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Heinzer et al. J Transl Genet Genom 2024;8:1-12 Journal of Translational
DOI: 10.20517/jtgg.2023.39
Genetics and Genomics

Review Open Access

What have genetic studies of rare sequence variants
taught us about the aetiology of schizophrenia?

Lea Heinzer, David Curtis

UCL Genetics Institute, University College London, London WC1E 6BT, UK.
Correspondence to: Dr. David Curtis, UCL Genetics Institute, University College London, Darwin Building, Gower Street, London
WC1E 6BT, UK. E-mail: d.curtis@ucl.ac.uk

How to cite this article: Heinzer L, Curtis D. What have genetic studies of rare sequence variants taught us about the aetiology of
schizophrenia? J Transl Genet Genom 2024;8:1-12. https://dx.doi.org/10.20517/jtgg.2023.39

Received: 6 Sep 2023 First Decision: 5 Dec 2023 Revised: 18 Dec 2023 Accepted: 2 Jan 2024 Published: 12 Jan 2024
Academic Editor: Richard E. Frye Copy Editor: Fangyuan Liu Production Editor: Fangyuan Liu

Abstract
With a population prevalence of 1%, schizophrenia is widespread, yet the aetiology of this psychiatric disorder
remains elusive. There is an evident genetic component of schizophrenia, with heritability estimates lying at
60%-80%. While genome-wide association studies have identified 120 gene loci associated with schizophrenia
risk, these involved common variants that confer only small effects on individual risk (median odds ratio < 1.2). The
recent emergence of whole exome sequencing (WES) technologies has facilitated the identification of rare
sequence variants, including some protein-truncating variants that have significant effects on risk. Three key large-
scale WES studies have demonstrated that rare sequence variants in the genes SETD1A, CACNA1G, CUL1, GRIA3,
GRIN2A, HERC1, RB1CC1, SP4, TRIO, XPO7, and AKAP11 confer substantial risk for schizophrenia. These genes are
highly expressed in central nervous system neurons and their products participate in diverse molecular functions
including synaptic transmission, transcriptional regulation, and ubiquitin ligation. The understanding of these
functional roles illuminates putative molecular mechanisms which may lead to schizophrenia-like phenotypes. It
will also be possible to develop model systems in which the effects of impaired function of these genes can be
further explored. Genetic studies of rare variants to date suggest that glutamatergic system dysregulation,
chromatin modification, and the ubiquitin-proteasome system play key roles in schizophrenia aetiology.

Keywords: Schizophrenia, exome sequencing, rare sequence variants, protein-truncating variants, glutamatergic
dysfunction, ubiquitin-proteasome system

INTRODUCTION
Schizophrenia is a severe and chronic psychiatric disorder with a population prevalence in the order of 1%,

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