Genetic architecture of schizophrenia: a review of major advancements.

Sophie E Legge,Sathish Periyasamy,Marcos L Santoro,Adeniran Okewole,Arsalan Arsalan,Kaarina Kowalec

doi:10.1017/s0033291720005334

Abstract

Schizophrenia is a severe psychiatric disorder with high heritability. Consortia efforts and technological advancements have led to a substantial increase in knowledge of the genetic architecture of schizophrenia over the past decade. In this article, we provide an overview of the current understanding of the genetics of schizophrenia, outline remaining challenges, and summarise future directions of research. World-wide collaborations have resulted in genome-wide association studies (GWAS) in over 56 000 schizophrenia cases and 78 000 controls, which identified 176 distinct genetic loci. The latest GWAS from the Psychiatric Genetics Consortium, available as a pre-print, indicates that 270 distinct common genetic loci have now been associated with schizophrenia. Polygenic risk scores can currently explain around 7.7% of the variance in schizophrenia case-control status. Rare variant studies have implicated eight rare copy-number variants, and an increased burden of loss-of-function variants in SETD1A, as increasing the risk of schizophrenia. The latest exome sequencing study, available as a pre-print, implicates a burden of rare coding variants in a further nine genes. Gene-set analyses have demonstrated significant enrichment of both common and rare genetic variants associated with schizophrenia in synaptic pathways. To address current challenges, future genetic studies of schizophrenia need increased sample sizes from more diverse populations. Continued expansion of international collaboration will likely identify new genetic regions, improve fine-mapping to identify causal variants, and increase our understanding of the biology and mechanisms of schizophrenia.

Highlights

Schizophrenia is a severe and often chronic psychiatric disorder causing substantial personal and societal burden from severe and long-term disability
The subsequent meta-analysis of East Asian and European ancestries reported 208 independent associations in 176 independent genetic loci, 53 of which were novel. These findings suggest that the common genetic basis for schizophrenia is largely shared between populations, there are likely to be population-specific risk variants driven by underlying differences in linkage disequilibrium and/or allele frequency
In the last two decades, the sample size for genetic studies of schizophrenia has increased from hundreds to hundreds of thousands of individuals, resulting in the identification of >300 common variants, 10 genes with a burden of rare coding variants, and at least 8 copy number variants (CNVs)

Summary

Introduction

Schizophrenia is a severe and often chronic psychiatric disorder causing substantial personal and societal burden from severe and long-term disability. In European populations, common variant associations identified from GWAS explain around one third (24%) of genetic liability to schizophrenia (Lee et al, 2012; Ripke et al, 2013; Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014). These results are consistent in non-European populations (Lam et al, 2019), and in a PRS analysis of a large real-world sample of patients from four US-based healthcare systems (Zheutlin et al, 2019) These findings indicate that a substantial proportion of the common genetic architecture among psychiatric disorders and cognition is shared and has implications for the validity of current clinical diagnostic boundaries. As new ongoing consortia and biobanks are established, it is essential that ancestry disparities are addressed

Conclusions

Funding Statement

Findings

SUMMARY OF SCHIZOPHRENIA GENETICS