Some success stories

It is not the remit of this chapter to provide a comprehensive list of linkage and association success stories, as a number of these will be covered in the chapters of this book dealing with specific diseases. Nonetheless, a few success stories are described which illustrate the progress made in a range of diseases via a variety of study designs.

Linkage studies for common disease do not usually directly lead to underlying causal variants because the effect of any one allele is too small to result in a mapping resolution at the level of individual genes. However, the BRCA1 and BRCA2 susceptibility genes for breast cancer were first mapped using linkage in highly enriched families (Goldgar et al., 1993) and subsequently identified using association and sequencing studies. A number of variants at these genes have a very large relative risk in carriers. The frequency of these variants varies across ethnic groups, and a number of them are at relatively high frequency in Ashkenazi Jews. Since the frequency of these alleles is relatively rare in the overall population, it is doubtful that a genome-wide association analysis would detect them. This example highlights the value of pursuing rare monogenic variants of common diseases as a strategy to increase understanding of complex disorders (Antonarakis and Beckmann, 2006).

In 2001 three papers reported on the association between the gene NOD2 and Crohn's disease (an inflammatory bowel disease), however, the paths of the research that led to these independent findings were quite different. The first (Hugot et al., 2001) followed the classic research paradigm of genome-wide linkage study (which identified the pericen-tromeric region of chromosome 16), fine mapping study (where more microsatellite markers are genotyped in the linkage region) and association study. This study identified three causal mutations, a single base-pair insertion (3020Cins) and two missense variants. In contrast, the other studies (Hampe etal., 2001; Ogura etal., 2001) selected the NOD2 gene as a candidate gene based on position (within the reported linkage region), structural homology to plant apoptosis regulatory and disease resistance genes and known function of NOD proteins in recognizing bacterial components. Both studies identified the single base-pair insertion and reported GRR for the heterozygote of 1.5 and 2.6 and for the homozygote of 17.6 and 42.1 respectively. There is no doubt that genetics research has made a major contribution to the understanding of inflammatory bowel disease and use of genetic markers for diagnosis, prognosis and as a decision tool for choice of drug treatments is predicted for the near future (Vermeire and Rutgeerts, 2005).

Results of genome-wide association studies are only now starting to be published, but a surge of results is expected over the next couple of years. Initial results are promising. For example, the first large scale association studies for schizophrenia (Mah et al., 2006) and Parkinson's disease (Maraganore et al., 2005) both identified variants in genes not previously considered for these diseases but which were interesting functional candidates. A genome-wide association study of age-related macular degeneration (AMD, the leading cause of blindness in the elderly) found (with a very small sample size) association (p<10~7) with a polymorphism in the gene for complement factor H. This gene was simultaneously studied in positional candidate gene association studies (Edwards et al., 2005; Haines et al., 2005) of genes in the previously reported linkage region (1q31-32). The functional variant was identified as tyrosine-histidine change at amino acid 402, with possession of at least one histidine variant increasing risk to AMD 2-7-fold. The histidine variant is common (frequency about 0.35 in controls) and is estimated to account for up to 50% of population attributable risk (Edwards et al., 2005). In the long term the success of linkage and association studies will depend on the, as yet unknown, genetic architecture underlying complex diseases. Only by doing the studies will we begin to understand the number of genes, the number of variants within genes and the effect sizes of those variants. Evidence to date suggests that the Common Variant Common Disease hypothesis is likely to be valid, at least in part, and identification of common variants will open doors to further our understanding of complex disease. However, it is hard to imagine that the experience of Mendelian disorders will not follow through to complex diseases whereby genes influencing disease are found to have many disease risk variants segregating within the population (Stone et al., 2004).

The challenge to develop methodology that can identify as yet unknown disease risk genes which are characterized by rare allelic variants alone is still waiting to be met.

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