Identification and Evaluation of Endophenotypes and Biomarkers of Schizophrenia and Bipolar Disorder: Genomic Dissection of the Psychosis Phenotype

Background: Psychotic disorders affect approximately 3% of the population. Over 100 genetic variants have been associated with schizophrenia and about 50 with bipolar disorder. Each of them individually has a small effect on disease risk but combined in a cumulative polygenic risk score (PRS), they have a major impact. Copy number variants (CNVs) have also been associated with schizophrenia. However, little is known about their functional effects. The investigation of endophenotypes, which fall in the genotype to phenotype pathway, could help us understand the role of genetic variants and their mechanisms. Methods: In chapter 1 of my thesis, I reviewed the literature on endophenotypes, and genetic variants associated with psychosis, which revealed that the interrelationships between several well-established cognitive, neuroimaging and electrophysiological psychosis endophenotypes, and the joint contributions of CNV burden and polygenic risk scores on psychosis risk have not been studied yet. I investigated those topics in chapters 3 and 4 respectively. In chapter 2 I carried out a scoping review of CNVs associated with neurodevelopmental disorders, psychosis and cognition and carried out a meta-analysis of 16p11.2 distal deletion in schizophrenia. I also investigated the influences of CNV size on schizophrenia risk for 53 CNVs. For all the analyses, I used CNVcatalog, which is a new repository me and my supervisors created, incorporating data from published studies examining associations of CNV loci with several clinical phenotypes, including schizophrenia. Finally, in chapter 5 I summarise the main findings of my thesis and I discuss the strengths, limitations and clinical implications of my research. Results: Chapter 2: The meta-analysis of 16p11.2 distal deletion in schizophrenia revealed that carriers of that CNV had higher risk of developing schizophrenia compared to non carriers. I also found that larger CNV size was associated with larger effect sizes when examining all CNVs together (both deletions and duplications) and CNV deletions. However, the size was not significanly associated with disease risk for CNV duplications. Chapter 3: All the cognitive endophenotypes were associated with each other. Endophenotypes across imaging, cognitive and electrophysiological domains did not show a correlation. The relationships between pairs of endophenotypes were consistent in all three participant groups (cases with psychosis, their unaffected relatives and healthy controls), differing for some of the cognitive pairings only in the strengths of the relationships. Chapter 4: I examined the joint contributions of CNV burden and polygenic risk scores on psychosis risk. I analysed two datasets separately and then combined them by meta-analysis. CNV burden and PRS could explain 11.8% and 10.8% of the variance in disease risk in each dataset. The classification accuracy of my models was 81%, 83% and 77% for the comparisons of all psychosis cases vs controls, schizophrenia cases vs controls and bipolar cases vs controls respectively. The addition of CNV burden to the models increased the variance explained only by 0.1% for MPL dataset and by 0.08% in the PEIC dataset. Discussion: Findings from my thesis contribute to our current knowledge on psychosis endophenotypes and on the genetic influences in psychoses. Deciphering the genetic architecture of psychotic disorders could hopefully in the future improve the lives of affected individuals

Endophenotypes of executive functions in obsessive compulsive disorder? A meta-analysis in unaffected relatives.

Endophenotypes are mediator traits between genetic influences and clinical phenotypes. Meta-analyses have consistently shown modest impairments of executive functioning in obsessive compulsive disorder (OCD) patients compared to healthy controls. Similar deficits have also been reported in unaffected relatives of OCD patients, but have not been quantified. We conducted the first meta-analysis combining all studies investigating executive functioning in unaffected relatives of individuals with OCD to quantify any deficits. A search of Pubmed, Medline and PsychInfo databases identified 21 suitable papers comprising 707 unaffected relatives of OCD patients and 842 healthy controls. Effect sizes were calculated using random effects models. Unaffected relatives displayed a significant impairment in global executive functioning. Analyses of specific executive functioning subdomains revealed impairments in: planning, visuospatial working memory and verbal fluency. Deficits in executive functioning are promising endophenotypes for OCD. To identify further biomarkers of disease risk/resilience in OCD, we suggest examining specific executive functioning domains

Functional hemispheric asymmetry and nicotine dependency as variables mediating neurobiological vulnerability to schizotypy in a non-clinical population of college students

In the present study, schizotypal personality traits and their neuropsychological correlates were examined amongst a non-clinical sample, so as to gain insight into the variables mediating neurobiological vulnerability to schizotypy. To that effect, 50 young adults completed the Oxford-Liverpool Inventory of Feelings and Experiences, the Fagerström Test of Nicotine Dependence, the Edinburgh Handedness Questionnaire, and a dichotic listening task. Analyses revealed a significant right-hemisphere dominance association to positive schizotypy, and a left-hemisphere dominance association to negative schizotypy. Nicotine dependence emerged as a significant correlate of positive and overall schizotypy, and left-hemisphere dominance. Gender-based interactions were significant for females on positive schizotypy, nicotine dependence and right-hemisphere dominance, and on negative schizotypy for males. The findings of this study can be used to advance our understanding of the factors of risk and resilience in the schizophrenia spectrum

Estimating nonbelief: Translation, cultural adaptation, and statistical validation of the Nonreligious-Nonspiritual Scale in a nationwide Greek sample

Nonbelievers represent an understudied population in Greece. This investigation reports on the translation, cultural adaptation, and initial validation of the Nonreligious-Nonspiritual Scale (NRNSS), a measure designed to assess nonbelief. Data from 1754 participants were collected to examine the psychometric properties of the Greek version of the instrument and to assess the nationwide interpretability of the measure. Factor analyses suggested that the 16-item scale retained its bifactor model. Convergent validity was supported through associations with additional measures, namely, the Meaning in Life Questionnaire (MLQ) and the Connor–Davidson Resilience Scale (CD-RISC), which were used as reference criteria. Potential utility of the measure and future directions for ongoing development are discussed

Development of the Greek version of the Spiritual Intelligence Self-Report Inventory-24 (KAPN): factor structure and validation

The Spiritual Intelligence Self-Report Inventory 24 (SISRI-24) is widely used to assess spiritual intelligence (SI) in general population samples. The current study explored the Greek version SISRI-24 factor structure in a convenience sample of 1777 adults. A translation of the original scale was performed in different stages, so as to obtain a fully comprehensible and accurate equivalent. Psychometric properties were analyzed at the level of item. The four-factor solution proposed in the original SISRI-24 was not confirmed. Instead, an alternative model, in which the SISRI-24 structure was revised and trimmed to a final three-factor, 17-item short-form version (KAPN), produced an instrument of sound construct validity [fit indices: CFI = .92, TLI = .91, RMSEA = .06, SRMR = .06] and robust internal consistency. The results are sufficient for endorsing the suitability of KAPN in Greek speaking populations, and extend cross-cultural support for the SI model. Implications and recommendations for future directions of research are discussed

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 effects of acute serotonin challenge on executive planning in patients with obsessive-compulsive disorder (OCD), their first-degree relatives, and healthy controls

© 2020 Springer-Verlag. The final publication is available at Springer via https://doi.org/10.1007/s00213-020-05597-7.Rationale: OCD is characterized by executive function impairment and by clinical responsivity to selective serotonin reuptake inhibitors (SSRIs). Executive planning deficits constitute a candidate endophenotype for OCD. It is not known whether this endophenotype is responsive to acute serotonin manipulation. Objective: To investigate the effects of acute SSRI administration on executive function in patients with OCD, first-degree relatives of patients with OCD and healthy controls. Methods: A randomized double-blind crossover study assessed the effects of single dose escitalopram (20mg) and placebo on executive planning in 24 patients with OCD, 13 clinically unaffected first-degree relatives of patients with OCD and 28 healthy controls. Performance on a Tower of London task measuring executive planning was assessed 4 hours after oral administration of the pharmacological challenge / placebo, and compared across and within groups using a mixed model ANOVA. Results: On the outcome measure of interest, i.e. the mean number of choices to obtain the correct solution, there was a marginally significant effect of group (F(2, 59)=3.1; p=0.052), with patients (Least square [LS] mean: 1.43; Standard Error [SE]: 0.06; 95% confidence interval [CI], 1.31-1.55) and their relatives (LS mean: 1.46; SE: 0.08; 95% CI, 1.30-1.62) performing worse than matched healthy controls (LS mean: 1.26; SE: 0.05; 95% CI, 1.15-1.37) on placebo. There was a trend towards a significant group x treatment interaction (F(2, 58)=2.8, p=0.069), with post hoc tests showing (i) patients (p=0.009; LS mean difference: 0.23; SE: 0.08) and relatives (p=0.03; LS mean difference: 0.22; SE: 0.10) were more impaired compared to controls and (ii) escitalopram was associated with improved executive planning in patients with OCD (p=0.013; LS mean difference: 0.1; SE: 0.04), but not other groups (both p>0.1; controls: LS mean difference: -0.03; SE: 0.04; relatives: LS mean difference: 0.02; SE: 0.05). Conclusion: Our findings are consistent with a view that there is impaired executive planning in OCD, and that this constitutes a behavioral endophenotype. In patients with OCD, but not in relatives, acute SSRI administration ameliorated this deficit. Further investigation is needed to understand common and differential involvement of neurochemical systems in patients with OCD and their relatives.Peer reviewe