The human genome project has produced high-precision tools for disease gene mapping and identification, solely based on the genetics. These tools, including a high number of catalogued sequence variants enable genome-wide studies of genetic loci behind rare and common diseases and disease-related phenotypes. So far the characterization of gene defects has successfully accomplished in over 1500 human diseases. Most successes so far have been in rare, monogenic diseases, where one major gene has a high impact, and environment or lifestyle has very little effect on the clinical outcome of patients. Characteristically genotyping informative multiallelic markers and linkage-based strategies adapted in families with multiple affected individuals, have initially positioned the locus. The subsequent fine mapping and linkage disequilibrium and association analyses have typically resulted in the successful identification of the disease genes. Special populations with a small number of founders and varying degree of isolation have proven to be especially valuable in the identification of novel disease genes. LD and haplotype sharing strategies have provided short cuts to disease gene identification in isolates (Peltonen, Palotie and Lange: Nature Reviews Genetics 1:182-191,2000).
Concerning the gene variants predisposing to common diseases, multiple uncertainties must be solved before the best possible strategy for the gene hunt can be designed and large-scale genome-wide investigations undertaken. Which phenotypes to include, which study population (isolated or out bred) to choose, which type of markers to be employed (multiallelic or SNPs), and how to select the variants to be genotyped? Rapidly increasing information of the structural or functional variability within the genome (long range rearrangements, patterns of gene expression) will also affect the interpretation of data.
Today’s sequence information in the web has moved the disease gene identification from the map-based gene discovery to the sequence-based gene discovery. Future decades will witness the use of genome-wide tools also in the dissection of the genetic background of common diseases. Precise transcript maps, identification of millions of SNP-variants combined with novel biostatistical strategies will facilitate monitoring of “genome-wide risk profiles” and expose genetic variants predisposing to common diseases. However, increased understanding of genome geography in different chromosomal regions and different populations is needed to improve our chances to identify specific alleles predisposing to common diseases.
Special populations will undoubtedly play an important part also in the characterization of common disease alleles. Examples of this is less numerous but I will provide some examples of genes behind common diseases identified using study samples of an isolated population of Finland.