Christina Sobin

Genetic variation at the 22q11 PRODH2/DGCR6 locus presents an unusual pattern and increases susceptibility to schizophrenia

The location of a schizophrenia susceptibility locus at chromosome 22q11 has been suggested by genome-wide linkage studies. Additional support was provided by the observation of a higher-than-expected frequency of 22q11 microdeletions in patients with schizophrenia and the demonstration that ≈20–30% of individuals with 22q11 microdeletions develop schizophrenia or schizoaffective disorder in adolescence and adulthood. Analysis of the extent of these microdeletions by using polymorphic markers afforded further refinement of this locus to a region of ≈1.5 Mb. Recently, a high rate of 22q11 microdeletions was also reported for a cohort of 47 patients with Childhood Onset Schizophrenia, a rare and severe form of schizophrenia with onset by age 13. It is therefore likely that this 1.5-Mb region contains one or more genes that predispose to schizophrenia. In three independent samples, we provide evidence for a contribution of the PRODH2/DGCR6 locus in 22q11-associated schizophrenia. We also uncover an unusual pattern of PRODH2 gene variation that mimics the sequence of a linked pseudogene. Several of the pseudogene-like variants we identified result in missense changes at conserved residues and may prevent synthesis of a fully functional enzyme. Our results have implications for understanding the genetic basis of the 22q11-associated psychiatric phenotypes and provide further insights into the genomic instability of this region.

Family-based association studies support a sexually dimorphic effect of COMT and MAOA on genetic susceptibility to obsessive-compulsive disorder.

BACKGROUND Obsessive-compulsive disorder (OCD) is a common and severe psychiatric illness that affects 1-3% of the population and presents a well-established co-morbidity with major depressive disorder (MDD). Twin and family studies have suggested a genetic component in the etiology of OCD, although the mode of inheritance is unknown. Pharmacotherapy of the disease implicates both serotonergic and dopaminergic pathways. Previously, guided by the 22q11 microdeletion-related psychiatric phenotype, we provided evidence for a sexually dimorphic association between OCD and the gene for catechol-O-methyltransferase (COMT). In this report, we use 110 nuclear OCD families to analyze the inheritance of variants of COMT and monoamine oxidase-A (MAOA), another gene modulating monoamine metabolism. METHODS A sample of 110 nuclear OCD families was collected, and lifetime diagnoses were ascertained using the Diagnostic Interview for Genetic Studies (DIGS). DNA was genotyped for functional variants of the COMT and MAO genes, and allele inheritance was examined using the Transmission Disequilibrium Test (TDT) and Haplotype-based Haplotype Relative Risk (HHRR) test. RESULTS We provide evidence supporting the previously reported sexually dimorphic association between low COMT enzymatic activity and OCD. We also provide evidence for a similar sexually dimorphic association between OCD and an allele of the MAOA gene, previously linked to high MAO-A enzymatic activity. In agreement with the well-established action of MAO-A inhibitors as antidepressants, this association is particularly marked among male OCD probands with co-morbid MDD, who represent more than 50% of our male OCD sample. CONCLUSIONS Our analysis indicates that variants of two genes modulating monoamine metabolism contribute significantly to OCD susceptibility. Most importantly, an unexpected sexually dimorphic pattern of genetic susceptibility to OCD is revealed and suggests the possibility that profound gender differences in genetic predisposition may exist not only for other OCD susceptibility genes, but for an array of other psychiatric disorders as well.

Diagnostic interviewing for family studies: Comparing telephone and face-to-face methods for the diagnosis of lifetime psychiatric disorders

Family studies require assessment of large numbers of family members, many of whom are geographically dispersed, live in different time zones, are not available during working hours, live in neighborhoods which are unsafe, or do not wish to have attention drawn to them by the presence of an interviewer in their home. For these reasons, telephone interviews are a potentially valuable and economical method. We present a comparison of results from telephone and face-to-face interviews conducted with 435 relatives of 193 probands from a family study. No significant differences were found between telephone versus face-to-face interviewed relatives in rates of RDC or of DSM-III-R diagnoses. Nor were differences found in the length of interviews; number of family history reports completed; or number of relatives requiring consensus diagnoses due to diagnostic disagreement. We conclude that telephone and face-to-face interviews yielded comparable diagnostic information in this family study and that telephone interviewing is an acceptable and valuable alternative method for the diagnosis of lifetime psychiatric disorder in relatives.

Networks of attention in children with the 22q11 deletion syndrome

The 22q11 chromosomal deletion syndrome (22q11 DS) is associated with learning disabilities and a complex neuropsychological profile. Previous findings have suggested that executive attention deficits might underlie other neurocognitive anomalies. We administered the child Attention Network Test (ANT) to 52 children ages 5.0 to 11.5, 32 22q11 DS children (19 girls) and 20 controls (13 girls) and assessed the efficiency of segregated executive, orienting, and alerting networks. We hypothesized that 22q11 DS children have impaired executive network efficiency as compared to control siblings. The internal validity of the child ANT was confirmed for this population. Analysis of variance results showed significant main effects for flanker and cue types and no interaction effect in either 22q11 DS children or control siblings. Compared to control siblings, 22q11 DS children had significantly larger (less efficient) executive network scores, significantly increased errors on only incongruent trials, and a significant correlation between executive network scores and accuracy. The implications of these findings for future neurocognitive studies of 22q11 DS children are considered.

NEUROPSYCHOLOGICAL CHARACTERISTICS OF CHILDREN WITH THE 22Q11 DELETION SYNDROME: A DESCRIPTIVE ANALYSIS

Previous reports of cognitive functioning in children with the 22q11 Deletion Syndrome have reported marked variability in IQ and achievement subtest scores. Studies have begun to explore neuropsychological function in 22q11 DS however results are inconsistent and the profile incomplete. We assessed 40 children ages 5–12 with 22q11 DS. Consistent with past results, visual-spatial memory was significantly lower than verbal memory. Differentially lowered scores were found only in visual attention, working memory and motor function. Contrary with some past results quantitative, verbal ability, and visual spatial memory scores were within 1 SD from the standardization sample mean. Motor behavior, not typically discussed with regard to 22q11 DS school-age children, may be critical to incorporate in neurocognitive studies of children with 22q11 DS. Implications of these findings are considered with regard to past results.

Evidence of a schizotypy subtype in OCD

OCD patients represent a heterogeneous mix of clinical phenotypes, likely reflecting a wide range of genetic vulnerabilities. In other medical illnesses, neurobiologically-based traits with a genetic component that are associated with the target disorder have been successfully used to detect patients with a specific genetic liability to disease. The overlap between symptoms of OCD and Schizophrenia suggested that schizotypal traits could have the potential to distinguish a relatively homogeneous subtype of OCD. We obtained schizotypy scores for 119 affected adult probands who met lifetime criteria for DSM-IV OCD. Five subscales from the Structured Interview of Schizotypy were used to assess ideas of reference, suspiciousness, magical thinking, illusions and psychotic-like thought. Selected for their obvious face validity with the cardinal signs of schizophrenia, Cronbachs alpha suggested that these subscales also provided a reliable measure of positive sign schizotypy (0.83). Fifty percent of our OCD sample had mild to severe positive schizotypy signs. t- and chi2 tests of significance suggested seven variables that distinguished OCD patients with schizotypy, including earlier age of onset, greater number of comorbid diagnoses and increased rates of learning disability, aggressive and somatic obsessions and counting and arranging compulsions. Three of these seven variables, including learning disabilities, counting compulsions and history of specific phobia, significantly increased the odds of schizotypy among patients with lifetime OCD. These findings enhanced the validity of the schizotypy construct in OCD. Whether this schizotypy subtype can distinguish a subgroup of patients with relatively homogeneous genetic characteristics waits further investigation.

Social Skills and Executive Function Deficits in Children With the 22q11 Deletion Syndrome

The 22q11 Deletion Syndrome (22q11DS) is among the most frequent gene deletion disorders, occurring once in every 6,000 live births. Descriptive reports have suggested marked social differences in affected children. Empirical studies are needed to verify possible social skills deficits among children with 22q11DS, and also to examine possible associations between their frequently reported executive function deficits and social anomalies. Fifty-two parents of affected children (n = 52) and participating control siblings (n = 26) completed the Social Skills Rating System (SSRS) and Behavior Inventory of Executive Function (BRIEF). When compared with control siblings, children with 22q11DS had significantly lower SSRS ratings for Cooperation, Assertion, Responsibility, and Self-Control. Affected children had significantly higher BRIEF ratings for Initiation, Planning, Working Memory, and Monitoring. In affected children, global Social Skill was negatively correlated with BRIEF Global Composite scores. Initiation and Monitoring significantly predicted Social Skill. Children with 22q11DS have marked differences in social skill development which are associated with executive dysfunction.

Genome-wide scan in a large complex pedigree with predominantly male schizophrenics from the island of Kosrae: evidence for linkage to chromosome 2q

It is widely accepted that founder populations hold promise for mapping loci for complex traits. However, the outcome of these mapping efforts will most likely depend on the individual demographic characteristics and historical circumstances surrounding the founding of a given genetic isolate. The ‘ideal’ features of a founder population are currently unknown. The Micronesian islandic population of Kosrae, one of the four islands comprising the Federated States of Micronesia (FSM), was founded by a small number of settlers and went through a secondary genetic ‘bottleneck’ in the mid-19th century. The potential for reduced etiological (genetic and environmental) heterogeneity, as well as the opportunity to ascertain extended and statistically powerful pedigrees makes the Kosraen population attractive for mapping schizophrenia susceptibility genes. Our exhaustive case ascertainment from this islandic population identified 32 patients who met DSM-IV criteria for schizophrenia or schizoaffective disorder. Three of these were siblings in one nuclear family, and 27 were from a single large and complex schizophrenia kindred that includes a total of 251 individuals. One of the most startling findings in our ascertained sample was the great difference in male and female disease rates. A genome-wide scan provided initial suggestive evidence for linkage to markers on chromosomes 1, 2, 3, 7, 13, 15, 19, and X. Follow-up multipoint analyses gave additional support for a region on 2q37 that includes a schizophrenia locus previously identified in another small genetic isolate, with a well-established recent genealogical history and a small number of founders, located on the eastern border of Finland. In addition to providing further support for a schizophrenia susceptibility locus at 2q37, our results highlight the analytic challenges associated with extremely large and complex pedigrees, as well as the limitations associated with genetic studies of complex traits in small islandic populations.

Phenotypic characteristics of Obsessive-Compulsive Disorder ascertained in adulthood.

Over the past decade, the increased awareness and knowledge of Obsessive-Compulsive Disorder (OCD) has allowed the in-depth study of its phenotypic characteristics. The largest studies to date have described the symptom and syndrome characteristics of treatment-seeking patients. While usefully homogeneous with regard to their current state, the clinical characteristics of patients seeking treatment may only partially represent the OCD population. We report findings from 100 self-selected volunteers at various stages of their OCD illness who were participating in a genetic study. Many similarities with past reports were found, including high rates of mood disorder, significantly more mood disorder in females as compared with males, and increased social impairment among males despite an equal amount of time in episodes of disorder. On the other hand, mean age of onset in this nontreatment seeking population was younger. Lifetime rates of obsessions and compulsions in this population were substantially higher than previous reports, suggesting that the content of obsessions and compulsions shifted over time, and evolved into a lifetime repertoire. Furthermore, a separate analysis of the age of clinically significant O-C symptom onset without impairment revealed that males and females did not differ, suggesting that previous reports of earlier onset age in males may actually reflect earlier onset of impairment. Future genetic studies may benefit from the analysis of both significant O-C symptom onset, as well as the onset of full-syndromal OCD. These findings may suggest phenotypic characteristics that define homogeneous subgroups of patients with OCD.

Associations between prepulse inhibition and executive visual attention in children with the 22q11 deletion syndrome

The 22q11 deletion syndrome (DS) results in the loss of approximately 30 gene copies and is associated with possible physical anomalies, varied learning disabilities, and a specific cluster of neurocognitive deficits, including primary impairment in working memory, executive visual attention, and sensorimotor processing. Retrospective studies have suggested that children with 22q11DS are at 25 times greater risk of developing schizophrenia, thus specification of early brain network vulnerabilities among children with 22q11DS is critical. Previously, we reported that children with 22q11DS as compared with sibling controls had selective deficits in visual executive attention, and subsequently found lowered prepulse inhibition (PPI) in these same children. Visual executive attention and PPI recruit the same brain pathways linking prefrontal cortex to basal ganglia structures. To test the specificity of brain pathway vulnerability among children with 22q11DS, we examined visual executive attention and PPI paradigm data collected during the same test session from 21 children with 22q11DS and 25 sibling controls. We predicted lower %PPI and less efficient executive attention scores, and a significant inverse correlation between measures. %PPI in children with 22q11DS as compared with sibling controls was 20% lower, and visual executive attention efficiency scores 40% worse. As predicted, %PPI was inversely correlated only with executive attention efficiency scores. The implications of these findings with regard to brain pathway vulnerability in children with 22q11DS are considered. These results suggest that children with 22q11DS have early functional abnormality in pathways linking the prefrontal cortex and basal ganglia.