Schizophrenia genetics: where next?

Abstract

The purpose of this invited review is to summarize the state of genetic research into the etiology of schizophrenia (SCZ) and to consider options for progress. The fundamental uncertainty in SCZ genetics has always been the nature of the beast, the underlying genetic architecture. If this were known, studies using the appropriate technologies and sample sizes could be designed with an excellent chance of producing high-confidence results. Until recently, few pertinent data were available, and the field necessarily relied on speculation. However, for the first time in the complex and frustrating history of inquiry into the genetics of SCZ, we now have empirical data about the genetic basis of SCZ that implicate specific loci and that can be used to plan the next steps forward.

Fig. 1.

The allelic spectrum of SCZ. Y-axis is genotypic relative risk, and x-axis is the risk allele prevalence (both log₁₀ scale). In the upper left are rare CNVs of strong effect, common variants of quite subtle effect are on the lower right (red and yellow dots) and a polygenic signal (turquoise dots plus a blue best fit line). The inset expands the lower right to provide gene names.

Fig. 2.

Relation between number of genome-wide significant regions and number of cases for 8 GWAS of SCZ.