Heinzer, Lea;
Curtis, David;
(2024)
What have genetic studies of rare sequence variants taught us about the aetiology of schizophrenia?
Journal of Translational Genetics and Genomics
, 8
(1)
pp. 1-12.
10.20517/jtgg.2023.39.
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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.
| Type: | Article |
|---|---|
| Title: | What have genetic studies of rare sequence variants taught us about the aetiology of schizophrenia? |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.20517/jtgg.2023.39 |
| Publisher version: | http://dx.doi.org/10.20517/jtgg.2023.39 |
| Language: | English |
| Additional information: | © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/). |
| Keywords: | Schizophrenia, exome sequencing, rare sequence variants, protein-truncating variants, glutamatergic dysfunction, ubiquitin-proteasome system |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Genetics, Evolution and Environment |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10188583 |
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