Context  Human and animal studies have implicated the gene NOS1 in both cognition and schizophrenia susceptibility.

Objective  To investigate whether a potential schizophrenia risk single-nucleotide polymorphism (rs6490121) identified in a recent genome-wide association study negatively influences cognition in patients with schizophrenia and healthy control subjects.

Design  A comparison of both cases and controls grouped according to NOS1 genotype (GG vs AG vs AA) on selected measures of cognition in 2 independent samples. We tested for association between NOS1 rs6490121 and cognitive functions known to be impaired in schizophrenia (IQ, episodic memory, working memory, and attentional control) in an Irish sample. We then sought to replicate the significant results in a German sample.

Setting  Unrelated patients from general adult psychiatric inpatient and outpatient services and unrelated healthy volunteers from the general population were ascertained.

Participants  Patients with DSM-IV–diagnosed schizophrenia and healthy control subjects from independent samples of Irish (cases, n = 349; controls, n = 230) and German (cases, n = 232; controls, n = 1344) nationality.

Results  A main effect of NOS1 genotype on verbal IQ and working memory was observed in the Irish sample where the homozygous carriers of the schizophrenia risk G allele performed poorly compared with the other genotype groups. These findings were replicated in the German sample, again with the GG genotype carriers performing below other genotype groups. Post hoc analysis of additional IQ measures (full-scale and performance IQ) in the German sample revealed that NOS1 GG carriers underperformed on these measures also.

Conclusions  NOS1 is associated with clinically significant variation in cognition. Whether this is a mechanism by which schizophrenia risk is increased (eg, via an influence on cognitive reserve) is yet to be confirmed.

Context  Recent studies suggest that copy number variation in the human genome is extensive and may play an important role in susceptibility to disease, including neuropsychiatric disorders such as schizophrenia and autism. The possible involvement of copy number variants (CNVs) in bipolar disorder has received little attention to date.

Objectives  To determine whether large (>100 000 base pairs) and rare (found in <1% of the population) CNVs are associated with susceptibility to bipolar disorder and to compare with findings in schizophrenia.

Design  A genome-wide survey of large, rare CNVs in a case-control sample using a high-density microarray.

Setting  The Wellcome Trust Case Control Consortium.

Participants  There were 1697 cases of bipolar disorder and 2806 nonpsychiatric controls. All participants were white UK residents.

Main Outcome Measures  Overall load of CNVs and presence of rare CNVs.

Results  The burden of CNVs in bipolar disorder was not increased compared with controls and was significantly less than in schizophrenia cases. The CNVs previously implicated in the etiology of schizophrenia were not more common in cases with bipolar disorder.

Conclusions  Schizophrenia and bipolar disorder differ with respect to CNV burden in general and association with specific CNVs in particular. Our data are consistent with the possibility that possession of large, rare deletions may modify the phenotype in those at risk of psychosis: those possessing such events are more likely to be diagnosed as having schizophrenia, and those without them are more likely to be diagnosed as having bipolar disorder.

Background

Psychiatric phenotypes are currently defined according to sets of descriptive criteria. Although many of these phenotypes are heritable, it would be useful to know whether any of the various diagnostic categories in current use identify cases that are particularly helpful for biological–genetic research.

Aims

To use genome-wide genetic association data to explore the relative genetic utility of seven different descriptive operational diagnostic categories relevant to bipolar illness within a large UK case–control bipolar disorder sample.

Method

We analysed our previously published Wellcome Trust Case Control Consortium (WTCCC) bipolar disorder genome-wide association data-set, comprising 1868 individuals with bipolar disorder and 2938 controls genotyped for 276 122 single nucleotide polymorphisms (SNPs) that met stringent criteria for genotype quality. For each SNP we performed a test of association (bipolar disorder group v. control group) and used the number of associated independent SNPs statistically significant at P<0.00001 as a metric for the overall genetic signal in the sample. We next compared this metric with that obtained using each of seven diagnostic subsets of the group with bipolar disorder: Research Diagnostic Criteria (RDC): bipolar I disorder; manic disorder; bipolar II disorder; schizoaffective disorder, bipolar type; DSM–IV: bipolar I disorder; bipolar II disorder; schizoaffective disorder, bipolar type.

Results

The RDC schizoaffective disorder, bipolar type (v. controls) stood out from the other diagnostic subsets as having a significant excess of independent association signals (P<0.003) compared with that expected in samples of the same size selected randomly from the total bipolar disorder group data-set. The strongest association in this subset of participants with bipolar disorder was at rs4818065 (P = 2.42x10^–7). Biological systems implicated included gamma amniobutyric acid (GABA)_A receptors. Genes having at least one associated polymorphism at P<10^–4 included B3GALTS, A2BP1, GABRB1, AUTS2, BSN, PTPRG, GIRK2 and CDH12.

Conclusions

Our findings show that individuals with broadly defined bipolar schizoaffective features have either a particularly strong genetic contribution or that, as a group, are genetically more homogeneous than the other phenotypes tested. The results point to the importance of using diagnostic approaches that recognise this group of individuals. Our approach can be applied to similar data-sets for other psychiatric and non-psychiatric phenotypes.

Background

Attention-deficit hyperactivity disorder (ADHD) is recognised as a common, disabling condition. Little information is available regarding the long-term outcomes for individuals with ADHD in the UK.

Aims

To examine the 5-year outcome for a UK cohort of children with diagnosed, treated ADHD and identify whether maternal and social factors predict key outcomes.

Method

One hundred and twenty-six school-aged children (mean age 9.4 years, s.d. = 1.7) diagnosed with ADHD were reassessed 5 years later during adolescence (mean age 14.5 years, s.d. = 1.7) for ADHD, conduct disorder and other antisocial behaviours.

Results

Most adolescents (69.8%) continued to meet full criteria for ADHD, were known to specialist services and exhibited high levels of antisocial behaviour, criminal activity and substance use problems. Maternal childhood conduct disorder predicted offspring ADHD continuity; maternal childhood conduct disorder, lower child IQ and social class predicted offspring conduct disorder symptoms.

Conclusions

The treatment and monitoring of ADHD need to be intensified as outcomes are poor especially in offspring of mothers with childhood conduct disorder symptoms.