Cognition, psychopathology and the role of genetic variation in Catechol-O-Methyltransferase in children at increased risk of schizophrenia

In this thesis I explored cognition, psychopathology and the role of Catechol-O-Methyltransferase (COMT) in children at increased risk of schizophrenia with the aim of making a contribution to our understanding of the processes that take place early in the development of psychosis. Two samples were studied. The first sample came from the population-based Avon Longitudinal Study of Parents and Children (ALSPAC) where I examined the relationships between a priori selected cognitive domains and psychotic experiences (PEs). The results indicated that impaired processing speed and attention were related to greater risk of PEs in children, with processing speed being a key cognitive feature. Moreover, the relationships between cognition and later occurrence of PEs were similar to those that have previously been reported between cognition and schizophrenia. I also examined whether genetic variation in COMT was associated with PEs indirectly through cognition and anxiety disorders. The findings showed that COMT was indirectly associated with PEs through processing speed, IQ and attention. The second sample comprised children with 22q11.2 Deletion Syndrome (22q11.2DS). I examined the nature and prevalence of psychopathology and cognitive dysfunction in the sample and their siblings and to what extent the children’s intellectual impairment indirectly influences the risk of psychopathology associated with the deletion. There were high rates of psychopathology and cognitive impairments in children with 22q11.2DS. However, I found no evidence for an indirect association between the deletion and the risk of psychopathology through cognition. Finally, there was no evidence that COMT is related to the susceptibility of children with 22q11.2DS to cognitive and psychiatric problems. These findings have potentially important implications for our understanding of the development of psychosis during childhood and they also show that using different research designs to investigate specific aims in samples at increased risk enables the researcher to widen their scope of interpretation

Psychopathology and cognition in children with 22q11.2 deletion syndrome

BACKGROUND: Children with 22q11.2 deletion syndrome (22q11.2DS) have been reported to have high rates of cognitive and psychiatric problems. AIMS: To establish the nature and prevalence of psychiatric disorder and neurocognitive impairment in children with 22q11.2DS and test whether risk of psychopathology is mediated by the children's intellectual impairment. METHOD: Neurocognition and psychopathology were assessed in 80 children with 22q11.2DS (mean age 10.2 years, s.d. = 2.1) and 39 sibling controls (mean age 10.9 years, s.d. = 2.0). RESULTS: More than half (54 of children with 22q11.2DS met diagnostic criteria for one or more DSM-IV-TR psychiatric disorder. These children had lower IQ (mean 76.8, s.d. = 13.0) than controls (mean 108.6, s.d. = 15.2) (

Childhood cognitive development in 22q11.2 deletion syndrome: case–control study

Background 22q11.2 deletion syndrome (22q11.2DS) is associated with a high risk of childhood as well as adult psychiatric disorders, in particular schizophrenia. Childhood cognitive deterioration in 22q11.2DS has previously been reported, but only in studies lacking a control sample. Aims To compare cognitive trajectories in children with 22q11.2DS and unaffected control siblings. Method A longitudinal study of neurocognitive functioning (IQ, executive function, processing speed and attention) was conducted in children with 22q11.2DS (n = 75, mean age time 1 (T1) 9.9, time 2 (T2) 12.5) and control siblings (n = 33, mean age T1 10.6, T2 13.4). Results Children with 22q11.2DS exhibited deficits in all cognitive domains. However, mean scores did not indicate deterioration. When individual trajectories were examined, some participants showed significant decline over time, but the prevalence was similar for 22q11.2DS and control siblings. Findings are more likely to reflect normal developmental fluctuation than a 22q11.2DS-specific abnormality. Conclusions Childhood cognitive deterioration is not associated with 22q11.2DS. Contrary to previous suggestions, we believe it is premature to recommend repeated monitoring of cognitive function to identifying individual children with 22q11.2DS at high risk of developing schizophrenia

The clinical presentation of attention deficit-hyperactivity disorder (ADHD) in children with 22q11.2 deletion syndrome

BACKGROUND: Although attention deficit-hyperactivity disorder (ADHD) is the most prevalent psychiatric disorder in children with 22q11.2DS, it remains unclear whether its clinical presentation is similar to that in children with idiopathic ADHD. The aim of this study is to compare the ADHD phenotype in children with and without 22q11.2DS by examining ADHD symptom scores, patterns of psychiatric comorbidity, IQ and gender distribution. METHODS: Forty-four children with 22q11.2DS and ADHD (mean age = 9.6), 600 clinic children (mean age = 10.8) and 77 children with ADHD from a population cohort (mean age = 10.8) participated in the study. Psychopathology was assessed using parent-report research diagnostic instruments. RESULTS: There was a higher proportion of females in the 22q11.2DS ADHD sample in relation to the clinical sample (χ2 = 18.2, P < 0.001). The 22q11.2DS group showed a higher rate of ADHD inattentive subtype (χ2 = 114.76, P < 0.001), and fewer hyperactive-impulsive symptoms compared to the clinical group (z = 8.43, P < 0.001). The 22q11.2DS ADHD group parents reported fewer oppositional defiant disorder/conduct disorder symptoms (z = 6.33, P < 0.001) and a higher rate of generalized anxiety disorder (χ2 = 4.56, P = 0.03) in relation to the clinical group. Two percent of the 22q11.2 DS ADHD sample had received ADHD treatment. The results were similar when the 22q11.2 ADHD group was compared to the population cohort ADHD group. CONCLUSIONS: The clinical presentation of ADHD and patterns of co-morbidity in 22q11.2DS is different from that in idiopathic ADHD. This could lead to clinical under-recognition of ADHD in this group. Examining psychopathology in 22q11.2DS can provide insights into the genetic origins of psychiatric problems with implications beyond the 22q11.2DS population. © 2015 Wiley Periodicals, Inc

A neurogenetic model for the study of schizophrenia spectrum disorders: The International 22q11.2 Deletion Syndrome Brain Behavior Consortium

Rare copy number variants contribute significantly to the risk for schizophrenia, with the 22q11.2 locus consistently implicated. Individuals with the 22q11.2 deletion syndrome (22q11DS) have an estimated 25-fold increased risk for schizophrenia spectrum disorders, compared to individuals in the general population. The International 22q11DS Brain Behavior Consortium is examining this highly informative neurogenetic syndrome phenotypically and genomically. Here we detail the procedures of the effort to characterize the neuropsychiatric and neurobehavioral phenotypes associated with 22q11DS, focusing on schizophrenia and subthreshold expression of psychosis. The genomic approach includes a combination of whole genome sequencing and genome-wide microarray technologies, allowing the investigation of all possible DNA variation and gene pathways influencing the schizophrenia-relevant phenotypic expression. A phenotypically rich data set provides a psychiatrically well-characterized sample of unprecedented size (n=1,616) that informs the neurobehavioral developmental course of 22q11DS. This combined set of phenotypic and genomic data will enable hypothesis testing to elucidate the mechanisms underlying the pathogenesis of schizophrenia spectrum disorders

Psychopathology in mothers of children with pathogenic copy number variants

Background: Caring for children with pathogenic neurodevelopmental Copy Number Variants (CNVs) (i.e., deletions and duplications of genetic material) can place a considerable burden on parents, and their quality of life. Our study is the first to examine the frequency of psychiatric diagnoses in mothers of children with CNVs compared to the frequency of psychiatric problems in age-matched mothers from a large community study. Methods: Case-control study. 268 mothers of children with a CNV diagnosed in a medical genetics clinic and 2,680 age-matched mothers taking part in the ALSPAC study. Results: Mothers of children with CNVs reported higher frequency of depression, anorexia, bulimia, alcohol abuse and drug addiction problems compared to the age-matched mothers from the community sample. Focusing on psychiatric problems arising immediately after the birth of the index child, the levels of depression symptoms were similar between the two groups (48% in mothers of children with CNVs vs. 44% in mothers of the community sample, p=0.43), but mothers of children with CNVs had higher frequency of anxiety symptoms (55%) compared to mothers from the community sample (30%, p=0.03). Conclusion: Our study highlights the need for health-care providers to devise treatment plans that not only focus on meeting the child’s needs, but also assessing and if needed, addressing the mental health needs of the parent