SNP & Disease Susceptibility

What has changed radically since the pioneering days of linkage analysis studies is the power of the tools available for gene hunting. Any search for a susceptibility gene has to be guided by a genomic map on which known reference points are clearly marked. The pioneers had to make do with a map comprising no more than a couple of hundred genes serving as markers. With the subsequent development of other markers, including rflps (restriction fragment length polymorphisms), vntrs (variable number of tandem repeats) and - most recently - snps (single nucleotide polymorphisms) that are densely distributed throughout the genome, the number and usefulness of genomic markers have increased exponentially.

Simultaneously, genetic epidemiology has developed new, more powerful statistical paradigms, and the bioinformatic tools for analysing genetic data have already attained a level of efficiency inconceivable only a few years ago. The combined effect of these advances is that we can make much more effective use of the data from fewer subjects. In the future, it is conceivable that genomic and bioinformatic tools will become sufficiently powerful to allow families of patients to be replaced by more general populations, although the characterization of appropriate control populations will remain vital.

Once appropriate patient data is to hand, the innovative bioinformatic tools already at our disposal can rapidly scan hundreds of thousands of single nucleotide polymorphisms (snps) for each individual, looking for a consecutive string of snps that is identical in people with the same disease. When an identical linear series of snps is found, this can then be pulled out and examined more closely for a single nucleotide variation correlating with a specific disease phenotype. Obviously, the more detailed and genomically complete the snp map is, the faster this search can be accomplished.

Building such maps and using them to hunt for disease susceptibility genes is therefore the hottest focus of pharmacogenetics today. Undoubtedly, the systematic search for the genetic variations associated with a particular disease will also turn up a number of rare mutations that are responsible for illness in small subsets of patients. However, the primary objective of pharmaceutical researchers will be to find common disease susceptibility polymorphisms, because this information will assist the quest to discover new medicines that can help large populations of patients.

The goal of identifying hereditary factors in the multifactorial diseases of great epidemiological significance is no longer a utopian ideal. High-density snp maps of the complete human genome are on the near horizon - just two or three years away - and rapid methods to read each person's dna snp genotype accurately and practically will no doubt be developed in the next few years. Given the major research efforts that are now beginning to be focused on target diseases such as asthma, depression, Parkinson's disease, osteoarthritis and others, we can anticipate the discovery of numerous susceptibility genes in the early years of the new millennium.

By Dr Allen Roses, vice-president and Worldwide director of Genetics at Glaxo Wellcome, together with Andrea Dingemans, Editor of Odyssey.