Adolescent Verbal Memory as a Psychosis Endophenotype: A Genome-Wide Association Study in an Ancestrally Diverse Sample

Verbal memory impairment is one of the most prominent cognitive deficits in psychosis. However, few studies have investigated the genetic basis of verbal memory in a neurodevelopmental context, and most genome-wide association studies (GWASs) have been conducted in European-ancestry populations. We conducted a GWAS on verbal memory in a maximum of 11,017 participants aged 8.9 to 11.1 years in the Adolescent Brain Cognitive Development Study®, recruited from a diverse population in the United States. Verbal memory was assessed by the Rey Auditory Verbal Learning Test, which included three measures of verbal memory: immediate recall, short-delay recall, and long-delay recall. We adopted a mixed-model approach to perform a joint GWAS of all participants, adjusting for ancestral background and familial relatedness. The inclusion of participants from all ancestries increased the power of the GWAS. Two novel genome-wide significant associations were found for short-delay and long-delay recall verbal memory. In particular, one locus (rs9896243) associated with long-delay recall was mapped to the NSF (N-Ethylmaleimide Sensitive Factor, Vesicle Fusing ATPase) gene, indicating the role of membrane fusion in adolescent verbal memory. Based on the GWAS in the European subset, we estimated the SNP-heritability to be 15% to 29% for the three verbal memory traits. We found that verbal memory was genetically correlated with schizophrenia, providing further evidence supporting verbal memory as an endophenotype for psychosis

Associations of antidepressants and antipsychotics with lipid parameters: Do CYP2C19/CYP2D6 genes play a role? A UK population-based study

Background: Dyslipidaemia is an important cardiovascular risk factor for people with severe mental illness, contributing to premature mortality. The link between antipsychotics and dyslipidaemia is well established, while evidence on antidepressants is mixed. Aims: To investigate if antidepressant/antipsychotic use was associated with lipid parameters in UK Biobank participants and if CYP2C19 and CYP2D6 genetic variation plays a role. Methods: Review of self-reported prescription medications identified participants taking antidepressants/antipsychotics. Total, low-, and high-density lipoprotein cholesterol (L/HDL-C) and triglycerides derived from blood samples. CYP2C19 and CYP2D6 metabolic phenotypes were assigned from genetic data. Linear regression investigated aims, adjusted for key covariates. Results: Of 469,739 participants, 36,043 took antidepressants (53% female, median age 58, 17% taking cholesterol-lowering medications) and 3255 took antipsychotics (58% female, median age 57, 27% taking cholesterol-lowering medications). Significant associations were found between use of each amitriptyline, fluoxetine, citalopram/escitalopram, sertraline, paroxetine and venlafaxine with higher total cholesterol, LDL-C, and triglycerides and lower HDL-C, compared to participants not taking each medication. Venlafaxine was associated with the worst lipid profile (total cholesterol, adjusted mean difference: 0.21 mmol/L, 95% confidence interval (CI): 0.17 to 0.26, p < 0.001). Antipsychotic use was significantly associated with lower HDL-C and higher triglycerides. In participants taking sertraline, CYP2C19 intermediate metabolisers had higher HDL-C (0.05 mmol/L, 95% CI: 0.01 to 0.09, p = 0.007) and lower triglycerides (−0.17 mmol/L, 95% CI: −0.29 to −0.05, p = 0.007), compared to normal metabolisers. Conclusions: Antidepressants were significantly associated with adverse lipid profiles, potentially warranting baseline and regular monitoring. Further research should investigate the mechanistic pathways underlying the protective effects of the CYP2C19 intermediate metaboliser phenotype on HDL-C and triglycerides in people taking sertraline

The effect of CYP2D6 variation on antipsychotic-induced hyperprolactinaemia: a systematic review and meta-analysis

Hyperprolactinemia is a known adverse drug reaction to antipsychotic treatment. Antipsychotic blood levels are influenced by cytochrome P450 enzymes, primarily CYP2D6. Variation in CYP450 genes may affect the risk of antipsychotic-induced hyperprolactinemia. We undertook a systematic review and meta-analysis to assess whether CYP2D6 functional genetic variants are associated with antipsychotic-induced hyperprolactinemia. The systematic review identified 16 relevant papers, seven of which were suitable for the meta-analysis (n = 303 participants including 134 extreme metabolisers). Participants were classified into four phenotype groups as poor, intermediate, extensive, and ultra-rapid metabolisers. A random effects meta-analysis was used and Cohen’s d calculated as the effect size for each primary study. We found no significant differences in prolactin levels between CYP2D6 metabolic groups. Current evidence does not support using CYP2D6 genotyping to reduce risk of antipsychotic-induced hyperprolactinemia. However, statistical power is limited. Future studies with larger samples and including a range of prolactin-elevating drugs are needed

The influence of CYP2D6 and CYP2C19 genetic variation on diabetes mellitus risk in people taking antidepressants and antipsychotics

CYP2D6 and CYP2C19 enzymes are essential in the metabolism of antidepressants and antipsychotics. Genetic variation in these genes may increase risk of adverse drug reactions. Antidepressants and antipsychotics have previously been associated with risk of diabetes. We examined whether individual genetic differences in CYP2D6 and CYP2C19 contribute to these effects. We identified 31,579 individuals taking antidepressants and 2699 taking antipsychotics within UK Biobank. Participants were classified as poor, intermediate, or normal metabolizers of CYP2D6, and as poor, intermediate, normal, rapid, or ultra-rapid metabolizers of CYP2C19. Risk of diabetes mellitus represented by HbA1c level was examined in relation to the metabolic phenotypes. CYP2D6 poor metabolizers taking paroxetine had higher Hb1Ac than normal metabolizers (mean difference: 2.29 mmol/mol; p < 0.001). Among participants with diabetes who were taking venlafaxine, CYP2D6 poor metabolizers had higher HbA1c levels compared to normal metabolizers (mean differences: 10.15 mmol/mol; p < 0.001. Among participants with diabetes who were taking fluoxetine, CYP2D6 intermediate metabolizers and decreased HbA1c, compared to normal metabolizers (mean difference −7.74 mmol/mol; p = 0.017). We did not observe any relationship between CYP2D6 or CYP2C19 metabolic status and HbA1c levels in participants taking antipsychotic medication. Our results indicate that the impact of genetic variation in CYP2D6 differs depending on diabetes status. Although our findings support existing clinical guidelines, further research is essential to inform pharmacogenetic testing for people taking antidepressants and antipsychotics

The association between reasons for first using cannabis, later pattern of use, and risk of first-episode psychosis: the EU-GEI case-control study.

While cannabis use is a well-established risk factor for psychosis, little is known about any association between reasons for first using cannabis (RFUC) and later patterns of use and risk of psychosis. We used data from 11 sites of the multicentre European Gene-Environment Interaction (EU-GEI) case-control study. 558 first-episode psychosis patients (FEPp) and 567 population controls who had used cannabis and reported their RFUC.We ran logistic regressions to examine whether RFUC were associated with first-episode psychosis (FEP) case-control status. Path analysis then examined the relationship between RFUC, subsequent patterns of cannabis use, and case-control status. Controls (86.1%) and FEPp (75.63%) were most likely to report 'because of friends' as their most common RFUC. However, 20.1% of FEPp compared to 5.8% of controls reported: 'to feel better' as their RFUC (χ &lt;sup&gt;2&lt;/sup&gt; = 50.97; p &lt; 0.001). RFUC 'to feel better' was associated with being a FEPp (OR 1.74; 95% CI 1.03-2.95) while RFUC 'with friends' was associated with being a control (OR 0.56; 95% CI 0.37-0.83). The path model indicated an association between RFUC 'to feel better' with heavy cannabis use and with FEPp-control status. Both FEPp and controls usually started using cannabis with their friends, but more patients than controls had begun to use 'to feel better'. People who reported their reason for first using cannabis to 'feel better' were more likely to progress to heavy use and develop a psychotic disorder than those reporting 'because of friends'

Psychosis Endophenotypes:A Gene-Set-Specific Polygenic Risk Score Analysis

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 testing their associations with endophenotypes.Study Design:We computed polygenic risk scores for schizophrenia and bipolar disorder restricted to brain-related gene sets retrieved from public databases and previous publications. Three hundred and seventy-eight gene-set-specific polygenic risk scores were generated for 4506 participants. Seven endophenotypes were also measured in the sample. Linear mixed-effects models were fitted to test associations between each endophenotype and each gene-set-specific polygenic risk score.Study Results:After correction for multiple testing, we found that a reduced P300 amplitude was associated with a higher schizophrenia polygenic risk score of the forebrain regionalization gene set (mean difference per SD increase in the polygenic risk score: −1.15 µV; 95% CI: −1.70 to −0.59 µV; P = 6 × 10−5). The schizophrenia polygenic risk score of forebrain regionalization also explained more variance of the P300 amplitude (R2 = 0.032) than other polygenic risk scores, including the genome-wide polygenic risk scores.Conclusions:Our finding on reduced P300 amplitudes suggests that certain genetic variants alter early brain development thereby increasing schizophrenia risk years later. Gene-set-specific polygenic risk scores are a useful tool to elucidate biological mechanisms of psychosis and endophenotypes, offering leads for experimental validation in cellular and animal models

Genetic copy number variants, cognition and psychosis: a meta-analysis and a family study

Article Open Access Published: 27 July 2020 Genetic copy number variants, cognition and psychosis: a meta-analysis and a family study Johan H. Thygesen, Amelia Presman, […]Elvira Bramon Molecular Psychiatry (2020)Cite this article 561 Accesses 10 Altmetric Metricsdetails Abstract The burden of large and rare copy number genetic variants (CNVs) as well as certain specific CNVs increase the risk of developing schizophrenia. Several cognitive measures are purported schizophrenia endophenotypes and may represent an intermediate point between genetics and the illness. This paper investigates the influence of CNVs on cognition. We conducted a systematic review and meta-analysis of the literature exploring the effect of CNV burden on general intelligence. We included ten primary studies with a total of 18,847 participants and found no evidence of association. In a new psychosis family study, we investigated the effects of CNVs on specific cognitive abilities. We examined the burden of large and rare CNVs (>200 kb, <1% MAF) as well as known schizophrenia-associated CNVs in patients with psychotic disorders, their unaffected relatives and controls (N = 3428) from the Psychosis Endophenotypes International Consortium (PEIC). The carriers of specific schizophrenia-associated CNVs showed poorer performance than non-carriers in immediate (P = 0.0036) and delayed (P = 0.0115) verbal recall. We found suggestive evidence that carriers of schizophrenia-associated CNVs had poorer block design performance (P = 0.0307). We do not find any association between CNV burden and cognition. Our findings show that the known high-risk CNVs are not only associated with schizophrenia and other neurodevelopmental disorders, but are also a contributing factor to impairment in cognitive domains such as memory and perceptual reasoning, and act as intermediate biomarkers of disease risk

Global, regional, and national burden of tuberculosis, 1990–2016: results from the Global Burden of Diseases, Injuries, and Risk Factors 2016 Study

Background Although a preventable and treatable disease, tuberculosis causes more than a million deaths each year. As countries work towards achieving the Sustainable Development Goal (SDG) target to end the tuberculosis epidemic by 2030, robust assessments of the levels and trends of the burden of tuberculosis are crucial to inform policy and programme decision making. We assessed the levels and trends in the fatal and non-fatal burden of tuberculosis by drug resistance and HIV status for 195 countries and territories from 1990 to 2016. Methods We analysed 15 943 site-years of vital registration data, 1710 site-years of verbal autopsy data, 764 site-years of sample-based vital registration data, and 361 site-years of mortality surveillance data to estimate mortality due to tuberculosis using the Cause of Death Ensemble model. We analysed all available data sources, including annual case notifications, prevalence surveys, population-based tuberculin surveys, and estimated tuberculosis cause-specific mortality to generate internally consistent estimates of incidence, prevalence, and mortality using DisMod-MR 2.1, a Bayesian meta-regression tool. We assessed how the burden of tuberculosis differed from the burden predicted by the Socio-demographic Index (SDI), a composite indicator of income per capita, average years of schooling, and total fertility rate. Findings Globally in 2016, among HIV-negative individuals, the number of incident cases of tuberculosis was 9·02 million (95% uncertainty interval [UI] 8·05–10·16) and the number of tuberculosis deaths was 1·21 million (1·16–1·27). Among HIV-positive individuals, the number of incident cases was 1·40 million (1·01–1·89) and the number of tuberculosis deaths was 0·24 million (0·16–0·31). Globally, among HIV-negative individuals the age-standardised incidence of tuberculosis decreased annually at a slower rate (–1·3% [–1·5 to −1·2]) than mortality did (–4·5% [–5·0 to −4·1]) from 2006 to 2016. Among HIV-positive individuals during the same period, the rate of change in annualised age-standardised incidence was −4·0% (–4·5 to −3·7) and mortality was −8·9% (–9·5 to −8·4). Several regions had higher rates of age-standardised incidence and mortality than expected on the basis of their SDI levels in 2016. For drug-susceptible tuberculosis, the highest observed-to-expected ratios were in southern sub-Saharan Africa (13·7 for incidence and 14·9 for mortality), and the lowest ratios were in high-income North America (0·4 for incidence) and Oceania (0·3 for mortality). For multidrug-resistant tuberculosis, eastern Europe had the highest observed-to-expected ratios (67·3 for incidence and 73·0 for mortality), and high-income North America had the lowest ratios (0·4 for incidence and 0·5 for mortality). Interpretation If current trends in tuberculosis incidence continue, few countries are likely to meet the SDG target to end the tuberculosis epidemic by 2030. Progress needs to be accelerated by improving the quality of and access to tuberculosis diagnosis and care, by developing new tools, scaling up interventions to prevent risk factors for tuberculosis, and integrating control programmes for tuberculosis and HIV

DISC1 genetics, biology and psychiatric illness

Psychiatric disorders are highly heritable, and in many individuals likely arise from the combined effects of genes and the environment. A substantial body of evidence points towards DISC1 being one of the genes that influence risk of schizophrenia, bipolar disorder and depression, and functional studies of DISC1 consequently have the potential to reveal much about the pathways that lead to major mental illness. Here, we review the evidence that DISC1 influences disease risk through effects upon multiple critical pathways in the developing and adult brain