- Title
- Polygenic disruption of retinoid signalling in schizophrenia and a severe cognitive deficit subtype
- Creator
- Reay, William R.; Atkins, Joshua R.; Quidé, Yann; Carr, Vaughan J.; Green, Melissa J.; Cairns, Murray J.
- Relation
- NHMRC.1067137 http://purl.org/au-research/grants/nhmrc/1067137 | NHMRC1147644 http://purl.org/au-research/grants/nhmrc/1147644
- Relation
- Molecular Psychiatry Vol. 25, Issue 4, p. 719-731
- Publisher Link
- http://dx.doi.org/10.1038/s41380-018-0305-0
- Publisher
- Nature Publishing Group
- Resource Type
- journal article
- Date
- 2020
- Description
- Retinoid metabolites of vitamin A are intrinsically linked to neural development, connectivity and plasticity, and have been implicated in the pathophysiology of schizophrenia. We hypothesised that a greater burden of common and rare genomic variation in genes involved with retinoid biogenesis and signalling could be associated with schizophrenia and its cognitive symptoms. Common variants associated with schizophrenia in the largest genome-wide association study were aggregated in retinoid genes and used to formulate a polygenic risk score (PRSRet) for each participant in the Australian Schizophrenia Research Bank. In support of our hypothesis, we found PRSRet to be significantly associated with the disorder. Cases with severe cognitive deficits, while not further differentiated by PRSRet, were enriched with rare variation in the retinoic acid receptor beta gene RARB, detected through whole-genome sequencing. RARB rare variant burden was also associated with reduced cerebellar volume in the cases with marked cognitive deficit, and with covariation in grey matter throughout the brain. An excess of rare variation was further observed in schizophrenia in retinoic acid response elements proximal to target genes, which we show are differentially expressed in the disorder in two RNA sequencing datasets. Our results suggest that genomic variation may disrupt retinoid signalling in schizophrenia, with particular significance for cases with severe cognitive impairment.
- Subject
- genetics; schizophrenia; retinoid metabolites; polygenic disruption
- Identifier
- http://hdl.handle.net/1959.13/1469772
- Identifier
- uon:48305
- Identifier
- ISSN:1359-4184
- Rights
- This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
- Language
- eng
- Full Text
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