GENOME PROJECTS AND THE PROSPECTS OF MODERN GENETICS –
WHAT HAVE WE LEARNED?
Leena Palotie, M.D., Ph.D.
Academy Professor
Department of Molecular Medicine, National Public Health Institute;
Department of Medical genetics, University of Helsinki, Finland;
Gordon and Virginia MacDonald Distinguished Chair in Human Genetics, UCLA, USA
The Human Genome Project has produced a high number of catalogued sequence variants for all
known, some 22 000 genes, enabling genome-wide studies of genetic loci behind disease-related
phenotypes. The molecular defect has been identified in over 1500 monogenic diseases and first
encouraging findings are reported for some common, polygenic traits, including many psychiatric
diseases. Further, genome projects of other species have facilitated the identification of functionally
important elements of human genome outside the coding regions of genes.
To maximally utilize the fruits of the genome project in the identification of genetic variants behind
common diseases, special, clinically well defined study sampled are needed. Population isolates like
Finland have been very useful for mapping and cloning genes for rare disorders; 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 concept that the isolates are
similarly advantageous for genetic studies of common diseases has been challenged, and only few
samples exist to prove if it really would be more straightforward in such populations to detect
disease-related haplotype signatures through association studies. The age, growth pattern, and
degree of historical isolation of a population determine the average length of shared haplotypes
around a disease mutation, among affected individuals. Detailed information of the population
history is increasingly understood as the crucial factor in genetic studies of common diseases.
I will describe the features of the Finnish population and our efforts to search for disease genes for
rare and common neuropsychiatric phenotypes to exemplify strategies we have used to identify
disease genes and predisposing alleles in Finnish data sets and study samples. Both the LD intervals
in general alleles and the prevalence of disease mutations are strikingly different in different
regional subpopulations reflecting differences in population history even within this homogeneous
population. We have relied on skillful clinical collaborators, excellent health care and population
registers, and used genealogical information to construct large pedigrees with multiple affected
individuals originating from regional subisolates. Initial genotyping has been carried out with
maximally informative multiallelic markers facilitating monitoring of shared haplotypes among
affected family members to identify the putative target regions for further analysis. These regions
have been followed by dense SNP mapping and statistical analyses combining the power of linkage
and association. This strategy has exposed well-defined critical chromosomal regions in common
diseases like multiple sclerosis, autism, bipolar disease and schizophrenia in regional subisolates of
Finland. Predisposing DNA-variants have been identified in phenotypes like lactose intolerance and
familial combined hyperlipidemia and associated haplotypes in schizophrenia. The general
significance of these variants needs to be further verified in population cohorts and by functional
studies.