Genetics of psychiatric disorders methods: molecular approaches

Abstract

The practice of psychiatry has long suffered from the limited information available on the biological basis of mental disorders. This limitation is now coming to an end. Advances in DNA analysis technologies and in our understanding of the human genome, together with our new knowledge of the properties of the genome and significant efforts toward generating large patient and control sample collections, have paved the way for successful genome-wide association studies. As a result, reports now appear in the literature every week identifying new genes for complex disorders. Next-generation sequencing methods, combined with the results of association and perhaps linkage studies, will help us uncover missing heritability factors, achieve a better understanding of the genetic aspects of psychiatric disease, and devise the best strategies for incorporating genetics in the service of patients.

Figure 1

Linkage disequilibrium. Three SNPs and their observed haplotypes in the population are shown. A new mutation generates an additional variant on one of the haplotypes. In the simplistic example shown here the mutation is in perfect LD with SNP2 (r-squared=1) and any disease association would also be observed with that SNP. The other SNPs are correlated with the mutation, but not perfectly (r-squared <1). As long as recombination does not break this haplotype block, the variants remain in complete LD (D′=1) and certain combinations of alleles are never observed.

Figure 2

Example of LD islands. A 100 Kb region around the APOE gene is shown using data from the HapMap project and the Haploview software (www.broadinstitute.org/mpg/haploview). Colored diamonds show the strength of LD between the SNPs corresponding to the extension of their sides up to the SNP line-up at the top. Red is for strong LD (high D′) while purple signifies insufficient information to infer LD. Islands of LD are revealed as large red triangles. An island of strong LD is labeled.

Figure 3

ChIP-chip vs. ChIP-seq. The first three steps are identical. DNA is cross-linked to chromatin and fragmented and then antibodies specific to modifications of interest are used for immunoprecipitation (IP). Cross links are reversed and the selected DNA is analyzed for content. This analysis was traditionally done through hybridization on a chip (hence ChIP-chip) and is now often done by next-generation sequencing (ChIP-seq).