title: Use of a genetic isolate to identify rare disease variants: C7 on 5p associated with MS.
abstract: 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.
authors.affiliation: Finnish Institute for Molecular Medicine, Biomedicum, Helsinki, Finland.
authors.forename: Suvi P
authors.initials: SP
authors.lastname: Kallio
authors.forename: Eveliina
authors.initials: E
authors.lastname: Jakkula
authors.forename: Shaun
authors.initials: S
authors.lastname: Purcell
authors.forename: Minna
authors.initials: M
authors.lastname: Suvela
authors.forename: Keijo
authors.initials: K
authors.lastname: Koivisto
authors.forename: Pentti J
authors.initials: PJ
authors.lastname: Tienari
authors.forename: Irina
authors.initials: I
authors.lastname: Elovaara
authors.forename: Tuula
authors.initials: T
authors.lastname: Pirttilä
authors.forename: Mauri
authors.initials: M
authors.lastname: Reunanen
authors.forename: Denis
authors.initials: D
authors.lastname: Bronnikov
authors.forename: Markku
authors.initials: M
authors.lastname: Viander
authors.forename: Seppo
authors.initials: S
authors.lastname: Meri
authors.forename: Jan
authors.initials: J
authors.lastname: Hillert
authors.forename: Frida
authors.initials: F
authors.lastname: Lundmark
authors.forename: Hanne F
authors.initials: HF
authors.lastname: Harbo
authors.forename: Aslaug R
authors.initials: AR
authors.lastname: Lorentzen
authors.forename: Philip L
authors.initials: PL
authors.lastname: De Jager
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.forename: David A
authors.initials: DA
authors.lastname: Hafler
authors.forename: Aarno
authors.initials: A
authors.lastname: Palotie
authors.forename: Leena
authors.initials: L
authors.lastname: Peltonen
authors.forename: Janna
authors.initials: J
authors.lastname: Saarela
mesh_terms: D016022:Case-Control Studies; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics*; D003184:Complement C7 / Q000235:genetics*; D005387:Finland; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D009103:Multiple Sclerosis / Q000235:genetics*
chemical_list: D003184:Complement C7