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.

Genetics of Multiple Sclerosis

“…It contains complement component 7 (C7), again an important factor in the innate immune system (84). These results exemplify the power of population isolates in the identification of rare disease alleles .…”

Characterizing runs of homozygosity and their impact on risk for psychosis in a population isolate

“…Examples of this abound in human populations, especially for Mendelian diseases of recessive inheritance, such as lysosomal storage diseases [Risch et al, ], cystic fibrosis [Fares et al, ], and glycogen storage disease [Ekstein et al, ]. For complex diseases, the impact of founder effects and population bottlenecks is less clear regarding prevalence, but the distortion of risk allele frequencies is still an expected outcome and can be useful for gene mapping [Kallio et al, ].…”

A 425 T>C polymorphism in complement C7 association with resistance to Aeromonas hydrophila in grass carp

“…C7 is primarily synthesized extrahepatically at the site of inflammation by granulocytes (Høgåsen et al, 1995) and endothelial cells (Tedesco et al, 1997), thereby modulating lytic or sublytic membrane attack (Würzner, 2000;Langeggen et al, 2000). A number of studies have reported that variations in C7 play an important role in the resistance to a variety of diseases in humans (Kallio et al, 2009;Barroso et al, 2010). To date, at least 25 different sequence variants have been reported that can lead to C7 deficiency (RameixWelti et al, 2007).…”