Human Disease Genes: From Families to Populations
Population isolates have been very useful for mapping and cloning of disease genes, in such isolates genetic drift leads to an overabundance of disease-alleles for particular disorders, and a high proportion of patients share these alleles, identical by descent. The disease genes of Finns are among the best characterized in the world and the identified mutations have provided tools for efficient diagnosis and carrier screening. Equally importantly, identification and characterization of mutated genes have exposed novel disease mechanisms and metabolic pathways, critical for human cells and tissues. This feature has extended the benefits of this knowledge beyond the Finnish population. Good examples are: 1) Aire gene, identified in Finnish APECED (OMIM 240300) families, and later proven to be the critical regulator of ectopic expression of antigens in thymus, providing new insights into autoimmunity in human; 2) DAP12 and TREM2 genes, identified in PLOSL (OMIM 221770) families, and linking dementia and demyelination to the abnormal behavior of dendritic cells.
The concept that isolates would be similarly advantageous for genetic studies of common diseases has been challenged. Only a few examples exist to prove that study samples from isolates facilitate detection of disease-related haplotype signatures through association studies. However, detailed information of the population history is increasingly understood as one crucial factor of success in genetic studies of common diseases. Our studies on the gene identification in lactose intolerance, dyslipidemias, multiple sclerosis and schizophrenia exemplify the strategies used to identify allelic variants behind common diseases in Finnish data sets and study samples. The data obtained also demonstrate how the impact of specific allelic variants of disease genes, initially identified in families, can be addressed in epidemiological cohorts containing excessive amount of quantitive phenotype information.