Conrad O Iyegbe

King's College London | KCL · Department of Psychosis Studies

The rising prevalence and legalisation of cannabis worldwide have underscored the need for a comprehensive understanding of its biological impact, particularly on mental health. Epigenetic mechanisms, specifically DNA methylation, have gained increasing recognition as vital factors in the interplay between risk factors and mental health. This study...

Background: Up to 80% of psychosis patients experience cognitive impairment. High heritability of both psychosis and cognition means cognitive performance could be an endophenotype for psychosis. Methods: Using samples of adults (N=4,506) and children (N=10,981), we investigated the effect of polygenic scores (PGSs) for schizophrenia and bipolar di...

While 1–2% of individuals meet the criteria for a clinical diagnosis of obsessive-compulsive disorder (OCD), many more (~13–38%) experience subclinical obsessive-compulsive symptoms (OCS) during their life. To characterize the genetic underpinnings of OCS and its genetic relationship to OCD, we conducted the largest genome-wide association study (G...

Psychotic disorders, such as schizophrenia, can be devastating and long-lasting and are associated with significant individual, familial, and societal costs. Schizophrenia is one of the top ten leading causes of disability worldwide. The overwhelming majority of research on psychotic disorders is conducted in countries in North America, Europe, and...

The rising prevalence and legalization of cannabis worldwide have underscored the need for a comprehensive understanding of its biological impact, particularly on mental health. Epigenetic mechanisms, specifically DNA methylation, have gained increasing recognition as vital factors in the interplay between risk factors and mental health. This study...

Background and hypothesis: Endophenotypes can help to bridge the gap between psychosis and its genetic predispositions, but their underlying mechanisms remain largely unknown. This study aims to identify biological mechanisms that are relevant to the endophenotypes for psychosis, by partitioning polygenic risk scores into specific gene sets and te...

Background Psychosis rates are higher among some migrant groups. We hypothesized that psychosis in migrants is associated with cumulative social disadvantage during different phases of migration. Methods We used data from the EUropean Network of National Schizophrenia Networks studying Gene-Environment Interactions (EU-GEI) case-control study. We...

The GAP multidisciplinary study carried out in South London, recruited 410 first episode of psychosis patients and 370 controls; the aim was to elucidate the multiple genetic and environmental factors influencing the onset and outcome of psychosis. The study demonstrated the risk increasing effect of adversity in childhood (especially parental loss...

Background A range of endophenotypes characterise psychosis, however there has been limited work understanding if and how they are inter-related. Methods This multi-centre study includes 8754 participants: 2212 people with a psychotic disorder, 1487 unaffected relatives of probands, and 5055 healthy controls. We investigated cognition [digit span...

Epidemiological studies suggest that obstetric complications, particularly those related to hypoxia during labor and delivery, are a risk factor for development of schizophrenia. The impact of perinatal asphyxia on postnatal life has been studied in a rodent model of global hypoxia, which is accompanied by cesarean section birth. This asphyxia mode...

This large multi-center study investigates the relationships between genetic risk for schizophrenia and bipolar disorder, and multi-modal endophenotypes for psychosis. The sample included 4,242 individuals; 1,087 patients with psychosis, 822 unaffected first-degree relatives of patients, and 2,333 controls. Endophenotypes included the P300 event-re...

By performing a meta-analysis of rare coding variants in whole-exome sequences from 4,133 schizophrenia cases and 9,274 controls, de novo mutations in 1,077 family trios, and copy number variants from 6,882 cases and 11,255 controls, we show that individuals with schizophrenia carry a significant burden of rare, damaging variants in 3,488 genes pre...

Circulating autoantibodies against glutamatergic N-methyl-D-aspartate receptor (NMDAR-Ab) have been reported in a proportion of patients with psychotic disorders, raising hopes for more appropriate treatment for these antibody-positive patients. However, the prevalence of circulating NMDAR-Ab in psychotic disorders remains controversial with detect...

By performing a meta-analysis of rare coding variants in whole-exome sequences from 4,133 schizophrenia cases and 9,274 controls, de novo mutations in 1,077 family trios, and copy number variants from 6,882 cases and 11,255 controls, we show that individuals with schizophrenia carry a significant burden of rare, damaging variants in 3,488 genes pre...

Background: Neuronal surface autoantibodies (NSAbs) have been identified in patients with psychotic disorders, with meta-analytical evidence indicating a higher prevalence in first-episode psychosis (FEP), probably dependent on the assay used. The causal significance of these NSAbs is unclear, with a suggestion that that blood–brain barrier disrupt...

Background: A history of childhood adversity is associated with psychotic disorder, with an increase in risk according to number or severity of exposures. However, it is not known why only some exposed individuals go on to develop psychosis. One possibility is preexisting genetic vulnerability. Research on gene–environment interaction in psychosis...

A history of childhood adversity is associated with psychotic disorder, with an increase in risk according to number or severity of exposures. However, it is not known why only some exposed individuals go on to develop psychosis. One possibility is pre-existing genetic vulnerability. Research on gene-environment interaction in psychosis has primari...

Background: Polygenic risk scores (PRSs) have successfully summarized genome-wide effects of genetic variants in schizophrenia with significant predictive power. In a clinical sample of first-episode psychosis (FEP) patients, we estimated the ability of PRSs to discriminate case-control status and to predict the development of schizophrenia as opp...

Background Suboptimal vitamin D levels have been identified in populations with psychotic disorders. We sought to explore the relationship between vitamin D deficiency, clinical characteristics and cardiovascular disease risk factors among people with established psychosis. Methods Vitamin D levels were measured in 324 community dwelling individu...

By analyzing the whole-exome sequences of 4,264 schizophrenia cases, 9,343 controls and 1,077 trios, we identified a genome-wide significant association between rare loss-of-function (LoF) variants in SETD1A and risk for schizophrenia (P = 3.3 × 10(-9)). We found only two heterozygous LoF variants in 45,376 exomes from individuals without a neurops...

Background: Many studies have reported that cannabis use increases the risk of a first episode of psychosis (FEP). However, only a few studies have investigated the nature of cannabis-related experiences in FEP patients, and none has examined whether these experiences are similar in FEP and general populations. The aim of this study was to explore...

We sought to test the hypothesis that the rs1344706 A allele will be associated with worse clinical outcome in first-episode psychosis. A data linkage was set up between a large systematic study of first-episode psychosis and an electronic health-record case register at the South London and Maudsley NHS Foundation Trust—a large provider of secondar...

[This corrects the article DOI: 10.1038/npjschz.2015.25.].

Background: This work addresses the existing and emerging evidence of overlap within the environmental and genetic profiles of multiple sclerosis (MS) and schizophrenia. Aims: To investigate whether a genetic risk factor for MS (rs703842), whose variation is indicative of vitamin D status in the disorder, could also be a determinant of vitamin D...

Genetic factors may explain the differences in individual sensitivity to the psychosis-inducing effects of cannabis.1,2 In view of the converging data from candidate gene and genome-wide association studies that the D2-AKT1 signaling pathway is relevant for the pathophysiology and outcome of schizophrenia,3 and on the basis of previous association...

Background The association between childhood adversity and psychosis in adulthood is well established. However, genetic factors might confound or moderate this association. Aims Using a catchment-based case–control sample, we explored the main effects of, and interplay between, childhood adversity and family psychiatric history on the onset of psy...

Both cannabis use and the dopamine receptor (DRD2) gene have been associated with schizophrenia, psychosis-like experiences, and cognition. However, there are no published data investigating whether genetically determined variation in DRD2 dopaminergic signaling might play a role in individual susceptibility to cannabis-associated psychosis. We gen...

Background: The risk of individuals having adverse effects from drug use (eg, alcohol) generally depends on the frequency of use and potency of the drug used. We aimed to investigate how frequent use of skunk-like (high-potency) cannabis in south London affected the association between cannabis and psychotic disorders. Methods: We applied adjust...

Background The risk of individuals having adverse effects from drug use (eg, alcohol) generally depends on the frequency of use and potency of the drug used. We aimed to investigate how frequent use of skunk-like (high-potency) cannabis in south London affected the association between cannabis and psychotic disorders. Methods We applied adjusted lo...

Background: Failure to account for the etiological diversity that typically occurs in psychiatric cohorts may increase the potential for confounding as a proportion of genetic variance will be specific to exposures that have varying distributions in cases. This study investigated whether minimizing the potential for such confounding strengthened th...

Background: What determines inter-individual variability to impairments in behavioural control that may underlie road-traffic accidents, and impulsive and violent behaviours occurring under the influence of cannabis, the most widely used illicit drug worldwide? Method: Employing a double-blind, repeated-measures design, we investigated the genet...

Background: Genome-wide association studies (GWAS) have identified several loci associated with schizophrenia and/or bipolar disorder. We performed a GWAS of psychosis as a broad syndrome rather than within specific diagnostic categories. Methods: 1239 cases with schizophrenia, schizoaffective disorder, or psychotic bipolar disorder; 857 of thei...

Background Epidemiological studies implicate cannabis use as a risk factor for psychosis. Daily users of high potency types of cannabis have the highest risk of developing psychotic disorders. Nevertheless, only a small proportion of users develop the illness, suggesting an underlying genetic susceptibility to the psychogenic effect. This study set...

Schizophrenia is a devastating mental disorder. The level of risk in the general population is sustained by the persistence of social, environmental and biological factors, as well as their interactions. Socio-environmental risk factors for schizophrenia are well established and robust. The same can belatedly be said of genetic risk factors for the...

Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-analysis with previous schizophrenia GWAS (8,832 cases and 12,0...

The relatively high heritability of schizophrenia suggests that genetic factors play an important role in the etiology of the disorder. On the other hand, a number of environmental factors significantly influence its incidence. As few direct genetic effects have been demonstrated, and there is considerable inter-individual heterogeneity in the resp...

Cannabis use is associated with an increased risk of psychosis. One study has suggested that genetic variation in the AKT1 gene might influence this effect. In a case-control study of 489 first-episode psychosis patients and 278 control subjects, we investigated the interaction between variation at the AKT1 rs2494732 single nucleotide polymorphism...

Genetic association studies investigating the association between genes of serotonergic and dopaminergic systems and behavioral and psychological symptoms in dementia (BPSD) are contradictory. We have utilized 1008 probable Alzheimer's disease (AD) patients from the UK and used the 12-item Neuropsychiatric Inventory. We applied a multiple indicator...

Reliability of BXD incubation data per trait. Summary of ‘Split-Half’ reliability estimates. BXD averages are calculated by strain across experiments. Experimental averages are calculated by condition across strains. *These reliability estimates are constrained by low phenotypic variance within the group. (0.07 MB DOC)

Summary of effect sizes derived from Random-Effects meta-analysis procedure. Weighted mean r's for combined BXD and F2s data, r± s.e.m (see methods). Conversion of Zr to r is performed using a standard conversion table. Standard error is calculated as √(1/∑w). *Suggestive (P<8×10−4), **Significant (P<2.6×10-5). (0.03 MB DOC)

Derived meta-analysis effect sizes summarised by agent/route. Weighted mean r (± s.e.m) for combined BXD and F2s data which is subsequently combined by route and by agent (see methods). *Suggestive (P<8×10−4), **Significant (P<2.6×10−5). (0.04 MB DOC)

Transmissible Spongiform Encephalopathies (TSEs) are a group of progressive fatal neurodegenerative disorders, triggered by abnormal folding of the endogenous prion protein molecule. The encoding gene is a major biological factor influencing the length of the asymptomatic period after infection. It remains unclear the extent to which the variation...

POLYMORPHISMS IN DISC1 PREDICT THE SEVERITY OF POSITIVE SYMPTOMS IN A MULTIETHNIC FIRST EPISODE COHORT

CANNABIS MODERATES THE EFFECT OF THE CANNABINOID RECEPTOR1 GENE IN A FIRST EPISODE PSYCHOSIS COHORT: THE GAP STUDY (GENETIC AND PSYCHOSIS)

Four strains of mice were inoculated intracerebrally with a primary isolate of bovine spongiform encephalopathy (BSE) and the cloned mouse-adapted scrapie strain ME7. Clinical prion disease diagnosis was made at the appearance of three or more neurological symptoms and their persistence for 3 consecutive weeks and confirmed by neuropathological cri...