Polygenic disruption of retinoid signalling in schizophrenia and a severe cognitive deficit subtype

Abstract

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 Ret ) for each participant in the Australian Schizophrenia Research Bank. In support of our hypothesis, we found PRS Ret to be significantly associated with the disorder. Cases with severe cognitive deficits, while not further differentiated by PRS Ret , 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.

Pharmacological enrichment of polygenic risk for precision medicine in complex disorders

“…The current analysis also used very stringent criteria for drug pathway gene inclusion and there are likely to be many more genes and pathways that may be implicated in future ontologies and other investigator curated gene sets. In a recent example of this we observed an enrichment of retinoid gene variation in schizophrenia 32 .…”

“…We sought to generate PES for the schizophrenia candidate pathways in a cohort of diagnosed schizophrenia cases and non-neuropsychiatric controls sourced from the Australian Schizophrenia Research Bank (ASRB) 12,32 . Detailed descriptions of consent procedures along with inclusion and exclusion criteria for the ASRB have been extensively described elsewhere 12…”

“…The Illumina Infinitium Human 610K (610-Quad) BeadChip platform was used to genotype genomic DNA extracted from peripheral blood mononucleocytes as per standard manufacturer protocols. Variant and individual level quality control, along with imputation using the 1000 genomes phase 3 European reference panel, has been outlined in detail for this cohort previously32 . High quality autosomal sites with low missigness (< 2%) and an imputation score greater than 0.8 (R 2 > 0.8) were retained for analysis in this study.…”

Regulation of Prefrontal Patterning, Connectivity and Synaptogenesis by Retinoic Acid

“…Clinically, disruptions in PFC development and reciprocal long-range connections between the MD nucleus of the thalamus and the PFC are thought to underlie cognitive dysfunction in schizophrenia 9 and pathophysiology of ASD 5 . Disruption of RA signaling has been implicated in schizophrenia 45–48 , including enrichment of rare variation mutations in RARB in cases with severe cognitive deficits 48 . Furthermore, RA is known teratogen that can cause defects in human cerebral cortical development 60 .…”

“…RA is also known to exert a trophic influence on nascent neurons to promote axon and dendritic outgrowth 33, 35, 39, 40 as well as synaptogenesis 35, 41 . Moreover, alterations in RA signaling have been implicated in the pathophysiology of ASD 42–44 and schizophrenia 45–48 . Given the enrichment of RA-related genes among those upregulated in the mid-fetal human PFC, we assessed whether RA concentration is increased in the PFC, using an RA-specific enzyme-linked immunosorbent assay (ELISA) in two anthropoid primates with laterally expanded PFC, human and macaque, and mouse, a rodent with fewer, medially located, PFC areas.…”