The sepiapterin reductase gene region reveals association in the PARK3 locus: analysis of familial and sporadic Parkinson’s disease in European populations
- M Sharma1,*,
- J C Mueller1,2,*,
- A Zimprich3,
- P Lichtner4,
- A Hofer1,
- P Leitner1,
- S Maass5,
- D Berg6,
- A Dürr7,
- V Bonifati8,
- G De Michele9,
- B Oostra10,
- A Brice7,
- N W Wood11,
- B Muller-Myhsok12,
- T Gasser1,
- European Consortium on Genetic Susceptibility in Parkinson’s Disease (GSPD)
- 1Hertie-Institute for Clinical Brain Research, Department of Neurodegenerative Diseases, University of Tübingen, Tübingen, Germany
- 2Institute for Medical Statistics and Epidemiology and Institute for Psychiatry and Psychotherapy, Technical University Munich, Munich, Germany
- 3Department of Neurology, Medical University of Vienna, Vienna, Austria
- 4Institute for Human Genetics–National Research Centre for Environment and Health, Neuherberg, Germany
- 5Department of Neurology, Ludwig-Maximilians-University, Munich, Germany
- 6Department for Medical Genetics, Eberhard Karls University Tübingen, Tübingen, Germany
- 7INSERM U289 and Department of Genetics, Cytogenetics and Embryology, AP-HP, Salpetriere Hospital, Paris, France
- 8Department of Neurological Sciences, University La Sapienza, Rome, Italy
- 9Department of Clinical Genetics, Erasmus University, Rotterdam, Netherlands
- 10Department of Neurological Sciences, Federico II University, Naples, Italy
- 11Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK
- 12Max-Planck Institute for Psychiatry, Munich, Germany
- Correspondence to: Prof Dr med Thomas Gasser Hertie-Institute for Clinical Brain Research, Department for Neurodegenerative Diseases, University of Tübingen, Hoppe-Seyler Str 3, 72076 Tübingen, Germany;
- Received 25 October 2005
- Accepted 5 January 2006
- Revised 4 January 2006
- Published Online First 27 January 2006
Background: Parkinson’s disease is a genetically complex disease with mixed mode of inheritance. Recently, a haplotype across the sepiapterin reductase (SPR) gene, which is located in the PARK3 linkage region, was shown to modulate age of onset of Parkinson’s disease in sibships from North America.
Objective: To make a thorough assessment of the SPR gene region in sporadic Parkinson’s disease.
Methods: A linkage study in 122 European sibship families with five microsatellite and 17 single nucleotide polymorphism (SNP) markers in and around the SPR gene region, and an association analysis in 340 sporadic cases of Parkinson’s disease and 680 control subjects from Germany with 40 SNPs. Linkage was evaluated by non-parametric linkage scores and genotypic or haplotype association was tested by regression analysis, assuming different risk effect models.
Results: Significant LOD scores between 2 and 3 were obtained at the two SPR-flanking markers D2S2110 and D2S1394 and seven SNP markers around the SPR gene. We found the previously reported promoter SNP rs1876487 also significantly associated with age of onset in our sib pair families (p-value 0.02). One strong linkage disequilibrium (LD) block of 45 kb including the entire SPR gene was observed. Within this LD block all 14 inter-correlated SNPs were significantly associated with Parkinson’s disease affection status (p-value 0.004).
Conclusions: DNA polymorphisms in a highly intercorrelated LD block, which includes the SPR gene, appear to be associated with both sporadic and familial Parkinson’s disease. This confirms a previous study showing that SPR potentially modulates the onset of or risk for Parkinson’s disease.
- LD, linkage disequilibrium
- MAF, minor allele frequency
- NPL, non-parametric linkage scores
- SNP, single nucleotide polymorphism
- SPR, sepiapterin reductase
- STR, short tandem repeat
↵* Both authors contributed equally to work
Published Online First 27 January 2006
We would like to thank the patients and their family members for their support. The KORA group consists of H E Wichmann (speaker), H Löwel, C Meisinger, T Illig, R Holle, J John and their coworkers, who are responsible for the design and conduct of the KORA studies. This study was supported by the German Ministery for Education and Research (BMBF – Competence Network Parkinson (01G10201), the German National Genome Research Network NGFN (01GS0116), and the Hertie-Institute for Clinical Brain Research, Tübingen, Germany.
Conflicts of interest: none declared
The European Consortium on Genetic Susceptibility in Parkinson’s disease: N W Wood, D Nicholl (UK); A Brice, A Dürr, M Martinez, Y Agid (France); T Gasser, B Müller-Myhsok (Germany); M Breteler, S Harhangi, B Oostra (Netherlands); V Bonifati, E Fabrizio, N Vanacore, G Meco, G DeMichele, G Volpe, A Filla (Italy).