We report results from the Bipolar Exome (BipEx) collaboration analysis of whole-exome sequencing of 13,933 patients with bipolar disorder (BD) matched with 14,422 controls. We find an excess of ...ultra-rare protein-truncating variants (PTVs) in patients with BD among genes under strong evolutionary constraint in both major BD subtypes. We find enrichment of ultra-rare PTVs within genes implicated from a recent schizophrenia exome meta-analysis (SCHEMA; 24,248 cases and 97,322 controls) and among binding targets of CHD8. Genes implicated from genome-wide association studies (GWASs) of BD, however, are not significantly enriched for ultra-rare PTVs. Combining gene-level results with SCHEMA, AKAP11 emerges as a definitive risk gene (odds ratio (OR) = 7.06, P = 2.83 × 10
). At the protein level, AKAP-11 interacts with GSK3B, the hypothesized target of lithium, a primary treatment for BD. Our results lend support to BD's polygenicity, demonstrating a role for rare coding variation as a significant risk factor in BD etiology.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Genomic CNVs increase the risk for early-onset neurodevelopmental disorders, but their impact on medical outcomes in later life is still poorly understood. The UK Biobank allows us to study the ...medical consequences of CNVs in middle and old age in half a million well-phenotyped adults.
We analysed all Biobank participants for the presence of 54 CNVs associated with genomic disorders or clinical phenotypes, including their reciprocal deletions or duplications. After array quality control and exclusion of first-degree relatives, we compared 381 452 participants of white British or Irish origin who carried no CNVs with carriers of each of the 54 CNVs (ranging from 5 to 2843 persons). We used logistic regression analysis to estimate the risk of developing 58 common medical phenotypes (3132 comparisons).
Many of the CNVs have profound effects on medical health and mortality, even in people who have largely escaped early neurodevelopmental outcomes. Forty-six CNV-phenotype associations were significant at a false discovery rate threshold of 0.1, all in the direction of increased risk. Known medical consequences of CNVs were confirmed, but most identified associations are novel. Deletions at 16p11.2 and 16p12.1 had the largest numbers of significantly associated phenotypes (seven each). Diabetes, hypertension, obesity and renal failure were affected by the highest numbers of CNVs. Our work should inform clinicians in planning and managing the medical care of CNV carriers.
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 neuropsychiatric diagnosis, indicating that SETD1A is substantially depleted of LoF variants in the general population. Seven of the ten individuals with schizophrenia carrying SETD1A LoF variants also had learning difficulties. We further identified four SETD1A LoF carriers among 4,281 children with severe developmental disorders and two more carriers in an independent sample of 5,720 Finnish exomes, both with notable neuropsychiatric phenotypes. Together, our observations indicate that LoF variants in SETD1A cause a range of neurodevelopmental disorders, including schizophrenia. Combining these data with previous common variant evidence, we suggest that epigenetic dysregulation, specifically in the histone H3K4 methylation pathway, is an important mechanism in the pathogenesis of schizophrenia.
IMPORTANCE: Psychotic experiences, such as hallucinations and delusions, are reported by approximately 5% to 10% of the general population, although only a small proportion develop psychotic ...disorders such as schizophrenia. Studying the genetic causes of psychotic experiences in the general population, and its association with the genetic causes of other disorders, may increase the understanding of their pathologic significance. OBJECTIVES: To determine whether genetic liability to psychotic experiences is shared with schizophrenia and/or other neuropsychiatric disorders and traits and to identify genetic loci associated with psychotic experiences. DESIGN, SETTING AND PARTICIPANTS: Analyses of genetic correlation, polygenic risk scores, and copy number variation were performed using data from participants in the UK Biobank from April 1, 2018, to March 20, 2019, to assess whether genetic liability to psychotic experiences is shared with schizophrenia and/or other neuropsychiatric disorders and traits. Genome-wide association studies of psychotic experience phenotypes were conducted to identify novel genetic loci. Participants in the final analyses after exclusions included 6123 individuals reporting any psychotic experience, 2143 individuals reporting distressing psychotic experiences, and 3337 individuals reporting multiple occurrences of psychotic experiences. A total of 121 843 individuals who did not report a psychotic experience formed the comparator group. Individuals with a psychotic disorder were excluded from all analyses. MAIN OUTCOMES AND MEASURES: Genetic associations with psychotic experience phenotypes. RESULTS: The study included a total of 127 966 participants (56.0% women and 44.0% men; mean SD age, 64.0 7.6 years). Psychotic experiences were genetically correlated with major depressive disorder, schizophrenia, autism spectrum disorder, and attention-deficit/hyperactivity disorder. Analyses of polygenic risk scores identified associations between psychotic experiences and genetic liability for major depressive disorder, schizophrenia, bipolar disorder, autism spectrum disorder, and attention-deficit/hyperactivity disorder. Individuals reporting psychotic experiences had an increased burden of copy number variations previously associated with schizophrenia (odds ratio OR, 2.04; 95% CI, 1.39-2.98; P = 2.49 × 10−4) and neurodevelopmental disorders more widely (OR, 1.75; 95% CI, 1.24-2.48; P = 1.41 × 10−3). Genome-wide association studies identified 4 significantly associated loci, including a locus in Ankyrin-3 (ANK3 GenBank NM_020987) (OR, 1.16; 95% CI, 1.10-1.23; P = 3.06 × 10−8) with any psychotic experience, and a locus in cannabinoid receptor 2 gene (CNR2 GenBank NM_001841) (OR, 0.66; 95% CI, 0.56-0.78; P = 3.78 × 10−8) with distressing psychotic experiences. The genome-wide association study of any psychotic experience had a low single-nucleotide polymorphism–based heritability estimate (h2 = 1.71%; 95% CI, 1.02%-2.40%). CONCLUSIONS AND RELEVANCE: A large genetic association study of psychotic experiences from the population-based UK Biobank sample found support for a shared genetic liability between psychotic experiences and schizophrenia, major depressive disorder, bipolar disorder, and neurodevelopmental disorders.
Levels of activity are often affected in psychiatric disorders and can be core symptoms of illness. Advances in technology now allow the accurate assessment of activity levels but it remains unclear ...whether alterations in activity arise from shared risk factors for developing psychiatric disorders, such as genetics, or are better explained as consequences of the disorders and their associated factors. We aimed to examine objectively-measured physical activity in individuals with psychiatric disorders, and assess the role of genetic liability for psychiatric disorders on physical activity. Accelerometer data were available on 95,529 UK Biobank participants, including measures of overall mean activity and minutes per day of moderate activity, walking, sedentary activity, and sleep. Linear regressions measured associations between psychiatric diagnosis and activity levels, and polygenic risk scores (PRS) for psychiatric disorders and activity levels. Genetic correlations were calculated between psychiatric disorders and different types of activity. Having a diagnosis of schizophrenia, bipolar disorder, depression, or autism spectrum disorders (ASD) was associated with reduced overall activity compared to unaffected controls. In individuals without a psychiatric disorder, reduced overall activity levels were associated with PRS for schizophrenia, depression, and ASD. ADHD PRS was associated with increased overall activity. Genetic correlations were consistent with PRS findings. Variation in physical activity is an important feature across psychiatric disorders. Whilst levels of activity are associated with genetic liability to psychiatric disorders to a very limited extent, the substantial differences in activity levels in those with psychiatric disorders most likely arise as a consequences of disorder-related factors.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
MicroRNA (miRNA) are small non-coding RNA involved in post-transcriptional gene regulation. Given their known involvement in early neurodevelopment processes, we here sought to identify ...common genetic variants associated with altered miRNA expression in the prenatal human brain. We performed small RNA sequencing on brain tissue from 112 genome-wide genotyped fetuses from the second trimester of gestation, identifying high-confidence (false discovery rate < 0.05) expression quantitative trait loci for 30 mature miRNA. Integrating our findings with genome-wide association study data for brain-related disorders, we implicate increased prenatal expression of miR-1908-5p as a risk mechanism for bipolar disorder and find that predicted mRNA targets of miR-1908-5p that are expressed in the fetal brain are enriched for common variant genetic association with the condition. Extending these analyses to other brain-related traits, we find that common genetic variation associated with increased miR-1908-5p expression in fetal brain is additionally associated with depressive symptoms, irritability, increased right cerebellum exterior volume and increased sleep duration in the general population. Our findings provide support to the view that altered miRNA expression can influence susceptibility to neuropsychiatric illness and suggest an early neurodevelopmental risk mechanism for bipolar disorder.
There has been substantial progress in understanding the genetics of schizophrenia over the past 15 years. This has revealed a highly polygenic condition with the majority of the currently explained ...heritability coming from common alleles of small effect but with additional contributions from rare copy number and coding variants. Many specific genes and loci have been implicated that provide a firm basis upon which mechanistic research can proceed. These point to disturbances in neuronal, and particularly synaptic, functions that are not confined to a small number of brain regions and circuits. Genetic findings have also revealed the nature of schizophrenia's close relationship to other conditions, particularly bipolar disorder and childhood neurodevelopmental disorders, and provided an explanation for how common risk alleles persist in the population in the face of reduced fecundity. Current genomic approaches only potentially explain around 40% of heritability, but only a small proportion of this is attributable to robustly identified loci. The extreme polygenicity poses challenges for understanding biological mechanisms. The high degree of pleiotropy points to the need for more transdiagnostic research and the shortcomings of current diagnostic criteria as means of delineating biologically distinct strata. It also poses challenges for inferring causality in observational and experimental studies in both humans and model systems. Finally, the Eurocentric bias of genomic studies needs to be rectified to maximise benefits and ensure these are felt across diverse communities. Further advances are likely to come through the application of new and emerging technologies, such as whole-genome and long-read sequencing, to large and diverse samples. Substantive progress in biological understanding will require parallel advances in functional genomics and proteomics applied to the brain across developmental stages. For these efforts to succeed in identifying disease mechanisms and defining novel strata they will need to be combined with sufficiently granular phenotypic data.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Copy number variants (CNVs) have been shown to increase risk for physical anomalies, developmental, psychiatric and medical disorders. Some of them have been associated with changes in weight, ...height, and other physical traits. As most studies have been performed on children and young people, these effects of CNVs in middle-aged and older people are not well established. The UK Biobank recruited half a million adults who provided a variety of physical measurements. We called all CNVs from the Affymetrix microarrays and selected a set of 54 CNVs implicated as pathogenic (including their reciprocal deletions/duplications) and that were found in five or more persons. Linear regression analysis was used to establish their association with 16 physical traits relevant to human health.
396,725 participants of white British or Irish descent (excluding first-degree relatives) passed our quality control filters. Out of the 864 CNV/trait associations, 214 were significant at a false discovery rate of 0.1, most of them novel. Many of these traits increase risk for adverse health outcomes: e.g. increases in weight, waist-to-hip ratio, pulse rate and body fat composition. Deletions at 16p11.2, 16p12.1, NRXN1 and duplications at 16p13.11 and 22q11.2 produced the highest numbers of significant associations. Five CNVs produced average changes of over one standard deviation for the 16 traits, compared to controls: deletions at 16p11.2 and 22q11.2, and duplications at 3q29, the Williams-Beuren and Potocki-Lupski regions. CNVs at 1q21.1, 2q13, 16p11.2 and 16p11.2 distal, 16p12.1, 17p12 and 17q12 demonstrated one or more mirror image effects of deletions versus duplications.
Carriers of many CNVs should be monitored for physical traits that increase morbidity and mortality. Genes within these CNVs can give insights into biological processes and therapeutic interventions.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
IMPORTANCE: Bipolar disorder (BD) overlaps schizophrenia in its clinical presentation and genetic liability. Alternative approaches to patient stratification beyond current diagnostic categories are ...needed to understand the underlying disease processes and mechanisms. OBJECTIVE: To investigate the association between common-variant liability for schizophrenia, indexed by polygenic risk scores (PRSs), and psychotic presentations of BD. DESIGN, SETTING, AND PARTICIPANTS: This case-control study in the United Kingdom used multinomial logistic regression to estimate differential PRS associations across categories of cases and controls. Participants included in the final analyses were 4436 cases of BD from the Bipolar Disorder Research Network. These cases were compared with the genotypic data for 4976 cases of schizophrenia and 9012 controls from the Type 1 Diabetes Genetics Consortium study and the Generation Scotland study. Data were collected between January 1, 2000, and December 31, 2013. Data analysis was conducted from March 1, 2016, to February 28, 2017. EXPOSURES: Standardized PRSs, calculated using alleles with an association threshold of P < .05 in the second Psychiatric Genomics Consortium genome-wide association study of schizophrenia, were adjusted for the first 10 population principal components and genotyping platforms. MAIN OUTCOMES AND MEASURES: Multinomial logit models estimated PRS associations with BD stratified by Research Diagnostic Criteria subtypes of BD, by lifetime occurrence of psychosis, and by lifetime mood-incongruent psychotic features. Ordinal logistic regression examined PRS associations across levels of mood incongruence. Ratings were derived from the Schedules for Clinical Assessment in Neuropsychiatry interview and the Bipolar Affective Disorder Dimension Scale. RESULTS: Of the 4436 cases of BD, 2966 (67%) were female patients, and the mean (SD) age at interview was 46 12 years. Across clinical phenotypes, there was an exposure-response gradient, with the strongest PRS association for schizophrenia (risk ratio RR = 1.94; 95% CI, 1.86-2.01), followed by schizoaffective BD (RR = 1.37; 95% CI, 1.22-1.54), bipolar I disorder subtype (RR = 1.30; 95% CI, 1.24-1.36), and bipolar II disorder subtype (RR = 1.04; 95% CI, 0.97-1.11). Within BD cases, there was an effect gradient, indexed by the nature of psychosis. Prominent mood-incongruent psychotic features had the strongest association (RR = 1.46; 95% CI, 1.36-1.57), followed by mood-congruent psychosis (RR = 1.24; 95% CI, 1.17-1.33) and BD with no history of psychosis (RR = 1.09; 95% CI, 1.04-1.15). CONCLUSIONS AND RELEVANCE: For the first time to date, a study shows a polygenic-risk gradient across schizophrenia and BD, indexed by the occurrence and level of mood-incongruent psychotic symptoms.
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