The 1000 Genomes Project: deep genomic sequencing waiting for deep psychiatric phenotyping

Abstract

Recently, the interim results of the 1000 Genomes Project were published and revealed that the genome of an apparently healthy individual contains hundreds of potentially harmful, rare variants occurring at various places among thousands of possible different loci.1 Genetic variants are divided into 3 domains according to their frequency: very rare ( 5%). This division is based on the assumption that the rarer a variant, the more strongly selected out of the gene pool. This selection pressure is due to a substantially reduced reproductive fitness that is associated with the phenotype caused by this variant. Results from the last few decades of research in psychiatric genetics strongly suggest that genetic variants at the 2 extremes of the frequency spectrum ( 5%) seem not to play a meaningful role in psychiatric disorders. Very rare mutations, which are most efficiently detected through reverse genetic mapping, have not been uncovered despite very serious efforts. Similarly, common variants that were the focus of recent genome-wide association studies appear not to greatly increase the risk for psychiatric disorders, although more work is needed in this field.2 Even in somatic disorders, most of the heritability (> 95%) remains unexplained by common variants.3 Thus it is hoped that many rare genetic variants with relatively high penetrance may capture most of the heritability, which is often greater than 40%, of psychiatric disorders.