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.

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.

Supplementary Material Supplementary Table 1: Inclusion and exclusion criteria for primary studies Inclusion Criteria Randomised controlled trials, non-randomised trials, observational studies Samples genotypes for CYP2D6 functional polymorphisms Blood/plasma prolactin levels measured and reported Patients treated with antipsychotics or healthy volunteers given a single oral dose of antipsychotic Exclusion Criteria Single case report, narrative reviews, systematic reviews, opinions, editorials, conference abstracts, in vitro studies Participants not genotyped for CYP2D6 gene Prolactin levels not measured/reported Studies in which Aripiprazole was used, since despite being metabolised by CYP2D6, it tends to decrease prolactin levels Supplementary Table 2: CYP2D6 phenotypes Phenotype Genotype Poor Metaboliser (PM) mt/mt Intermediate Metaboliser (IM) mt/red Extensive/Normal Metaboliser (EM) wt/wt, wt/DUPred, red/DUPred, red/red, mt/wt, mut/DUPred Ultra-rapid Metaboliser (UM) wt/wtDUP, red/wtDUP wt = normal function allele (*1 and *2), mt = non-functional allele (*3, *4, *5,*6, *7, *8, *11 and *15), red = reduced function allele (*9, *10, *17, *29 and *41) , DUPwt = duplication of normal function allele, DUPred = duplication of reduced function allele