New discoveries in schizophrenia genetics reveal neurobiological pathways: A review of recent findings

Abstract

Schizophrenia research has undergone a recent transformation. By leveraging large sample sizes, genome-wide association studies of common genetic variants have approximately tripled the number of candidate genetic loci. Rare variant studies have identified copy number variants that are schizophrenia risk loci. Among these, the 3q29 microdeletion is now known to be the single largest schizophrenia risk factor. Next-generation sequencing studies are increasingly used for rare variant association testing, and have already facilitated identification of large effect alleles. Collectively, recent findings implicate voltage-gated calcium channel and cytoskeletal pathways in the pathogenesis of schizophrenia. Taken together, these results suggest the possibility of imminent breakthroughs in the molecular understanding of schizophrenia.

Keywords: Copy number variation; GWAS; Psychiatric genetics; Schizophrenia genetics.

Figure 1. Locations of SZ-associated alleles

Chromosomal locations of SZ-associated variants: copy number variants [33, 51] (red squares), recurrent de-novo mutations and rare variants identified by NGS [50, 85] (blue circles), and GWAS loci [49] (green triangles).

Figure 2. A comparison of significant allele odds ratios and population frequencies

Shown is a comparison of odds ratio (y-axis) and population frequency (log scale; x-axis) for selected GWAS loci (left side of center y-axis) and CNV (right side of center y-axis) associated with SZ. GWAS SNPs from [49] were ranked by odds ratio, and a representative SNP from each quartile was selected for display here.