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Annals of neurology 90(3), 464-476 (2021). doi:10.1002/ana.26174, Published by Wiley-Blackwell, Hoboken, NJ

Genome‐wide association studies (GWASs) are highly effective at identifying common risk variants for schizophrenia. Rare risk variants are also important contributors to schizophrenia etiology but, with the exception of large copy number variants, are difficult to detect with GWAS. Exome and genome sequencing, which have accelerated the study of rare variants, are expensive so alternative methods are needed to aid detection of rare variants. Here we re‐analyze an Irish schizophrenia GWAS dataset (n = 3,473) by performing identity‐by‐descent (IBD) mapping followed by exome sequencing of individuals identified as sharing risk haplotypes to search for rare risk variants in coding regions. We identified 45 rare haplotypes (>1 cM) that were significantly more common in cases than controls. By exome sequencing 105 haplotype carriers, we investigated these haplotypes for functional coding variants that could be tested for association in independent GWAS samples. We identified one rare missense variant in PCNT but did not find statistical support for an association with schizophrenia in a replication analysis. However, IBD mapping can prioritize both individual samples and genomic regions for follow‐up analysis but genome rather than exome sequencing may be more effective at detecting risk variants on rare haplotypes. National Institutes of Health, Grant/Award Numbers: R01‐MH041953, R01‐MH083094; Science Foundation Ireland, Grant/Award Numbers: 08/IN.1/B1916, 12/IP/1359, 12/IP/1670; Wellcome Trust, Grant/Award Number: 085475/B/08/Z peer-reviewed

The “dysconnection hypothesis” of psychosis suggests that a disruption of functional integration underlies cognitive deficits and clinical symptoms. Impairments in the P300 potential are well documented in psychosis. Intrinsic (self-)connectivity in a frontoparietal cortical hierarchy during a P300 experiment was investigated. Dynamic Causal Modeling was used to estimate how evoked activity results from the dynamics of coupled neural populations and how neural coupling changes with the experimental factors. Twenty-four patients with psychotic disorder, twenty-four unaffected relatives, and twenty-five controls underwent EEG recordings during an auditory oddball paradigm. Sixteen frontoparietal network models (including primary auditory, superior parietal, and superior frontal sources) were analyzed and an optimal model of neural coupling, explaining diagnosis and genetic risk effects, as well as their interactions with task condition were identified. The winning model included changes in connectivity at all three hierarchical levels. Patients showed decreased self-inhibition—that is, increased cortical excitability—in left superior frontal gyrus across task conditions, compared with unaffected participants. Relatives had similar increases in excitability in left superior frontal and right superior parietal sources, and a reversal of the normal synaptic gain changes in response to targets relative to standard tones. It was confirmed that both subjects with psychotic disorder and their relatives show a context-independent loss of synaptic gain control at the highest hierarchy levels. The relatives also showed abnormal gain modulation responses to task-relevant stimuli. These may be caused by NMDA-receptor and/or GABAergic pathologies that change the excitability of superficial pyramidal cells and may be a potential biological marker for psychosis.

Genome-wide studies have identified allele A (adenine) of single nucleotide polymorphism (SNP) rs1006737 of the calcium-channel CACNA1C gene as a risk factor for both schizophrenia (SZ) and bipolar disorder (BD) as well as allele A for rs1344706 in the ZNF804A gene. These illnesses have also been associated with white matter abnormalities, reflected by reductions in fractional anisotropy (FA), measured using diffusion tensor imaging (DTI). We assessed the impact of the CACNA1C psychosis risk variant on FA in SZ, BD and health. 230 individuals (with existing ZNF804A rs1344706 genotype data) were genotyped for CACNA1C rs1006737 and underwent DTI. FA data was analysed with tract-based spatial statistics and threshold-free cluster enhancement significance correction (P

The oligodendrocyte lineage transcription factor 2 (OLIG2) regulates the genesis of oligodendrocytes, the brain cells responsible for axonal myelination. Although it has been associated with psychiatric and neurological disorders, the impact of this gene on white matter integrity has never been investigated in humans. Using diffusion tensor imaging, we examined the effect of a single nucleotide polymorphism (rs1059004) in OLIG2 previously associated with reduced gene expression, and with psychiatric disorders on fractional anisotropy in 78 healthy subjects. We found that the risk allele (A) was associated with reduced white matter integrity in the corona radiata bilaterally. This is consistent with evidence that it is a schizophrenia susceptibility gene, and suggests that it may confer increased risk through an effect on neuroanatomical connectivity.

The genes for the dopamine transporter (DAT) and the D-Amino acid oxidase activator (DAOA or G72) have been independently implicated in the risk for schizophrenia and in bipolar disorder and/or their related intermediate phenotypes. DAT and G72 respectively modulate central dopamine and glutamate transmission, the two systems most robustly implicated in these disorders. Contemporary studies have demonstrated that elevated dopamine function is associated with glutamatergic dysfunction in psychotic disorders. Using functional magnetic resonance imaging we examined whether there was an interaction between the effects of genes that influence dopamine and glutamate transmission (DAT and G72) on regional brain activation during verbal fluency, which is known to be abnormal in psychosis, in 80 healthy volunteers. Significant interactions between the effects of G72 and DAT polymorphisms on activation were evident in the striatum, parahippocampal gyrus, and supramarginal/angular gyri bilaterally, the right insula, in the right pre-/postcentral and the left posterior cingulate/retrosplenial gyri (P < 0.05, FDR-corrected across the whole brain). This provides evidence that interactions between the dopamine and the glutamate system, thought to be altered in psychosis, have an impact in executive processing which can be modulated by common genetic variation.

Hall M-H, Spencer KM, Schulze K, McDonald C, Kalidindi S, Kravariti E, Kane F, Murray RM, Bramon E, Sham P, Rijsdijk F. The genetic and environmental influences of event-related gamma oscillations on bipolar disorder. Bipolar Disord 2011: 13: 260–271. © 2011 The Authors. Journal compilation © 2011 John Wiley & Sons A/S. Objectives: Gamma oscillations have been proposed to play an important role in neural information coding. There have been a limited number of electrophysiology studies in evoked gamma band responses (GBRs) in bipolar disorder (BPD). It is also unclear whether GBR deficits, if present, are potential endophenotypes for BPD as little is known about the heritability of GBRs. The present study aimed to examine whether GBRs derived from two auditory tasks, the oddball task and the dual-click paradigm, are potential BPD endophenotypes. Methods: A total of 308 subjects were included in this study: 198 healthy controls, 59 BPD patients (22 monozygotic BPD twins and 37 BPD patients from 31 families), and 51 unaffected relatives. The evoked gamma responses were calculated using a Morlet wavelet transformation. Structural equation modelling was applied to obtain the genetic (heritability) and environment estimates in each GBR variable and their (genetic) overlap with BPD. Results: The heritability estimates of GBR to standard stimuli were 0.51 and 0.35 to target stimuli in the oddball task. However, neither response type was impaired in BPD patients or their unaffected relatives. The heritability estimates of GBR to S1 stimuli were 0.54 and 0.50 to S2 stimuli in the dual-click paradigm. BPD patients had reduced gamma power and suppression to S1 stimuli but their unaffected relatives did not. Conclusions: Evoked GBRs are heritable traits. However, GBR deficits are not observed in clinically unaffected relatives nor associated with BPD. Gamma responses do not appear to satisfy criteria for being BPD endophenotypes.

Schulze KK, Walshe M, Stahl D, Hall MH, Kravariti E, Morris R, Marshall N, McDonald C, Murray RM, Bramon E. Executive functioning in familial bipolar I disorder patients and their unaffected relatives. Bipolar Disord 2011: 13: 208–216. © 2011 The Authors. Journal compilation © 2011 John Wiley & Sons A/S. Objective: To compare the executive function of patients with familial bipolar I disorder (BP-I) with a history of psychotic symptoms to their first-degree relatives and normal controls. Methods: Three domains of executive function: response inhibition, working memory, and cognitive set shifting were assessed in 44 familial patients with a lifetime diagnosis of BP-I who had experienced psychotic symptoms, 42 of their unaffected first-degree relatives, and 47 controls. Results: Bipolar disorder patients and their unaffected relatives had significantly worse scores for response inhibition compared to healthy controls. The groups did not differ in working memory or cognitive set shifting. Conclusions: Impairments in response inhibition are associated with both psychotic bipolar disorder and genetic liability for this illness. Our results indicate that deficits in this specific domain of executive functioning are a promising candidate endophenotype for psychotic bipolar disorder.

Objective: People with 'prodromal' symptoms have a very high risk of developing psychosis. We examined the neurocognitive basis of this vulnerability by using functional MRI to study subjects with an at-risk mental state (ARMS) while they performed a random movement generation task. Method: Cross-sectional comparison of individuals with an ARMS (n = 17), patients with first episode schizophreniform psychosis (n = 10) and healthy volunteers (n = 15). Subjects were studied using functional MRI while they performed a random movement generation paradigm. Results: During random movement generation, the ARMS group showed less activation in the left inferior parietal cortex than controls, but greater activation than in the first episode group. Conclusion: The ARMS is associated with abnormalities of regional brain function that are qualitatively similar to those in patients who have recently presented with psychosis but less severe.

Background: Superior temporal lobe dysfunction is a robust finding in functional neuroimaging studies of schizophrenia and is thought to be related to a disruption of fronto-temporal functional connectivity. However, the stage of the disorder at which these functional alterations Occur is unclear. We addressed this issue by using functional MRI (fMRI) to Study Subjects in the prodromal and first episode phases of schizophrenia. Methods: Subjects with an at risk mental state (ARMS) for psychosis, a first psychotic episode (FEP), and controls were studied using fMRI while performing a working memory task. Activation in the Superior temporal gyrus (STG) was assessed using statistical parametric mapping, and its relationship to frontal activation was examined using dynamic causal modeling. Results: The STG was differentially engaged across the three groups. There was deactivation of this region during the task in controls, whereas Subjects with FEP showed activation and the response in subjects with ARMS was intermediately relative to the two other groups. There were corresponding differences in the effective connectivity between the STG and the middle frontal gyrus across the three groups, with a negative coupling between these areas in controls, a positive coupling in the FEP group, and an intermediate value in the ARMS group. Conclusions: A failure to deactivate the superior temporal lobe during tasks that engage prefrontal cortex is evident at the onset of schizophrenia and may reflect a disruption of fronto-temporal connectivity. Qualitatively similar alterations are evident in people with prodromal symptoms of the disorder. Hum Brain Mapp 30:4129-4137, 2009. (C) 2009 Wiley-Liss, Inc.

Objective: The aim of this study was to compare the memory function of patients with familial bipolar I disorder (BD I) who had shown psychotic features, their non-psychotic, non-bipolar first-degree relatives, and normal controls. Method: We assessed 38 patients with a lifetime diagnosis of BD I who had experienced psychotic symptoms, 49 of their non-psychotic, non-bipolar first-degree relatives, and 44 controls. Patients and relatives were from families multiply affected with functional psychotic illness. A five-subtest short form of the Wechsler Adult Intelligence Scale–Revised and three Wechsler Memory Scale subtests were administered to all participants. Results: BD I patients showed deficits in verbal memory and verbal learning but not in visual memory. Compared to controls, relatives showed worse verbal learning at a statistically significant or suggestive level and performed significantly worse in both immediate and delayed verbal memory. Similar to patients, there were no differences between the relatives and control group for visual memory. Conclusion: Impaired verbal memory and learning were found in patients and their relatives. These deficits may represent candidate endophenotypic markers for bipolar disorder.

Objectives: There is evidence that genetic susceptibility may be shared between bipolar disorder (BD) and schizophrenia, but electrophysiological phenotypes which have been extensively used in studies of genetic susceptibility for schizophrenia remain far less explored in bipolar illness. This study assesses whether auditory P300 latency delays and amplitude reductions, which have been demonstrated in patients with schizophrenia and their unaffected first-degree relatives, are associated with familial liability to psychotic bipolar illness. Methods: The P300 auditory evoked potential was obtained using an oddball task from 37 participants with BD who had a history of psychotic symptoms, 38 of their unaffected first-degree relatives and 42 healthy unrelated comparison subjects. Patients and relatives came from families multiply affected with BD or another functional psychotic disorder. P300 amplitude and latency at midline sites were compared between the groups, using linear regression analyses and robust variance estimators for clustered data, including age and gender as covariates. Results: Bipolar disorder patients with a history of psychosis and their unaffected relatives showed significantly delayed P300 latency at Pz compared to controls. The groups did not differ in P300 amplitude. Conclusions: P300 latency delays are associated with both psychotic BD and familial liability for this illness. Sample size limited our ability to test for multimodal distribution of P300 measures among relatives, which might be expected if only a subgroup inherits any deficits. In future it will be of interest to directly compare groups of families with psychotic and non-psychotic forms of BD to explore further the role of psychotic symptoms with regard to P300 measures in the disorder. Our results indicate that delayed P300 latency is a promising candidate endophenotype for psychotic BD, as well as schizophrenia, and may reflect the impact of shared susceptibility genes for both types of psychosis.

BACKGROUND: Disgust is a basic emotion that has been relatively neglected in psychiatry in general and in eating disorders in particular. Nevertheless, there are features of disgust and its more complex derivatives (e.g., shame) which suggest that disgust may have a role to play in eating disorders. METHOD: Seventy-four patients with a DSM-IV diagnosis of anorexia nervosa, bulimia nervosa, eating disorder not otherwise specified, and obese binge eater were compared with 15 control subjects on their levels of disgust sensitivity. RESULTS: Overall, eating disorder patients did not appear to be more sensitive to disgust-eliciting stimuli than comparison subjects, although there was a tendency for patients to be more disgusted by body products. However, drive for thinness and bulimia scores were related to higher levels of disgust sensitivity to food, death, and magical contagion. General psychopathology did not appear to be related to levels of disgust sensitivity. DISCUSSION: Although patients are not more sensitive than controls to the disgust-eliciting stimuli measured, disgust still has a positive relationship to eating disorder symptoms. Future studies will need to examine more precisely what this relationship might be.

It is controversial whether males and females with eating disorders differ in a relevant way. We present a comparison of 30 male and 30 female patients assessed at The Maudsley Hospital in 2.5 years. Of the male group 33 per cent were anorexic, 50 per cent were bulimic, and 17 per cent met criteria for an eating disorder not otherwise specified. The female sample was matched to the males by diagnosis. Male and female patients are essentially similar, in particular there are no differences in severity of eating disorder. However, homosexuality appears to be more frequent among males. Moreover, males with an eating disorder show a stronger psychiatric co-morbidity and a higher rate of suicide attempts. Copyright (C) 2000 John Wiley and Sons, Ltd and Eating Disorders Association.