Further evidence for high rates of schizophrenia in 22q11.2 deletion syndrome

Abstract

22q11.2 deletion syndrome (22q11.2DS) is associated with high rates of psychotic disorder, particularly schizophrenia. The deletion is considered to be a biological model for understanding this debilitating psychiatric disorder. It is unclear whether the psychotic manifestations in 22q11.2DS are similar to those in schizophrenia patients without the deletion. Catechol-O-methyltransferase (COMT), a positional candidate gene for schizophrenia, resides within the 22q11.2 region. It remains unknown whether hemizygosity for this gene is associated with risk of psychotic disorder. This study includes 83 adults with 22q11.2DS, 90 non-deleted individuals with schizophrenia, and 316 normal controls. Psychopathology was assessed using the Schedules for Clinical Assessment in Neuropsychiatry, the Schedules for the Assessment of Positive and Negative Symptoms and the Global Assessment Scale. Schizotypy was assessed with the Kings Schizotypy Questionnaire and Oxford Liverpool Inventory of Feelings and Emotions. IQ estimates were also obtained. Adults with 22q11.2DS were genotyped for a number of COMT polymorphisms as well as the Ashkenazi risk haplotype.

This study confirms high rates of psychotic disorder (29%) in individuals with 22q11.2DS of which the majority had schizophrenia (22%). There does not appear to be a differential expression of schizophrenic symptom clusters in 22q11.2DS in relation to sporadic schizophrenia, though schizophrenia in 22q11.2DS seems to be less severe in terms of global assessment scores. Psychosis proneness seems to be of genetic origin in 22q11.2DS as individuals with 22q11.2DS without schizophrenia had higher schizotypy scores than normal controls. Finally, COMT was not associated with schizophrenia status or schizotypy.

Introduction

Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a multiple anomaly syndrome associated with interstitial deletions on the long arm (q) of chromosome 22q11. Over 180 clinical features have been associated with this syndrome, which impact upon nearly every organ group and system (Shprintzen, 2008), the majority of which are associated with disruptions of neural crest cell development (Scambler, 2000). In addition to the commonly reported congenital anomalies (cleft palate, congenital heart defects, velopharyngeal insufficiency and a characteristic facial appearance) (McDonald-McGinn et al., 1999), 22q11.2DS is also associated with a range of cognitive and psychiatric problems (Karayiorgou et al., 2010). The rate of psychotic disorder in adults with 22q11.2DS may be as high as 30% (Murphy et al., 1999) while reported rates of schizophrenia tend to be between 20 and 25% (Pulver et al., 1994, Murphy et al., 1999, Bassett et al., 2005).

It remains to be determined, however, whether the phenotype in 22q11.2DS is distinct from that in non-22q11.2DS schizophrenia, perhaps representing a more genetically homogeneous subtype of the disorder. In studies comparing adult schizophrenic patients with and without the deletion, some studies have found no differences (Bassett et al., 2003) while others have reported that 22q11.2DS patients present with a later age of onset of psychotic illness and fewer negative symptoms (Murphy et al., 1999).

A growing body of evidence suggests that schizotypy is an endophenotype for schizophrenia (Siever et al., 1990, Kendler et al., 1993, Bergman et al., 1996, Cadenhead et al., 2000, Vollema and Hoijtink, 2000, Fanous et al., 2007, Grant et al., 2013). An excess of schizotypal traits has also been reported in people with 22q11.2DS compared to the general population (Baker and Skuse, 2005). In a previous study, we also found that adults with 22q11.2DS but without psychosis (n = 32) had higher scores than normal controls (recruited through National Blood Transfusion Services (NBTS)) (Murphy et al., 1999). However, this remains to be replicated in a larger sample.

The converging lines of evidence underpinning the association between schizophrenia and 22q11DS suggest that a susceptibility gene (or genes) for schizophrenia maps to the deleted region on chromosome 22 (Murphy, 2002). The gene coding for catechol-O-methyltransferase (COMT), an enzyme responsible for dopamine catabolism in the brain, maps to the deleted region and has long been implicated in the pathogenesis of schizophrenia. Many studies have looked at the Val/Met locus at codon 158 of COMT which confers high and low activity to COMT enzyme with the potential to alter cerebral metabolism of dopamine especially in the prefrontal cortex (Egan et al., 2001, Malhotra et al., 2002). However, three meta-analyses have found no evidence of association (Glatt et al., 2003, Fan et al., 2005, Munafo et al., 2005, Allen et al., 2008). Findings have been inconclusive with regard to COMT in relation to the cognitive and psychiatric problems in individuals with 22q11.2DS, with studies reporting associations (Gothelf et al., 2005, Schneider et al., 2012) while others do not (Murphy et al., 1999, Bassett et al., 2007). In a previous study, we did not find associations of Val/Met with schizotypy either (Murphy et al., 1999).

The inconsistency in findings could indicate that, if COMT is a susceptibility gene for psychosis, its contribution could be mediated through effects on COMT function other than the Val/Met variant alone. Shifman et al. (2002) reported a strong association between schizophrenia and a COMT haplotype in a large sample of Ashkenazi Jews (Shifman et al., 2002). However, this was not replicated in two large samples of people with schizophrenia (Williams et al., 2007).

The aims of the current study are (a) to describe the neuropsychiatric phenotype in a relatively large sample of adults with 22q11.2DS, (b) to examine whether the schizophrenia phenotype in 22q11.2DS is distinct from non-deleted schizophrenia by making comparisons with a non-deleted sample of individuals with schizophrenia, (c) to evaluate whether individuals with 22q11.2DS have high rates of schizotypy by comparing them to normal controls and (d) to test the hypothesis that three polymorphisms and a risk haplotype in COMT are associated with the presence of schizophrenia and schizotypy in 22q11.2DS.