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Associations Between Neurodevelopmental Genes, Neuroanatomy, and Ultra High Risk Symptoms of Psychosis in 22Q11.2 Deletion Syndrome

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Associations Between Neurodevelopmental Genes, Neuroanatomy, and Ultra High Risk Symptoms of Psychosis in 22Q11.2 Deletion Syndrome Associations between neurodevelopmental genes, neuroanatomy, and ultra high risk symptoms of psychosis in 22q11.2 deletion syndrome Item Type Article Authors Thompson, Carlie A.; Karelis, Jason; Middleton, Frank A.; Gentile, Karen; Coman, Ioana L.; Radoeva, Petya D.; Mehta, Rashi; Fremont, Wanda P.; Antshel, Kevin M.; Faraone, Stephen V.; Kates, Wendy R. Citation Thompson CA, Karelis J, Middleton FA, Gentile K, Coman IL, Radoeva PD, Mehta R, Fremont WP, Antshel KM, Faraone SV, Kates WR. 2017. Associations Between Neurodevelopmental Genes, Neuroanatomy, and Ultra High Risk Symptoms of Psychosis in 22q11.2 Deletion Syndrome. Am J Med Genet Part B 174B:295–314 DOI 10.1002/ajmg.b.32515 Publisher Wiley Rights Attribution-NonCommercial-NoDerivatives 4.0 International Download date 01/10/2021 18:46:16 Item License http://doi.wiley.com/10.1002/tdm_license_1 Link to Item http://hdl.handle.net/20.500.12648/1796 RESEARCH ARTICLE Neuropsychiatric Genetics Associations Between Neurodevelopmental Genes, Neuroanatomy, and Ultra High Risk Symptoms of Psychosis in 22q11.2 Deletion Syndrome Carlie A. Thompson,1 Jason Karelis,1 Frank A. Middleton,1,2 Karen Gentile,2 Ioana L. Coman,3 Petya D. Radoeva,4 Rashi Mehta,5 Wanda P. Fremont,1 Kevin M. Antshel,1,6 Stephen V. Faraone,1 and Wendy R. Kates1* 1Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, New York 2Department of Neuroscience, SUNY Upstate Medical University, Syracuse, New York 3Department of Computer Science, SUNY Oswego, Oswego, New York 4Department of Psychiatry, University of Washington, Seattle, Washington 5Department of Radiology, SUNY Upstate Medical University, Syracuse, New York 6Department of Psychology, Syracuse University, Syracuse, New York Manuscript Received: 14 April 2016; Manuscript Accepted: 7 November 2016 22q11.2 deletion syndrome is a neurogenetic disorder resulting in the deletion of over 40 genes. Up to 40% of individuals with How to Cite this Article: 22q11.2DS develop schizophrenia, though little is known about Thompson CA, Karelis J, Middleton FA, the underlying mechanisms. We hypothesized that allelic varia- Gentile K, Coman IL, Radoeva PD, Mehta tion in functional polymorphisms in seven genes unique to the R, Fremont WP, Antshel KM, Faraone SV, deleted region would affect lobar brain volumes, which would Kates WR. 2017. Associations Between predict risk for psychosis in youth with 22q11.2DS. Participants Neurodevelopmental Genes, included 56 individuals (30 males) with 22q11.2DS. Anatomic Neuroanatomy, and Ultra High Risk MR images were collected and processed using Freesurfer. Symptoms of Psychosis in 22q11.2 Deletion Participants were genotyped for 10 SNPs in the COMT, Syndrome. DGCR8, GNB1L, PIK4CA, PRODH, RTN4R, and ZDHHC8 genes. All subjects were assessed for ultra high risk symptoms Am J Med Genet Part B 174B:295–314. 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. 2008]. The typically deleted region (TDR) is 3 Mb, found in Moreover, occipital gray matter volumes were robustly associ- approximately 87% of cases [Shaikh et al., 2000]. Low-copy ated with ultra high risk symptoms of psychosis in the presence DNA repeats (LCRs) specific to chromosome 22 have been impli- of the G allele of rs701428. Our results suggest that RTN4R, a cated in the formation of 22q11.2 deletions and are found in relatively under-studied gene at the 22q11 locus, constitutes a proximity to the end-points of the TDR [Shaikh et al., 2000]. It susceptibility gene for psychosis in individuals with this syn- has been hypothesized that homologous recombination errors drome through its alteration of the architecture of the brain. between these LCRs during meiosis results in the deletions (and Ó 2017 Wiley Periodicals, Inc. duplications) found in the sequences of individuals with 22q11.2DS [Edelmann et al., 1999]. Key words: velo-cardio-facial syndrome; RTN4R; axonal development; Freesurfer; schizophrenia Conflicts of interest: The authors have no conflicts of interest to declare. Grant sponsor: National Institutes of Health; Grant number: MH064824. ÃCorrespondence to: Wendy R. Kates, Ph.D., Department of Psychiatry and Behavioral INTRODUCTION Sciences, State University of New York at Upstate Medical University, 750 East Adams Street, Syracuse, New York. 22q11.2 deletion syndrome (22q11.2DS) is the most common E-mail: [email protected] micro-deletion syndrome found in humans [Edelmann et al., Article first published online in Wiley Online Library 1999]. The size of the region deleted can vary but almost always (wileyonlinelibrary.com): 31 January 2017 spans a shared minimal deletion region of 1.5 Mb [Maynard et al., DOI 10.1002/ajmg.b.32515 Ó 2017 Wiley Periodicals, Inc. 295 296 AMERICAN JOURNAL OF MEDICAL GENETICS PART B Individuals with 22q11.2DS have increased susceptibility to glutamate [Bender et al., 2005]. Alterations in glutamate signaling behavioral, anxiety and mood disorders, and psychosis [Schneider are very well-established as risk factors for psychosis [Moghaddam et al., 2014]. In particular, they have over a 30% chance of and Javitt, 2012]. We examined the SNP, rs4819756 (A/G), as noted developing schizophrenia, which is considerably higher than the in Table I. worldwide population risk of less than 1% [Murphy et al., 1999; The ZDDHC8 gene, located in the distal third of the 1.5 Mb- Saha et al., 2005; Green et al., 2009; van Os and Kapur, 2009]. minimal deletion region [Maynard et al., 2008], is broadly Consequently, there has been considerable interest in determining expressed in many regions of the adult human brain [Mukai which genes in the TDR might contribute to the elevated risk for et al., 2004], particularly in the olfactory bulb, neocortex, and schizophrenia. Several genes for which individuals with 22q11.2DS cerebellum [Maynard et al., 2008], as well as the adult mouse brain are hemizygous have been linked to the development of schizo- [Mukai et al., 2004]. Among 72 known SNPs located within the 1.5- phrenia in both individuals with this syndrome and the population Mb deleted region, a polymorphism in ZDDHC8, known as at large [Chen et al., 2004a,b; Mukai et al., 2004; Gothelf et al., 2005, rs175174, had the greatest association with schizophrenia [Mukai 2011; Budel et al., 2008; Jungerius et al., 2008; Vorstman et al., 2009; et al., 2004]. This polymorphism mediates the alternative splicing Kempf et al., 2008]. However, data supporting the association of ZDDHC8 such that intron 4 is included in the final mRNA between individual genetic variants and risk for psychosis are not transcript; when this intron is retained, a premature stop codon is consistent, most likely due to the relatively distal relationship introduced into the growing amino acid chain that could terminate between genetic variants and psychopathological behaviors translation and result in a truncated protein with diminished [Meyer-Lindenberg and Weinberger, 2007], and the evidence activity [Mukai et al., 2004]. that multiple genes most likely confer small effects on risk for The Reticulon 4 receptor, also known as the Nogo-66 receptor psychiatric disease [Manolio et al., 2009]. It has been suggested that (NgR), is a glycosylphosphatidylinositol (GPI)-linked protein a more fruitful approach would include the examination of inter- encoded by the RTN4R gene, which is located within the distal mediate phenotypes. In this context, intermediate phenotypes are third of the minimal 1.5-Mb deletion region [Maynard et al., 2008]. biologically—based traits or mechanisms through which genes Through interacting with Nogo-66 (Neurite Outgrowth Inhibitor might affect behavior [Meyer-Lindenberg and Weinberger, 66), the receptor plays a significant role in the inhibition of myelin- 2007]. Since neuroanatomic structure is considered such an inter- mediated axonal growth [Fournier et al., 2001]. Nogo-66 localizes mediate phenotype, we sought to examine the extent to which to axons and binds to oligodendrocyte-myelin glycoprotein allelic variants of candidate genes alter neuroanatomic structure to (OMgp), myelin-associated glycoprotein (MAG), and Nogo-A increase the risk for psychosis in individuals with 22q11.2DS. Here (RTN4), all of which inhibit axonal sprouting. The Nogo-66 we describe briefly the functions of the seven candidate genes at the receptor, together with other GPI-linked axonal proteins, is re- 22q11.2 locus that we examined, all of which are expressed in brain quired for Nogo-66 to retain its inhibitory functions [Fournier and implicated in schizophrenia. Table I summarizes studies that et al., 2001]. Nogo-66 collapses the axonal growth cones found in have examined the clinical and, if available, neuroanatomic studies the dorsal root ganglion and inhibits neurite outgrowth [Fournier that justify the inclusion of each gene in the current study. et al., 2001]. Due to its potential role in plasticity and neuronal The COMT gene is located in the 1.5 critical deletion region that regeneration, the Reticulon 4 receptor is being researched as a is consistently deleted in cases of 22q11.2DS. Its protein product, possible drug-target for spinal and cerebrovascular injury [Baptiste the COMT enzyme (EC 2.1.1.6), catabolizes catecholamines— and Fehlings, 2007]. We have previously reported that the rs701428 dopamine, norepinephrine, and epinephrine. The COMT gene SNP in RTN4R is associated with alterations in white matter encodes
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