The genomics of schizophrenia: update and implications

Abstract

Schizophrenia is strongly familial yet rarely (if ever) exhibits classical Mendelian inheritance patterns. The advent of large-scale genotyping and sequencing projects has yielded large data sets with higher statistical power in an effort to uncover new associations with schizophrenia. Here, we review the challenges in dissecting the genetics of schizophrenia and provide an update of the current understanding of the underlying genomics. We discuss the breadth of susceptibility alleles, including those that may occur with low frequency and high disease risk, such as the 22q11.2 hemideletion, as well as alleles that may occur with greater frequency but convey a lower risk of schizophrenia, such as variants in genes encoding subunits of the voltage-gated L-type calcium channel. Finally, we provide an overview of the clinical implications for the diagnosis and treatment of schizophrenia based on progress in understanding the underlying genetic basis.

Figure 1. The genetic landscape of schizophrenia.

(A) The allelic spectrum of schizophrenia. Shown are high-confidence empirical findings of the contribution of rare and common variants to the genotypic relative risk for developing schizophrenia. The x axis depicts the log10 of allele frequency in controls, and the y axis depicts the point estimate for log₁₀ of the genotypic relative risk. (i) No Mendelian variants for schizophrenia are known. A Mendelian form of schizophrenia would be expected to be rare with a very high genotypic relative risk (>50). (ii) CNVs associated with schizophrenia (represented by diamonds) are uncommon or rare and have an intermediate to high genotypic relative risks. (iii) Whole-exome sequencing studies have yet to identify protein-altering variants in this region, but the extant studies are few and small. (iv) High-confidence exclusion zone defined by risk allele prevalence >0.1 and genotypic relative risk >1.16, in which no loci have been identified despite statistical power nearing 100%. (v) Approximately 22 common variants have been significantly associated with schizophrenia to date (red circles). Common variants have a low genotypic relative risk individually but together account for more than 50% of the heritability of schizophrenia. (B) Expanded view of v, identifying the genomic regions achieving genome-wide significance. Circles denote the 22 common variants that have been significantly associated with schizophrenia; green circles represent long intergenic noncoding RNAs (lincRNAs).