Section Editor of Current Neurology and Neuroscience Reports, honoraria from the International Parkinson and Movement Disorder Society and Elsevier Ltd and research support from the Erasmus MC, Rotterdam, the Stichting ParkinsonFonds (The Netherlands) and The Netherlands Organization for Scientific Research (NWO).

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Authors and Affiliations

  1. Department of Clinical Genetics, Erasmus MC, PO Box 2040, 3000, CA, Rotterdam, The Netherlands

    Marialuisa Quadri, Simone Olgiati, Guido J. Breedveld, Josja Graafland, Ben A. Oostra & Vincenzo Bonifati

  2. BGI-Shenzhen, Beishan Industrial Zone, Yantian District, 518083, Shenzhen, China

    Xu Yang, Limei Ouyang, Jingchu Hu, Na Xu & Jun Wang

  3. Neurology Service and Stroke Unit, General Hospital S. Michele AOB “G. Brotzu”, Cagliari, Italy

    Giovanni Cossu, Valeria Ricchi, Daniela Murgia & Maurizio Melis

  4. Department of Neurology and Stroke Unit, San Francesco Hospital, ASL No.3, Nuoro, Italy

    Valeria M. Saddi

  5. Clinical Pharmacology Unit, Instituto de Medicina Molecular, University of Lisbon, Lisbon, Portugal

    Leonor Correia Guedes & Joaquim Ferreira

  6. Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy

    Claudio Mariani, Gianni Pezzoli & Stefano Goldwurm

  7. Neurology Service, Hospital Clínic de Barcelona, IDIBAPS, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Universitat de Barcelona, Barcelona, Catalonia, Spain

    Maria J. Marti, Francesc Valldeoriola & Eduardo Tolosa

  8. National Research Council, Section of Germaneto, Institute of Molecular Bioimaging and Physiology, Catanzaro, Italy

    Patrizia Tarantino, Monica Gagliardi, Aldo Quattrone & Grazia Annesi

  9. Dipartimento di Biotecnologie Mediche e Medicina Traslazionale (BIOMETRA), Università degli Studi di Milano, Milan, Italy

    Rosanna Asselta

  10. Institute of Neurology, Department of Medical Sciences, University Magna Graecia, Catanzaro, Italy

    Monica Gagliardi & Aldo Quattrone

  11. Laboratory of Neurodegenerative Disorders, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Fundació Clinic, Barcelona, Spain

    Mario Ezquerra

  12. Department of Biology, University of Copenhagen, Copenhagen, Denmark

    Jun Wang

  13. King Abdulaziz University, Jeddah, Saudi Arabia

    Jun Wang

  14. The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark

    Jun Wang

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  1. Marialuisa Quadri
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  2. Xu Yang
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  3. Giovanni Cossu
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  28. Maurizio Melis
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  29. Jun Wang
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  30. Vincenzo Bonifati
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Corresponding authors

Correspondence to Jun Wang or Vincenzo Bonifati.

Additional information

Marialuisa Quadri, Xu Yang, Giovanni Cossu and Simone Olgiati contributed equally to this work and should be considered as joint first authors.

Jun Wang and Vincenzo Bonifati contributed equally to this work and should be considered as joint senior author.

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Quadri, M., Yang, X., Cossu, G. et al. An exome study of Parkinson’s disease in Sardinia, a Mediterranean genetic isolate. Neurogenetics 16, 55–64 (2015). https://doi.org/10.1007/s10048-014-0425-x

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