We investigated the involvement of rare (<1%) copy number variants (CNVs) in 471 cases of schizophrenia and 2792 controls that had been genotyped using the Affymetrix GeneChip® 500K Mapping Array. ...Large CNVs >1 Mb were 2.26 times more common in cases (P = 0.00027), with the effect coming mostly from deletions (odds ratio, OR = 4.53, P = 0.00013) although duplications were also more common (OR = 1.71, P = 0.04). Two large deletions were found in two cases each, but in no controls: a deletion at 22q11.2 known to be a susceptibility factor for schizophrenia and a deletion on 17p12, at 14.0–15.4 Mb. The latter is known to cause hereditary neuropathy with liability to pressure palsies. The same deletion was found in 6 of 4618 (0.13%) cases and 6 of 36 092 (0.017%) controls in the re-analysed data of two recent large CNV studies of schizophrenia (OR = 7.82, P = 0.001), with the combined significance level for all three studies achieving P = 5 × 10−5. One large duplication on 16p13.1, which has been previously implicated as a susceptibility factor for autism, was found in three cases and six controls (0.6% versus 0.2%, OR = 2.98, P = 0.13). We also provide the first support for a recently reported association between deletions at 15q11.2 and schizophrenia (P = 0.026). This study confirms the involvement of rare CNVs in the pathogenesis of schizophrenia and contributes to the growing list of specific CNVs that are implicated.
Recent results indicate that genome-wide association studies (GWAS) have the potential to explain much of the heritability of common complex phenotypes, but methods are lacking to reliably identify ...the remaining associated single nucleotide polymorphisms (SNPs). We applied stratified False Discovery Rate (sFDR) methods to leverage genic enrichment in GWAS summary statistics data to uncover new loci likely to replicate in independent samples. Specifically, we use linkage disequilibrium-weighted annotations for each SNP in combination with nominal p-values to estimate the True Discovery Rate (TDR = 1-FDR) for strata determined by different genic categories. We show a consistent pattern of enrichment of polygenic effects in specific annotation categories across diverse phenotypes, with the greatest enrichment for SNPs tagging regulatory and coding genic elements, little enrichment in introns, and negative enrichment for intergenic SNPs. Stratified enrichment directly leads to increased TDR for a given p-value, mirrored by increased replication rates in independent samples. We show this in independent Crohn's disease GWAS, where we find a hundredfold variation in replication rate across genic categories. Applying a well-established sFDR methodology we demonstrate the utility of stratification for improving power of GWAS in complex phenotypes, with increased rejection rates from 20% in height to 300% in schizophrenia with traditional FDR and sFDR both fixed at 0.05. Our analyses demonstrate an inherent stratification among GWAS SNPs with important conceptual implications that can be leveraged by statistical methods to improve the discovery of loci.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
IMPORTANCE: Insomnia, hypersomnia, and an evening chronotype are common in individuals with bipolar disorder (BD), but whether this reflects shared genetic liability is unclear. Stratifying by BD ...subtypes could elucidate this association and inform sleep and BD research. OBJECTIVE: To assess whether polygenic risk scores (PRSs) for sleep traits are associated with BD subtypes I and II. DESIGN, SETTING, AND PARTICIPANTS: This case-control study was conducted in the United Kingdom and Sweden with participants with BD and control participants. Multinomial regression was used to assess whether PRSs for insomnia, daytime sleepiness, sleep duration, and chronotype are associated with BD subtypes compared with control participants. Affected individuals were recruited from the Bipolar Disorder Research Network. Control participants were recruited from the 1958 British Birth Cohort and the UK Blood Service. Analyses were repeated in an independent Swedish sample from August 2018 to July 2019. All participants were of European ancestry. EXPOSURES: Standardized PRSs derived using alleles from genome-wide association studies of insomnia, sleep duration, daytime sleepiness, and chronotype. These were adjusted for the first 10 population principal components, genotyping platforms, and sex. MAIN OUTCOMES AND MEASURES: Association of PRSs with BD subtypes, determined by semistructured psychiatric interview and case notes. RESULTS: The main analysis included 4672 participants with BD (3132 female participants 67.0%; 3404 with BD-I 72.9%) and 5714 control participants (2812 female participants 49.2%). Insomnia PRS was associated with increased risk of BD-II (relative risk RR, 1.14 95% CI, 1.07-1.21; P = 8.26 × 10−5) but not BD-I (RR, 0.98 95% CI, 0.94-1.03; P = .409) relative to control participants. Sleep-duration PRS was associated with BD-I (RR, 1.10 95% CI, 1.06-1.15; P = 1.13 × 10−5) but not BD-II (RR, 0.99 95% CI, 0.93-1.06; P = .818). Associations between (1) insomnia PRS and BD-II and (2) sleep-duration PRS and BD-I were replicated in the Swedish sample of 4366 individuals with BD (2697 female participants 61.8%; 2627 with BD-I 60.2%) and 6091 control participants (3767 female participants 61.8%). Chronotype and daytime-sleepiness PRS were not associated with BD subtypes. CONCLUSIONS AND RELEVANCE: Per this analysis, BD subtypes differ in genetic liability to insomnia and hypersomnia, providing further evidence that the distinction between BD-I and BD-II has genetic validity. This distinction will be crucial in selecting participants for future research on the role of sleep disturbance in BD.
Around 30% of individuals with schizophrenia remain symptomatic and significantly impaired despite antipsychotic treatment and are considered to be treatment resistant. Clinicians are currently ...unable to predict which patients are at higher risk of treatment resistance.
To determine whether genetic liability for schizophrenia and/or clinical characteristics measurable at illness onset can prospectively indicate a higher risk of treatment-resistant psychosis (TRP).
In 1070 individuals with schizophrenia or related psychotic disorders, schizophrenia polygenic risk scores (PRS) and large copy number variations (CNVs) were assessed for enrichment in TRP. Regression and machine-learning approaches were used to investigate the association of phenotypes related to demographics, family history, premorbid factors and illness onset with TRP.
Younger age at onset (odds ratio 0.94, P = 7.79 × 10-13) and poor premorbid social adjustment (odds ratio 1.64, P = 2.41 × 10-4) increased risk of TRP in univariate regression analyses. These factors remained associated in multivariate regression analyses, which also found lower premorbid IQ (odds ratio 0.98, P = 7.76 × 10-3), younger father's age at birth (odds ratio 0.97, P = 0.015) and cannabis use (odds ratio 1.60, P = 0.025) increased the risk of TRP. Machine-learning approaches found age at onset to be the most important predictor and also identified premorbid IQ and poor social adjustment as predictors of TRP, mirroring findings from regression analyses. Genetic liability for schizophrenia was not associated with TRP.
People with an earlier age at onset of psychosis and poor premorbid functioning are more likely to be treatment resistant. The genetic architecture of susceptibility to schizophrenia may be distinct from that of treatment outcomes.
Abstract Background Clozapine is uniquely effective in the management of treatment-resistant schizophrenia (TRS). However, a substantial proportion of patients discontinue treatment and this carries ...a poor prognosis. Methods We investigated the risk factors, reasons and timing of clozapine discontinuation in a two-year retrospective cohort study of 316 patients with TRS receiving their first course of clozapine. Reasons for discontinuation of clozapine and duration of treatment were obtained from case notes and Cox regression was employed to test the association of baseline clinical factors with clozapine discontinuation. Results A total of 142 (45%) patients discontinued clozapine within two years. By studying the reasons for discontinuations due to a patient decision, we found that adverse drug reactions (ADRs) accounted for over half of clozapine discontinuations. Sedation was the most common ADR cited as a reason for discontinuation and the risk of discontinuation due to ADRs was highest in the first few months of clozapine treatment. High levels of deprivation in the neighbourhood where the patient lived were associated with increased risk of clozapine discontinuation (HR = 2.12, 95% CI 1.30–3.47). Conclusions Living in a deprived neighbourhood was strongly associated with clozapine discontinuation. Clinical management to reduce the burden of ADRs in the first few months of treatment may have a significant impact and help more patients experience the benefits of clozapine treatment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
IMPORTANCE: Schizophrenia is a clinically heterogeneous disorder. It is currently unclear how variability in symptom dimensions and cognitive ability is associated with genetic liability for ...schizophrenia. OBJECTIVE: To determine whether phenotypic dimensions within schizophrenia are associated with genetic liability to schizophrenia, other neuropsychiatric disorders, and intelligence. DESIGN, SETTING, AND PARTICIPANTS: In a genetic association study, 3 cross-sectional samples of 1220 individuals with a diagnosis of schizophrenia were recruited from community, inpatient, and voluntary sector mental health services across the UK. Confirmatory factor analysis was used to create phenotypic dimensions from lifetime ratings of the Scale for the Assessment of Positive Symptoms, Scale for the Assessment of Negative Symptoms, and the MATRICS Consensus Cognitive Battery. Analyses of polygenic risk scores (PRSs) were used to assess whether genetic liability to schizophrenia, other neuropsychiatric disorders, and intelligence were associated with these phenotypic dimensions. Data collection for the cross-sectional studies occurred between 1993 and 2016. Data analysis for this study occurred between January 2019 and March 2021. MAIN OUTCOMES AND MEASURES: Outcome measures included phenotypic dimensions defined from confirmatory factor analysis relating to positive symptoms, negative symptoms of diminished expressivity, negative symptoms of motivation and pleasure, disorganized symptoms, and current cognitive ability. Exposure measures included PRSs for schizophrenia, bipolar disorder, major depression, attention-deficit/hyperactivity disorder, autism spectrum disorder, and intelligence. RESULTS: Of the 1220 study participants, 817 were men (67.0%). Participants’ mean (SD) age at interview was 43.10 (12.74) years. Schizophrenia PRS was associated with increased disorganized symptom dimension scores in both a 5-factor model (β = 0.14; 95% CI, 0.07-0.22; P = 2.80 × 10−4) and a 3-factor model across all samples (β = 0.10; 95% CI, 0.05-0.15; P = 2.80 × 10−4). Current cognitive ability was associated with genetic liability to schizophrenia (β = −0.11; 95% CI, −0.19 to −0.04; P = 1.63 × 10−3) and intelligence (β = 0.23; 95% CI, 0.16-0.30; P = 1.52 × 10−10). After controlling for estimated premorbid IQ, current cognitive performance was associated with schizophrenia PRS (β = −0.08; 95% CI, −0.14 to −0.02; P = 8.50 × 10−3) but not intelligence PRS. CONCLUSIONS AND RELEVANCE: The findings of this study suggest that genetic liability for schizophrenia is associated with higher disorganized dimension scores but not other symptom dimensions. Cognitive performance in schizophrenia appears to reflect distinct contributions from genetic liabilities to both intelligence and schizophrenia.
Schizophrenia is a highly polygenic disorder with important contributions from both common and rare risk alleles. We analyzed exome sequencing data for de novo variants (DNVs) in a new sample of 613 ...schizophrenia trios and combined this with published data to give a total of 3,444 trios. In this new data, loss-of-function (LoF) DNVs were significantly enriched among 3,471 LoF-intolerant genes, which supports previous findings. In the full dataset, genes associated with neurodevelopmental disorders (n = 159) were significantly enriched for LoF DNVs. Within these neurodevelopmental disorder genes, SLC6A1, which encodes a γ-aminobutyric acid transporter, was associated with missense-damaging DNVs. In 1,122 trios for which genome-wide common variant data were available, schizophrenia and bipolar disorder polygenic risk were significantly overtransmitted to probands. Probands carrying LoF or deletion DNVs in LoF-intolerant or neurodevelopmental disorder genes had significantly less overtransmission of schizophrenia polygenic risk than did non-carriers, which provides a second robust line of evidence that these DNVs increase liability to schizophrenia.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Objective:Clozapine is the only effective medication for treatment-resistant schizophrenia, but its worldwide use is still limited because of its complex titration protocols. While the discovery of ...pharmacogenomic variants of clozapine metabolism may improve clinical management, no robust findings have yet been reported. This study is the first to adopt the framework of genome-wide association studies (GWASs) to discover genetic markers of clozapine plasma concentrations in a large sample of patients with treatment-resistant schizophrenia.Methods:The authors used mixed-model regression to combine data from multiple assays of clozapine metabolite plasma concentrations from a clozapine monitoring service and carried out a genome-wide analysis of clozapine, norclozapine, and their ratio on 10,353 assays from 2,989 individuals. These analyses were adjusted for demographic factors known to influence clozapine metabolism, although it was not possible to adjust for all potential mediators given the available data. GWAS results were used to pinpoint specific enzymes and metabolic pathways and compounds that might interact with clozapine pharmacokinetics.Results:The authors identified four distinct genome-wide significant loci that harbor common variants affecting the metabolism of clozapine or its metabolites. Detailed examination pointed to coding and regulatory variants at several CYP* and UGT* genes as well as corroborative evidence for interactions between the metabolism of clozapine, coffee, and tobacco. Individual effects of single single-nucleotide polymorphisms (SNPs) fine-mapped from these loci were large, such as the minor allele of rs2472297, which was associated with a reduction in clozapine concentrations roughly equivalent to a decrease of 50 mg/day in clozapine dosage. On their own, these single SNPs explained from 1.15% to 9.48% of the variance in the plasma concentration data.Conclusions:Common genetic variants with large effects on clozapine metabolism exist and can be found via genome-wide approaches. Their identification opens the way for clinical studies assessing the use of pharmacogenomics in the clinical management of patients with treatment-resistant schizophrenia.
IMPORTANCE: At least 11 rare copy number variants (CNVs) have been shown to be major risk factors for schizophrenia (SZ). These CNVs also increase the risk for other neurodevelopmental disorders, ...such as intellectual disability. It is possible that additional intellectual disability–associated CNVs increase the risk for SZ but have not yet been implicated in SZ because of previous studies being underpowered. OBJECTIVE: To examine whether additional CNVs implicated in intellectual disability represent novel SZ risk loci. DESIGN, SETTING, AND PARTICIPANTS: We used single-nucleotide polymorphism (SNP) array data to evaluate a set of 51 CNVs implicated in intellectual disability (excluding the known SZ loci) in a large data set of patients with SZ and healthy persons serving as controls recruited in a variety of settings. We analyzed a new sample of 6934 individuals with SZ and 8751 controls and combined those data with previously published large data sets for a total of 20 403 cases of SZ and 26 628 controls. MAIN OUTCOMES AND MEASURES: Burden analysis of CNVs implicated in intellectual disability (excluding known SZ CNVs) for association with SZ. Association of individual intellectual disability CNV loci with SZ. RESULTS: Of data on the 20 403 cases (6151 30.15% female) and 26 628 controls (14 252 53.52% female), 51 intellectual disability CNVs were analyzed. Collectively, intellectual disability CNVs were significantly enriched for SZ (P = 1.0 × 10−6; odds ratio OR, 1.9 95% CI, 1.46-2.49). Of the 51 CNVs tested, 19 (37%) were more common in SZ cases; only 4 (8%) were more common in controls (no observations were made for the remaining 28 55% loci). One novel locus, deletion at 16p12.1, was significantly associated with SZ after correction for multiple testing (rate in SZ, 33 0.16%; rate in controls, 12 0.05%; corrected P = .017; OR, 3.3; 95% CI, 1.61-7.05), and 2 loci reached nominal levels of significance (deletions at 2q11.2: 6 0.03% vs 1 0.004%; OR, 9.3; 95% CI, 1.03-447.76; corrected P > .99; and duplications at 10q11.21q11.23: 5 0.2% vs 0 0.03%; OR, infinity; 95% CI, 1.26-infinity; corrected P = .71). Our new data set also provided independent support for the 11 SZ risk loci previously reported to be associated with the disorder and for the protective effect of 22q11.2 duplication. CONCLUSIONS AND RELEVANCE: A large proportion of CNV loci implicated in intellectual disability are risk factors for SZ, but the available sample size precludes statistical confirmation for additional individual loci.
Attention-deficit hyperactivity disorder (ADHD) is associated with later depression and there is considerable genetic overlap between them. This study investigated if ADHD and ADHD genetic liability ...are causally related to depression using two different methods.
First, a longitudinal population cohort design was used to assess the association between childhood ADHD (age 7 years) and recurrent depression in young-adulthood (age 18-25 years) in N = 8310 individuals in the Avon Longitudinal Study of Parents and Children (ALSPAC). Second, two-sample Mendelian randomization (MR) analyses examined relationships between genetic liability for ADHD and depression utilising published Genome-Wide Association Study (GWAS) data.
Childhood ADHD was associated with an increased risk of recurrent depression in young-adulthood (OR 1.35, 95% CI 1.05-1.73). MR analyses suggested a causal effect of ADHD genetic liability on major depression (OR 1.21, 95% CI 1.12-1.31). MR findings using a broader definition of depression differed, showing a weak influence on depression (OR 1.07, 95% CI 1.02-1.13).
Our findings suggest that ADHD increases the risk of depression later in life and are consistent with a causal effect of ADHD genetic liability on subsequent major depression. However, findings were different for more broadly defined depression.
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