School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW, Australia.
Centre for Brain and Mental Health Research, Hunter Medical Research Institute, Newcastle, NSW, Australia.
Mol Psychiatry. 2020 Apr;25(4):719-731. doi: 10.1038/s41380-018-0305-0. Epub 2018 Dec 7.
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 (PRS) for each participant in the Australian Schizophrenia Research Bank. In support of our hypothesis, we found PRS to be significantly associated with the disorder. Cases with severe cognitive deficits, while not further differentiated by PRS, 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.
视黄酸代谢物是维生素 A 的一种，与神经发育、连接和可塑性密切相关，并与精神分裂症的病理生理学有关。我们假设，与视黄醇生物合成和信号转导相关基因中的常见和罕见基因组变异负担增加，可能与精神分裂症及其认知症状有关。在最大的全基因组关联研究中与精神分裂症相关的常见变异在视黄醇基因中聚集，并用于为澳大利亚精神分裂症研究银行中的每个参与者制定多基因风险评分 (PRS)。支持我们的假设，我们发现 PRS 与该疾病显著相关。虽然认知缺陷严重的病例没有进一步根据 PRS 进行区分，但通过全基因组测序检测到视黄酸受体 β 基因 RARB 的罕见变异丰富。在认知缺陷明显的病例中，RARB 罕见变异负担也与小脑体积减少以及整个大脑灰质的变异性有关。在与目标基因近端的视黄酸反应元件中还观察到精神分裂症中存在过多的罕见变异，我们在两个 RNA 测序数据集显示这些基因在该疾病中存在差异表达。我们的研究结果表明，基因组变异可能会破坏精神分裂症中的视黄醇信号转导，对于认知障碍严重的病例具有特殊意义。
