Associations between neurodevelopmental genes, neuroanatomy, and ultra high risk symptoms of psychosis in 22q11.2 deletion syndrome

Abstract

22q11.2 deletion syndrome is a neurogenetic disorder resulting in the deletion of over 40 genes. Up to 40% of individuals with 22q11.2DS develop schizophrenia, though little is known about the underlying mechanisms. We hypothesized that allelic variation in functional polymorphisms in seven genes unique to the deleted region would affect lobar brain volumes, which would predict risk for psychosis in youth with 22q11.2DS. Participants included 56 individuals (30 males) with 22q11.2DS. Anatomic MR images were collected and processed using Freesurfer. Participants were genotyped for 10 SNPs in the COMT, DGCR8, GNB1L, PIK4CA, PRODH, RTN4R, and ZDHHC8 genes. All subjects were assessed for ultra high risk symptoms of psychosis. Allelic variation of the rs701428 SNP of RTN4R was significantly associated with volumetric differences in gray matter of the lingual gyrus and cuneus of the occipital lobe. Moreover, occipital gray matter volumes were robustly associated with ultra high risk symptoms of psychosis in the presence of the G allele of rs701428. Our results suggest that RTN4R, a relatively under-studied gene at the 22q11 locus, constitutes a susceptibility gene for psychosis in individuals with this syndrome through its alteration of the architecture of the brain. © 2017 Wiley Periodicals, Inc.

Brain morphometry in 22q11.2 deletion syndrome: an exploration of differences in cortical thickness, surface area, and their contribution to cortical volume

“…Further, genetic studies in 22q11.2DS, both in animals and humans, have found several genes within the microdeletion site that are thought to be implicated in some of the psychiatric difficulties associated with 22q11.2DS. For example, COMT and PRODH have been linked to both psychosis and ASD 34 , 35 . Although there are only a few post-mortem studies in 22q11.2DS to date, which report subtle cortical lamination defects in a 3 month old 36 , and a loss or failure to differentiate upper layer projection neurones in the cortex 37 , these appear to relatively consistent with the changes in the cortical architecture that are typically observed in Schizophrenia, and to some extent ADHD and ASD 33 .…”

Drosophila ZDHHC8 palmitoylates scribble and Ras64B and controls growth and viability

“…The function of hZDHHC8 has been mainly characterized to date in the brain, where loss of the genomic hZDHHC8 locus in microdeletions at 22q11 is associated with cognitive deficits and schizophrenia [24–26]. To our knowledge, hZDHHC8 has not been implicated in cancer so far, except that knockdown of hZDHHC8 makes mesothelioma cells more sensitive to radiotherapy [27].…”

Genetic and clinical features of social cognition in 22q11.2 deletion syndrome

“…Furthermore, RTN4R(−/−) mice have proven to have deficits in spatial learning (Lazar et al, ) and memory task (van Gaalen, Relo, Mueller, Gross, & Mezler, ). Thompson et al () found a correlation between a specific allelic variation of this gene and reduced posterior cerebral volumes, which are thought to be responsible for some visual and social cognitive deficits of the syndrome.…”