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Evidence for novel loci for late-onset Parkinson’s disease in a genetic isolate from the Netherlands

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Abstract

We studied patients with idiopathic Parkinson’s disease (PD) from an isolated population in the Netherlands aiming to map gene(s) involved in PD susceptibility. A total of 109 parkinsonism patients were independently ascertained, of whom 62 presented late-onset, idiopathic PD. Genealogical research showed that 45 index cases with idiopathic PD were linked to a common ancestor, indicating familiar clustering among the patients. This strong familial clustering was highly significant (P=0.005) when compared to random controls from the same population. We performed a genome wide scan using 382 polymorphic markers in 44 distantly related PD patients plus 112 unaffected first-degree relatives and spouses. Our genome wide association analysis (DISLAMB) revealed evidence of association at a nominal P-value<0.01 for markers D2S2333, D4S405, D9S158, D13S153. Other regions on chromosomes 3p, 4q, 14q, 17p and 17q were found at a significance level of P<0.05. In a follow-up study, we investigated all the positive regions using a denser marker set and a larger sample (total of 630 individuals including all late-onset PD patients). The strongest evidence for association remained for the 9q and 14q region. A significant association was found for marker D9S1838 (OR=2.0, 95% CI 1.1–3.5, P=0.014) and D14S65 (OR=3.2, 95% CI 1.7–6.1, P<0.001). Moreover, a common haplotype with excess of sharing among late-onset PD cases was observed on both regions. Our results suggest the existence of two loci influencing PD susceptibility on chromosome 9q and 14q.

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Acknowledgements

This study was supported by a grant from the Netherlands Organization for Scientific Research, the Centre for Medical Systems Biology, and a grant from the Internationaal Parkinson Fonds (B.A.O). Petra Veraart and Hilda Kornman are acknowledged for their contribution to the genealogical research, Erwin Wauters and Florencia Gosso for their help in genotyping and Tom de Vries Lentsch for the artwork. We are grateful to all patients and their relatives, general practitioners, neurologists and nursing home physicians for making this study possible.

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Authors and Affiliations

  1. Genetic-Epidemiologic Unit, Department of Clinical Genetics and Department of Epidemiology & Biostatistics, Erasmus MC Rotterdam, P.O. Box 1738, 3000 DR, Rotterdam, The Netherlands

    Aida M. Bertoli-Avella, Marieke C. J. Dekker, Yurii S. Aulchenko, Erik Simons, Leon Testers, Luba M. Pardo, Tessa A. M. Rademaker, Pieter J. L. M. Snijders, Vincenzo Bonifati, Cornelia M. van Duijn & Ben A. Oostra

  2. Department of Medical Statistics, Leiden University Medical Centre, Leiden, The Netherlands

    Jeanine J. Houwing-Duistermaat

  3. Department of Neurology, Erasmus MC Rotterdam, Rotterdam, The Netherlands

    John C. van Swieten

  4. Department of Neurological Sciences, “La Sapienza” University, Rome, Italy

    Vincenzo Bonifati

  5. Section Medical Genomics, Department of Human Genetics and Department of Biological Psychology, Center for Neurogenomics and Cognitive Research VU University and VU University Medical Center Amsterdam, Amsterdam, The Netherlands

    Peter Heutink

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  1. Aida M. Bertoli-Avella
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  8. Tessa A. M. Rademaker
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Correspondence to Aida M. Bertoli-Avella.

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Bertoli-Avella, A.M., Dekker, M.C., Aulchenko, Y.S. et al. Evidence for novel loci for late-onset Parkinson’s disease in a genetic isolate from the Netherlands. Hum Genet 119, 51–60 (2006). https://doi.org/10.1007/s00439-005-0108-7

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