Human Molecular Genetics Advance Access published online on February 16, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp073
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Use of a Genetic Isolate to Identify Rare Disease Variants: C7 on 5p associated with MS
1 Finnish Institute for Molecular Medicine, FIMM, and National Public Health Institute, Biomedicum, Helsinki, Finland 2 Department of Medical Genetics, University of Helsinki, Helsinki, Finland 3 Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA 4 Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA 5 Department of Neurology, Seinäjoki Central Hospital, Seinäjoki, Finland 6 Department of Neurology, Helsinki University Central Hospital and Molecular Neurology Research Program, University of Helsinki, Helsinki, Finland 7 Department of Neurology, Tampere University Hospital, Tampere, Finland 8 Medical School, University of Tampere, Tampere, Finland 9 Department of Neurology and Neuroscience, Kuopio University Hospital, Kuopio, Finland 10 Department of Neurology, Oulu University Hospital, Oulu, Finland 11 Department of Medical Microbiology and Immunology, University of Turku, Turku, Finland 12 Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, Helsinki, Finland 13 Department of Clinical Neuroscience, Karolinska Institutet at Karolinska University Hospital-Huddinge, Stockholm, Sweden 14 Department of Neurology, Ullevål University Hospital, Oslo, Norway 15 Institute of Immunology, Rikshospitalet University Hospital, Oslo, Norway 16 Department of Neurology, Faculty Division Ullevål University Hospital, University of Oslo, Oslo, Norway 17 Department of Neurology, Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA 18 Harvard Medical School / Partners Healthcare Center for Genetics and Genomics, Boston, MA, USA 19 Finnish Institute for Molecular Medicine, FIMM, Finnish Genome Center and Department of Clinical Chemistry, University of Helsinki, Finland 20 Wellcome Trust Sanger Institute, Cambridge, UK
* Corresponding author: Professor Leena Peltonen, M.D., Ph.D. Head of Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK, Tel No: +44 (0) 1223 496845, Fax No: +44 (0) 1223 496820 Email: leena{at}sanger.ac.uk
Received September 27, 2008; Revised December 10, 2008; Accepted February 10, 2009
Large case-control GWA studies primarily expose common variants contributing to disease pathogenesis with modest effects. Thus alternative strategies are needed to tackle rare, possibly more penetrant alleles. One strategy is to use special populations with a founder effect and isolation, resulting in allelic enrichment. For multiple sclerosis such a unique setting is reported in Southern Ostrobothnia in Finland, where the prevalence and familial occurrence of MS are exceptionally high. Here we have studied one of the best replicated MS loci, 5p, and monitored for haplotypes shared among 72 regional MS cases, the majority of which are genealogically distantly related. The haplotype analysis over the 45Mb region, covering the linkage peak identified in Finnish MS families, revealed only modest association at IL7R (p=0.04), recently implicated in MS, while most significant association was found with one haplotype covering the C7-FLJ40243 locus (p=0.0001), 5.1Mb centromeric of IL7R. The finding was validated in an independent sample from the isolate, and resulted in an OR of 2.73 (p=0.000003) in the combined data set. The identified relatively rare risk-haplotype contains C7 (complement component 7), an important player of the innate immune system. Suggestive association with alleles of the region was seen also in more heterogeneous populations. Interestingly, also the complement activity correlated with the identified risk-haplotype. These results suggest that the MS predisposing locus on 5p is more complex than assumed and exemplify power of population isolates in the identification of rare disease alleles.
These two authors contributed equally to this work.