Application of SNP Technologies in Medicine: Lessons Learned and Future Challenges

Over the past few years, single nucleotide polymorphisms (SNPs) have been proposed as the next generation of markers for the identification of loci associated with complex diseases and for pharmacogenetic applications (Lander and Schork 1994; Lander 1996;Risch and Merikangas 1996; Kruglyak 1997; Schafer and Hawkins 1998). SNPs are frequently present in the genome with a density of at least one common (>20% allele frequency) SNP per kilobase pair (Lai et al. 1998; Sachidanandam et al. 2001). They are mostly biallelic (<0.1% of SNPs are triallelic; http://snp.cshl.org/) and thus easy to assay. More importantly, SNPs allow the unification of the candidate gene approach and association-based fine mapping to identify gene(s) of interest. They also aid in the association of linkage analysis to the phenotypic and genotypic data.

Although quantitative analysis and mathematical modeling have suggested that whole-genome association is more effective than linkage analysis for the identification of complex disease genes and in pharmacogenetics, the application of SNPs had been hindered by the lack of sufficient markers. In 1997, several biotech companies started the race and took the initiative to isolate 60,000 or more SNPs to develop a whole genome SNP-based map (http://www.abbott.com/news/1997news/pr072897.htm). The publicly funded efforts (NIH RFA: HG-98–001, 1998;http://www.nhgri.nih.gov/Grant_info/Funding/rfa-hg-98-001.html) got a jump-start in 1999 when 13 pharmaceutical companies and the Wellcome Trust formed The SNP Consortium (TSC) to accelerate SNP discovery and to ensure public accessibility to a minimum of 300,000 SNPs (http://snp.cshl.org/). The combined efforts of the public projects and TSC have been extremely productive and there are currently >1.6 million SNPs in the public databases (Sachidanandam et al. 2001). In this article, I will attempt to summarize what we know about SNPs and identify some of the challenges that await us in the application of SNPs in research and medicine. …