Human Molecular Genetics Advance Access originally published online on February 16, 2009
Human Molecular Genetics 2009 18(9):1670-1683; 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), Biomedicum, Helsinki, Finland 2 Department of Medical Genetics 3 Molecular Neurology Research Program 4 Department of Bacteriology and Immunology 5 Finnish Genome Center and FIMM 6 Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland 7 National Institute for Health and Welfare, Biomedicum, Helsinki, Finland 8 Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA 9 Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA 10 Department of Neurology, Seinäjoki Central Hospital, Seinäjoki, Finland 11 Department of Neurology, Tampere University Hospital, Tampere, Finland 12 Medical School, University of Tampere, Tampere, Finland 13 Department of Neurology and Neuroscience, Kuopio University Hospital, Kuopio, Finland 14 Department of Neurology, Oulu University Hospital, Oulu, Finland 15 Department of Medical Microbiology and Immunology, University of Turku, Turku, Finland 16 Department of Clinical Neuroscience, Karolinska Institutet at Karolinska University Hospital-Huddinge, Stockholm, Sweden 17 Department of Neurology, Ullevål University Hospital 18 Department of Neurology, Faculty Division Ullevål University Hospital, University of Oslo, Oslo, Norway 19 Institute of Immunology, Rikshospitalet University Hospital, Oslo, Norway 20 Department of Neurology, Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA 21 Harvard Medical School, Boston, MA, USA 22 Harvard Medical School/Partners Healthcare Center for Genetics and Genomics, Boston, MA, USA and 23 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK
* To whom correspondence should be addressed. Tel: +44 1223496845; Fax: +44 1223496820; Email: leena{at}sanger.ac.uk
Received September 27, 2008; Revised December 10, 2008; Accepted February 10, 2009
Large case–control genome-wide association 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 multiple sclerosis (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 45 Mb region, covering the linkage peak identified in Finnish MS families, revealed only modest association at IL7R (P = 0.04), recently implicated in MS, whereas most significant association was found with one haplotype covering the C7-FLJ40243 locus (P = 0.0001), 5.1 Mb centromeric of IL7R. The finding was validated in an independent sample from the isolate and resulted in an odds ratio 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.