No evidence for the presence of genetic variants predisposing to psychotic disorders on the non-deleted 22q11.2 allele of VCFS patients

Abstract

The velo-cardio-facial syndrome (VCFS) is caused by hemizygous deletions on chromosome 22q11.2. The VCFS phenotype is complex and characterized by frequent occurrence of neuropsychiatric symptoms with up to 25–30% of cases suffering from psychotic disorders compared with only ~1% in the general population (odds ratio≈20–25). This makes the 22q11.2 deletion one of the most prominent risk factors for schizophrenia. However, its penetrance for neuropsychiatric phenotypes is incomplete suggesting that additional risk factors are required for disease development. These additional risk factors could lie anywhere on the genome, but by reducing the normal diploid to a haploid state, the 22q11.2 deletion could result in the unmasking of otherwise recessive alleles or functional variants on the non-deleted 22q11.2 allele. To test this hypothesis, we captured and sequenced the whole 22q11.2 non-deleted region in 88 VCFS patients with (n=40) and without (n=48) psychotic disorders to identify genetic variation that could increase the risk for schizophrenia. Single nucleotide variants (SNVs), small insertions/deletions (indels) and copy number variants were called and their distributions were compared between the two diagnostic groups using variant-, gene- and region-based association tests. None of these tests resulted in statistical evidence for the existence of a genetic variation in the non-deleted allele that would increase schizophrenia risk in VCFS patients. Power analysis showed that our study was able to achieve >80% statistical power to detect association of a risk variant with an odd ratio of ⩾22. However, it is certainly under-powered to detect risk variant of smaller effect sizes. Our study did not provide evidence that genetic variants of very large effect size located on the non-deleted 22q1.2 allele in VCFS patients increase the risk for developing psychotic disorders. Variants with smaller effects may be located in the remaining 22q11.2 allele and elsewhere in the genome. Therefore, whole exome or even genome sequencing for larger sample size would appear to be the next logical steps in the search for the genetic modifiers of the 22q11.2-deletion neuropsychiatric phenotype.

Differential DNA methylation at birth associated with mental disorder in individuals with 22q11.2 deletion syndrome

“…This could be driven by other genetic risk factors; however, there is no evidence of the presence of genetic factors on the non-deleted 22q11.2 copy to predispose these individuals to the development of, for example, psychotic disorders. 24 , 25 , 26 This suggests that alternative factors, such as environmental and epigenetic factors, could contribute to the development, onset and/or progression of psychiatric phenotypes in 22q11.2DS individuals.…”

Risk gene-set and pathways in 22q11.2 deletion-related schizophrenia: a genealogical molecular approach

“…The CLTCL1 has a role in synaptic plasticity (KEGG:hsa04721), neural crest development 44 , neuronal depolarization 45 , and histone modification 46 . Two previous case–control studies reported that variants on the 22q11.2 intact chromosome are not major contributors to SZ 36 and psychosis 47 . The haplotype analysis of large multiplex families, in contrast to case–control studies, enables to examine contribution of the 22q11.2 gene variants, inherited together as a haplotype, to psychosis using internal control for comparison that eliminates the need for population stratification.…”

Exploratory case study of monozygotic twins with 22q11.2DS provides further clues to circumscribe neurocognitive markers of psychotic symptoms

“…The etiology of the incomplete penetrance of psychosis in 22q11.2DS is a highly critical question. Regarding genetic explanations, several hypotheses have been raised, ranging from additional genomic mutation outside of the 22q region (Balan et al, 2014; Bassett et al, 2017; Toyosima et al, 2011) to epigenetic factors (Cirillo et al, 2014; Singh et al, 2002; Starnawska et al, 2017), without forgetting the potential role of the other allele and especially COMT polymorphisms (Gothelf et al, 2007, Gothelf et al, 2014; Guipponi et al, 2017; Merico et al, 2015; Thompson et al, 2017) or intergenic noncoding RNA genes (Merico et al, 2015). A more integrative model suggests that psychotic symptoms may occur from genetic risk combined with negative life events, traumatic experiences, and/or attachment disorder (Biswas and Furniss, 2016).…”

“…Critically, behavioural measures can be contaminated by response-related unspecific processes such as decision-making or response inhibition (Azuma et al, 2015; Leleu et al, 2016). Second, classical group studies insufficiently control genetic or environmental stress variability that could mediate the incomplete penetrance for psychiatric phenotypes (Biswas and Furniss, 2016; Chung et al, 2015; Guipponi et al, 2017; Toyosima et al, 2011). It remains thus unclear whether neurocognitive markers identified in group studies can be used in clinical care, i.e., for individual participants.…”