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1.  Synaptic scaffold evolution generated components of vertebrate cognitive complexity 
Nature neuroscience  2012;16(1):16-24.
The origins and evolution of higher cognitive functions including complex forms of learning, attention and executive functions are unknown. A potential mechanism driving the evolution of vertebrate cognition early in the vertebrate lineage (550 My ago) was genome duplication and subsequent diversification of postsynaptic genes. Here we report the first genetic analysis of a vertebrate gene family in cognitive functions measured using computerized touchscreens. Comparison of mice carrying mutations in all four Dlg paralogs show simple associative learning required Dlg4, while Dlg2 and Dlg3 diversified to play opposing roles in complex cognitive processes. Exploiting the translational utility of touchscreens in humans and mice, testing Dlg2 mutations in both species showed Dlg2’s role in complex learning, cognitive flexibility and attention has been highly conserved over 100 My. Dlg family mutations underlie psychiatric disorders suggesting genome evolution expanded the complexity of vertebrate cognition at the cost of susceptibility to mental illness.
doi:10.1038/nn.3276
PMCID: PMC4131247  PMID: 23201973
2.  The influence of polygenic risk for bipolar disorder on neural activation assessed using fMRI 
Translational Psychiatry  2012;2(7):e130-.
Genome-wide association studies (GWAS) have demonstrated a significant polygenic contribution to bipolar disorder (BD) where disease risk is determined by the summation of many alleles of small individual magnitude. Modelling polygenic risk scores may be a powerful way of identifying disrupted brain regions whose genetic architecture is related to that of BD. We determined the extent to which common genetic variation underlying risk to BD affected neural activation during an executive processing/language task in individuals at familial risk of BD and healthy controls. Polygenic risk scores were calculated for each individual based on GWAS data from the Psychiatric GWAS Consortium Bipolar Disorder Working Group (PGC-BD) of over 16 000 subjects. The familial group had a significantly higher polygene score than the control group (P=0.04). There were no significant group by polygene interaction effects in terms of association with brain activation. However, we did find that an increasing polygenic risk allele load for BD was associated with increased activation in limbic regions previously implicated in BD, including the anterior cingulate cortex and amygdala, across both groups. The findings suggest that this novel polygenic approach to examine brain-imaging data may be a useful means of identifying genetically mediated traits mechanistically linked to the aetiology of BD.
doi:10.1038/tp.2012.60
PMCID: PMC3410628  PMID: 22760554
amygdala; anterior cingulate; bipolar disorder; fMRI; polygenic
3.  The genetic association between personality and major depression or bipolar disorder. A polygenic score analysis using genome-wide association data 
Translational Psychiatry  2011;1(10):e50-.
The relationship between major depressive disorder (MDD) and bipolar disorder (BD) remains controversial. Previous research has reported differences and similarities in risk factors for MDD and BD, such as predisposing personality traits. For example, high neuroticism is related to both disorders, whereas openness to experience is specific for BD. This study examined the genetic association between personality and MDD and BD by applying polygenic scores for neuroticism, extraversion, openness to experience, agreeableness and conscientiousness to both disorders. Polygenic scores reflect the weighted sum of multiple single-nucleotide polymorphism alleles associated with the trait for an individual and were based on a meta-analysis of genome-wide association studies for personality traits including 13 835 subjects. Polygenic scores were tested for MDD in the combined Genetic Association Information Network (GAIN-MDD) and MDD2000+ samples (N=8921) and for BD in the combined Systematic Treatment Enhancement Program for Bipolar Disorder and Wellcome Trust Case–Control Consortium samples (N=6329) using logistic regression analyses. At the phenotypic level, personality dimensions were associated with MDD and BD. Polygenic neuroticism scores were significantly positively associated with MDD, whereas polygenic extraversion scores were significantly positively associated with BD. The explained variance of MDD and BD, ∼0.1%, was highly comparable to the variance explained by the polygenic personality scores in the corresponding personality traits themselves (between 0.1 and 0.4%). This indicates that the proportions of variance explained in mood disorders are at the upper limit of what could have been expected. This study suggests shared genetic risk factors for neuroticism and MDD on the one hand and for extraversion and BD on the other.
doi:10.1038/tp.2011.45
PMCID: PMC3309491  PMID: 22833196
bipolar disorder; genetic correlation; genome-wide association; polygenic score analysis; personality-major depression
4.  Illness behaviour in elite middle and long distance runners 
OBJECTIVES: To examine the illness attitudes and beliefs known to be associated with abnormal illness behaviour (where symptoms are present in excess of objective signs and pathology) in elite middle and long distance runners, in comparison with non-athlete controls. METHODS: A total of 150 athletes were surveyed using the illness behaviour questionnaire as an instrument to explore the psychological attributes associated with abnormal illness behaviour. Subjects also completed the general health questionnaire as a measure of psychiatric morbidity. A control group of 150 subjects, matched for age, sex, and social class, were surveyed using the same instruments. RESULTS: A multivariate analysis of illness behaviour questionnaire responses showed that the athletes' group differed significantly from the control group (Hotelling's T: Exact F = 2.68; p = 0.01). In particular, athletes were more somatically focused (difference between means -0.27; 95% confidence interval -0.50 to -0.03) and more likely to deny the impact of stresses in their life (difference between means 0.78; 95% confidence interval 0.31 to 1.25). Athletes were also higher scorers on the Whiteley Index of Hypochondriasis (difference between means 0.76; 95% confidence interval 0.04 to 1.48). There were no differences in the levels of psychiatric morbidity between the two groups. CONCLUSIONS: The illness attitudes and beliefs of athletes differ from those of a well matched control population. The origin of these psychological attributes is not clear but those who treat athletes need to be aware of them. 





PMCID: PMC1756131  PMID: 10027052
5.  Hypofrontality revisited: a high resolution single photon emission computed tomography study in schizophrenia. 
Hypofrontality or reduced activity in the prefrontal cortex, measured as reduced frontal perfusion or glucose uptake, has gained the status of an established finding in the medical literature on schizophrenia. Many relevant studies, however, have potential sources of bias, such as small subject numbers, or unreliable performance of activation tasks by the patients during the scanning procedure. Seventy patients with non-affective and non-organic psychoses were recruited--most qualifying for DSM III-R schizophrenia or schizophreniform psychosis (n = 60)--together with 20 healthy volunteers. They underwent single photon emission computed tomography with 99mTc-exametazime, carried out at rest. Tracer uptake was normalised to the occipital cortex. Group differences in tracer uptake were predicted in anterior regions of interest (prefrontal cortex and mesial frontal/cingulate cortex). Actively psychotic (including schizophrenic) patients not taking any drugs showed increased uptake in the prefrontal cortex. Reduced tracer uptake occurred in the mesial frontal cortex of schizophrenic patients, particularly if they were taking drugs. Relatively increased prefrontal tracer uptake associated with relatively decreased mesial frontal uptake characterised the patients in comparison with the controls. Generalised hypofrontality is, therefore, not a feature of schizophrenic patients at rest whether taking drugs or not.
PMCID: PMC1073432  PMID: 7738553
6.  Selective increase in plasma luteinising hormone concentrations in drug free young men with mania. 
The hypothalamic-pituitary-gonadal system was investigated in drug free young men with either mania or acute schizophrenia and in age matched controls by measuring, at frequent intervals during a 17 hour "neuroendocrine day," plasma concentrations of luteinising hormone (LH), follicle stimulating hormone, prolactin, testosterone, sex hormone binding globulin (SHBG), and cortisol. Plasma LH in mania was significantly increased compared with the control value at all time periods and increased in the morning and evening samples compared with values in the schizophrenic patients. Plasma prolactin and cortisol concentrations were significantly greater in mania and schizophrenia compared with control values at several times during the day, but there were no significant between group differences in plasma testosterone or SHBG. These results show that in young men with mania there is a major disturbance in the central mechanisms that control the release of LH, the control of prolactin and cortisol secretion is abnormal in mania and acute schizophrenia, and plasma LH concentrations may provide a useful hormonal diagnostic test for mania.
PMCID: PMC1415494  PMID: 3917741
7.  Low risk of late post-traumatic seizures following severe head injury: implications for clinical trials of prophylaxis. 
A randomised, controlled, double-blind clinical trial designed to determine the effectiveness of phenytoin in preventing epilepsy in patients who had suffered a serious head injury is reported. One hundred and sixty-four patients were randomly assigned to treatment with phenytoin or placebo capsules for one year. Patients who had a fit within one week of injury were excluded. Drug levels were monitored throughout with appropriate dosage adjustment; however only 48% of the phenytoin group had plasma levels greater than 40 mumol/l. There were seven deaths during the study. Only 11 patients (six in the phenytoin group and five in the placebo group) developed post-traumatic epilepsy within one year; a further four patients developed seizures between 1 and 2 years after injury. This low incidence of post-traumatic epilepsy (7% (SE 2%) at one year and 10 (SE 2%) at two years) means that future clinical trials of prophylaxis will have to be much larger (at least six fold).
PMCID: PMC1027602  PMID: 6417279
8.  A study of the incidence of epilepsy following ECT 
In a group of 166 patients who had received electroconvulsive therapy more than one year previously the prevalence of epilepsy did not differ significantly from that found in the community as a whole. The findings suggest that a kindling process is not a clinical hazard following repeated electrically induced seizures.
PMCID: PMC490782  PMID: 7217955
9.  Genome-wide association study of major depressive disorder: new results, meta-analysis, and lessons learned 
Molecular Psychiatry  2010;17(1):36-48.
Major depressive disorder (MDD) is a common complex disorder with a partly genetic etiology. We conducted a genome-wide association study of the MDD2000+ sample (2431 cases, 3673 screened controls and >1 M imputed single-nucleotide polymorphisms (SNPs)). No SNPs achieved genome-wide significance either in the MDD2000+ study, or in meta-analysis with two other studies totaling 5763 cases and 6901 controls. These results imply that common variants of intermediate or large effect do not have main effects in the genetic architecture of MDD. Suggestive but notable results were (a) gene-based tests suggesting roles for adenylate cyclase 3 (ADCY3, 2p23.3) and galanin (GAL, 11q13.3); published functional evidence relates both of these to MDD and serotonergic signaling; (b) support for the bipolar disorder risk variant SNP rs1006737 in CACNA1C (P=0.020, odds ratio=1.10); and (c) lack of support for rs2251219, a SNP identified in a meta-analysis of affective disorder studies (P=0.51). We estimate that sample sizes 1.8- to 2.4-fold greater are needed for association studies of MDD compared with those for schizophrenia to detect variants that explain the same proportion of total variance in liability. Larger study cohorts characterized for genetic and environmental risk factors accumulated prospectively are likely to be needed to dissect more fully the etiology of MDD.
doi:10.1038/mp.2010.109
PMCID: PMC3252611  PMID: 21042317
major depressive disorder; depression; genome-wide association study; CACNA1C; ADCY3; GAL
10.  708 Common and 2010 rare DISC1 locus variants identified in 1542 subjects: analysis for association with psychiatric disorder and cognitive traits 
Molecular Psychiatry  2013;19(6):668-675.
A balanced t(1;11) translocation that transects the Disrupted in schizophrenia 1 (DISC1) gene shows genome-wide significant linkage for schizophrenia and recurrent major depressive disorder (rMDD) in a single large Scottish family, but genome-wide and exome sequencing-based association studies have not supported a role for DISC1 in psychiatric illness. To explore DISC1 in more detail, we sequenced 528 kb of the DISC1 locus in 653 cases and 889 controls. We report 2718 validated single-nucleotide polymorphisms (SNPs) of which 2010 have a minor allele frequency of <1%. Only 38% of these variants are reported in the 1000 Genomes Project European subset. This suggests that many DISC1 SNPs remain undiscovered and are essentially private. Rare coding variants identified exclusively in patients were found in likely functional protein domains. Significant region-wide association was observed between rs16856199 and rMDD (P=0.026, unadjusted P=6.3 × 10−5, OR=3.48). This was not replicated in additional recurrent major depression samples (replication P=0.11). Combined analysis of both the original and replication set supported the original association (P=0.0058, OR=1.46). Evidence for segregation of this variant with disease in families was limited to those of rMDD individuals referred from primary care. Burden analysis for coding and non-coding variants gave nominal associations with diagnosis and measures of mood and cognition. Together, these observations are likely to generalise to other candidate genes for major mental illness and may thus provide guidelines for the design of future studies.
doi:10.1038/mp.2013.68
PMCID: PMC4031635  PMID: 23732877
DISC1; recurrent major depressive disorder; sequencing

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