Monogenic genes as genetic risk factors in common disease

One other potential benefit deriving from the study of single gene disorders is that it provides candidate genetic risk factors for common disease. Given the chequered history of association studies, which have often been underpowered, it is difficult to tell whether most of the claimed associations will stand the test of time. However, there are

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Figure 10.1 Mortality from familial hypercholesterolemia according to sex and time. Mortality was estimated among 250 persons with 0.5 probability of carrying the V408M. Probands and the first 20 years of life were ignored. From Sijbrands et al., 2001.

a number of encouraging examples which have been replicated and where there is a convincing explanation for the mechanism by which the particular SNP exerts its effect on the disease risk.

Several such examples come from studies on the genetic basis of osteoporosis. Osteoporosis is a complex disease characterized by reduced bone mass (see Chapter 27), deterioration of the skeleton and increased risk of fracture. The most important clinical predictor of fracture risk is bone mineral density (BMD). Twin and family studies have shown that genetic factors account for 50-85% of the variation in BMD. One of the most convincing genetic risk factors for BMD is the type I collagen gene. Type I collagen is the most abundant protein in bone and is a heterotrimer made up of two collagen type I al protein chains (encoded by the COL1A1 gene) and one collagen type 1 a2 chain (encoded by the COL1A2 gene). Mutations in the coding region of COL1A1 are found in 90% of cases of osteogenesis imperfecta, a rare condition associated with reduced BMD and multiple fractures. A polymorphism in the first intron of the COL1A1 gene was found to be associated with BMD and restriction analysis has confirmed this result. Functional studies have shown that the risk allele increases binding to the transcription factor Spl leading to increased COL1A1 transcription and an imbalance in collagen chains. Another interesting example concerns LRP5, an LDL receptor related protein which is a co-receptor for Wnt signalling. Mutations in LRP5 are responsible for an autosomal recessive form of osteoporosis. Single nucleotide polymorphisms in the LRP5 gene are associated with BMD in Japanese women (see Chapter 27). Other examples, where genes mutated in Mendelian subsets appear to be risk factors for common disease are quoted throughout this book. As only l% of claimed associations in common disease can be replicated (L. Cardon, personal communication) genes mutated in monogenic subsets are likely to enrich for true candidates and simultaneously help to reveal mechanism.


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