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Substance use disorders represent a significant public health concern with considerable socioeconomic implications worldwide. Twin and family-based studies have long established a heritable component underlying these disorders. In recent years, genome-wide association studies of large, broadly phenotyped samples have identified regions of the genome that harbour genetic risk variants associated with substance use disorders. These regions have enabled the discovery of putative causal genes and improved our understanding of genetic relationships among substance use disorders and other traits. Furthermore, the integration of these data with clinical information has yielded promising insights into how individuals respond to medications, allowing for the development of personalized treatment approaches based on an individual's genetic profile. This review article provides an overview of recent advances in the genetics of substance use disorders and demonstrates how genetic data may be used to reduce the burden of disease and improve public health outcomes.
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STUDY QUESTION: Which genetic factors regulate female propensity for giving birth to spontaneous dizygotic (DZ) twins? SUMMARY ANSWER: We identified four new loci, GNRH1, FSHR, ZFPM1, and IPO8, in addition to previously identified loci, FSHB and SMAD3. WHAT IS KNOWN ALREADY: The propensity to give birth to DZ twins runs in families. Earlier, we reported that FSHB and SMAD3 as associated with DZ twinning and female fertility measures. STUDY DESIGN, SIZE, DURATION: We conducted a genome-wide association meta-analysis (GWAMA) of mothers of spontaneous dizygotic (DZ) twins (8265 cases, 264â567 controls) and of independent DZ twin offspring (26â252 cases, 417â433 controls). PARTICIPANTS/MATERIALS, SETTING, METHODS: Over 700â000 mothers of DZ twins, twin individuals and singletons from large cohorts in Australia/New Zealand, Europe, and the USA were carefully screened to exclude twins born after use of ARTs. Genetic association analyses by cohort were followed by meta-analysis, phenome wide association studies (PheWAS), in silico and in vivo annotations, and Zebrafish functional validation. MAIN RESULTS AND THE ROLE OF CHANCE: This study enlarges the sample size considerably from previous efforts, finding four genome-wide significant loci, including two novel signals and a further two novel genes that are implicated by gene level enrichment analyses. The novel loci, GNRH1 and FSHR, have well-established roles in female reproduction whereas ZFPM1 and IPO8 have not previously been implicated in female fertility. We found significant genetic correlations with multiple aspects of female reproduction and body size as well as evidence for significant selection against DZ twinning during human evolution. The 26 top single nucleotide polymorphisms (SNPs) from our GWAMA in European-origin participants weakly predicted the crude twinning rates in 47 non-European populations (r = 0.23 between risk score and population prevalence, s.e. 0.11, 1-tail P = 0.058) indicating that genome-wide association studies (GWAS) are needed in African and Asian populations to explore the causes of their respectively high and low DZ twinning rates. In vivo functional tests in zebrafish for IPO8 validated its essential role in female, but not male, fertility. In most regions, risk SNPs linked to known expression quantitative trait loci (eQTLs). Top SNPs were associated with in vivo reproductive hormone levels with the top pathways including hormone ligand binding receptors and the ovulation cycle. LARGE SCALE DATA: The full DZT GWAS summary statistics will made available after publication through the GWAS catalog (https://www.ebi.ac.uk/gwas/). LIMITATIONS, REASONS FOR CAUTION: Our study only included European ancestry cohorts. Inclusion of data from Africa (with the highest twining rate) and Asia (with the lowest rate) would illuminate further the biology of twinning and female fertility. WIDER IMPLICATIONS OF THE FINDINGS: About one in 40 babies born in the world is a twin and there is much speculation on why twinning runs in families. We hope our results will inform investigations of ovarian response in new and existing ARTs and the causes of female infertility. STUDY FUNDING/COMPETING INTEREST(S): Support for the Netherlands Twin Register came from the Netherlands Organization for Scientific Research (NWO) and The Netherlands Organization for Health Research and Development (ZonMW) grants, 904-61-193, 480-04-004, 400-05-717, Addiction-31160008, 911-09-032, Biobanking and Biomolecular Resources Research Infrastructure (BBMRI.NL, 184.021.007), Royal Netherlands Academy of Science Professor Award (PAH/6635) to DIB, European Research Council (ERC-230374), Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06), the Avera Institute, Sioux Falls, South Dakota (USA) and the National Institutes of Health (NIH R01 HD042157-01A1) and the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health and Grand Opportunity grants 1RC2 MH089951. The QIMR Berghofer Medical Research Institute (QIMR) study was supported by grants from the National Health and Medical Research Council (NHMRC) of Australia (241944, 339462, 389927, 389875, 389891, 389892, 389938, 443036, 442915, 442981, 496610, 496739, 552485, 552498, 1050208, 1075175). L.Y. is funded by Australian Research Council (Grant number DE200100425). The Minnesota Center for Twin and Family Research (MCTFR) was supported in part by USPHS Grants from the National Institute on Alcohol Abuse and Alcoholism (AA09367 and AA11886) and the National Institute on Drug Abuse (DA05147, DA13240, and DA024417). The Women's Genome Health Study (WGHS) was funded by the National Heart, Lung, and Blood Institute (HL043851 and HL080467) and the National Cancer Institute (CA047988 and UM1CA182913), with support for genotyping provided by Amgen. Data collection in the Finnish Twin Registry has been supported by the Wellcome Trust Sanger Institute, the Broad Institute, ENGAGE-European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4-2007, grant agreement number 201413, National Institute of Alcohol Abuse and Alcoholism (grants AA-12502, AA-00145, AA-09203, AA15416, and K02AA018755) and the Academy of Finland (grants 100499, 205585, 118555, 141054, 264146, 308248, 312073 and 336823 to J. Kaprio). TwinsUK is funded by the Wellcome Trust, Medical Research Council, Versus Arthritis, European Union Horizon 2020, Chronic Disease Research Foundation (CDRF), Zoe Ltd and the National Institute for Health Research (NIHR) Clinical Research Network (CRN) and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. For NESDA, funding was obtained from the Netherlands Organization for Scientific Research (Geestkracht program grant 10000-1002), the Center for Medical Systems Biology (CSMB, NVVO Genomics), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL), VU University's Institutes for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam, University Medical Center Groningen, Leiden University Medical Center, National Institutes of Health (NIH, ROI D0042157-01A, MH081802, Grand Opportunity grants 1 RC2 Ml-1089951 and IRC2 MH089995). Part of the genotyping and analyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health. Computing was supported by BiG Grid, the Dutch e-Science Grid, which is financially supported by NWO. Work in the Del Bene lab was supported by the Programme Investissements d'Avenir IHU FOReSIGHT (ANR-18-IAHU-01). C.R. was supported by an EU Horizon 2020 Marie Sklodowska-Curie Action fellowship (H2020-MSCA-IF-2014 #661527). H.S. and K.S. are employees of deCODE Genetics/Amgen. The other authors declare no competing financial interests. TRIAL REGISTRATION NUMBER: N/A.
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Fertilidade , Estudo de Associação Genômica Ampla , Gemelação Dizigótica , Animais , Feminino , Humanos , Gravidez , Proteínas de Transporte/genética , Fertilidade/genética , Hormônios , Proteínas/genética , Estados Unidos , Peixe-Zebra/genéticaRESUMO
Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.
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Aprendizagem , Memória de Curto Prazo , Memória de Curto Prazo/fisiologia , Aprendizagem Verbal , Herança Multifatorial , EncéfaloRESUMO
Migraine is a highly common and debilitating disorder that often affects individuals in their most productive years of life. Previous studies have identified both genetic variants and brain morphometry differences associated with migraine risk. However, the relationship between migraine and brain morphometry has not been examined on a genetic level, and the causal nature of the association between brain structure and migraine risk has not been determined. Using the largest available genome-wide association studies to date, we examined the genome-wide genetic overlap between migraine and intracranial volume, as well as the regional volumes of nine subcortical brain structures. We further focused the identification and biological annotation of genetic overlap between migraine and each brain structure on specific regions of the genome shared between migraine and brain structure. Finally, we examined whether the size of any of the examined brain regions causally increased migraine risk using a Mendelian randomization approach. We observed a significant genome-wide negative genetic correlation between migraine risk and intracranial volume (rG = -0.11, P = 1 × 10-3) but not with any subcortical region. However, we identified jointly associated regional genomic overlap between migraine and every brain structure. Gene enrichment in these shared genomic regions pointed to possible links with neuronal signalling and vascular regulation. Finally, we provide evidence of a possible causal relationship between smaller total brain, hippocampal and ventral diencephalon volume and increased migraine risk, as well as a causal relationship between increased risk of migraine and a larger volume of the amygdala. We leveraged the power of large genome-wide association studies to show evidence of shared genetic pathways that jointly influence migraine risk and several brain structures, suggesting that altered brain morphometry in individuals with high migraine risk may be genetically mediated. Further interrogation of these results showed support for the neurovascular hypothesis of migraine aetiology and shed light on potentially viable therapeutic targets.
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Estudo de Associação Genômica Ampla , Transtornos de Enxaqueca , Tonsila do Cerebelo , Encéfalo/diagnóstico por imagem , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Hipocampo , Humanos , Transtornos de Enxaqueca/genéticaRESUMO
MOTIVATION: Genome-wide association studies have successfully identified multiple independent genetic loci that harbour variants associated with human traits and diseases, but the exact causal genes are largely unknown. Common genetic risk variants are enriched in non-protein-coding regions of the genome and often affect gene expression (expression quantitative trait loci, eQTL) in a tissue-specific manner. To address this challenge, we developed a methodological framework, E-MAGMA, which converts genome-wide association summary statistics into gene-level statistics by assigning risk variants to their putative genes based on tissue-specific eQTL information. RESULTS: We compared E-MAGMA to three eQTL informed gene-based approaches using simulated phenotype data. Phenotypes were simulated based on eQTL reference data using GCTA for all genes with at least one eQTL at chromosome 1. We performed 10 simulations per gene. The eQTL-h2 (i.e. the proportion of variation explained by the eQTLs) was set at 1%, 2% and 5%. We found E-MAGMA outperforms other gene-based approaches across a range of simulated parameters (e.g. the number of identified causal genes). When applied to genome-wide association summary statistics for five neuropsychiatric disorders, E-MAGMA identified more putative candidate causal genes compared to other eQTL-based approaches. By integrating tissue-specific eQTL information, these results show E-MAGMA will help to identify novel candidate causal genes from genome-wide association summary statistics and thereby improve the understanding of the biological basis of complex disorders. AVAILABILITY AND IMPLEMENTATION: A tutorial and input files are made available in a github repository: https://github.com/eskederks/eMAGMA-tutorial. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Major depression is a common and severe psychiatric disorder with a highly polygenic genetic architecture. Genome-wide association studies have successfully identified multiple independent genetic loci that harbour variants associated with major depression, but the exact causal genes and biological mechanisms are largely unknown. Tissue-specific network approaches may identify molecular mechanisms underlying major depression and provide a biological substrate for integrative analyses. We provide a framework for the identification of individual risk genes and gene co-expression networks using genome-wide association summary statistics and gene expression information across multiple human brain tissues and whole blood. We developed a novel gene-based method called eMAGMA that leverages tissue-specific eQTL information to identify 99 biologically plausible risk genes associated with major depression, of which 58 are novel. Among these novel associations is Complement Factor 4A (C4A), recently implicated in schizophrenia through its role in synaptic pruning during postnatal development. Major depression risk genes were enriched in gene co-expression modules in multiple brain tissues and the implicated gene modules contained genes involved in synaptic signalling, neuronal development, and cell transport pathways. Modules enriched with major depression signals were strongly preserved across brain tissues, but were weakly preserved in whole blood, highlighting the importance of using disease-relevant tissues in genetic studies of psychiatric traits. We identified tissue-specific genes and gene co-expression networks associated with major depression. Our novel analytical framework can be used to gain fundamental insights into the functioning of the nervous system in major depression and other brain-related traits.
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Transtorno Depressivo Maior/genética , Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes , Estudo de Associação Genômica Ampla/métodos , Química Encefálica , Complemento C4a/genética , Regulação da Expressão Gênica , Humanos , Especificidade de Órgãos , Locos de Características Quantitativas , Análise de Sequência de RNARESUMO
Genome-wide association studies have identified multiple genetic risk factors underlying susceptibility to substance use, however, the functional genes and biological mechanisms remain poorly understood. The discovery and characterization of risk genes can be facilitated by the integration of genome-wide association data and gene expression data across biologically relevant tissues and/or cell types to identify genes whose expression is altered by DNA sequence variation (expression quantitative trait loci; eQTLs). The integration of gene expression data can be extended to the study of genetic co-expression, under the biologically valid assumption that genes form co-expression networks to influence the manifestation of a disease or trait. Here, we integrate genome-wide association data with gene expression data from 13 brain tissues to identify candidate risk genes for 8 substance use phenotypes. We then test for the enrichment of candidate risk genes within tissue-specific gene co-expression networks to identify modules (or groups) of functionally related genes whose dysregulation is associated with variation in substance use. We identified eight gene modules in brain that were enriched with gene-based association signals for substance use phenotypes. For example, a single module of 40 co-expressed genes was enriched with gene-based associations for drinks per week and biological pathways involved in GABA synthesis, release, reuptake and degradation. Our study demonstrates the utility of eQTL and gene co-expression analysis to uncover novel biological mechanisms for substance use traits.
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Redes Reguladoras de Genes , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Transtornos Relacionados ao Uso de Substâncias/genética , Perfilação da Expressão Gênica , Testes Genéticos , Estudo de Associação Genômica Ampla , Humanos , Fenótipo , Transtornos Relacionados ao Uso de Substâncias/patologiaRESUMO
BACKGROUND: Despite established clinical associations among major depression (MD), alcohol dependence (AD), and alcohol consumption (AC), the nature of the causal relationship between them is not completely understood. We leveraged genome-wide data from the Psychiatric Genomics Consortium (PGC) and UK Biobank to test for the presence of shared genetic mechanisms and causal relationships among MD, AD, and AC. METHODS: Linkage disequilibrium score regression and Mendelian randomization (MR) were performed using genome-wide data from the PGC (MD: 135 458 cases and 344 901 controls; AD: 10 206 cases and 28 480 controls) and UK Biobank (AC-frequency: 438 308 individuals; AC-quantity: 307 098 individuals). RESULTS: Positive genetic correlation was observed between MD and AD (rgMD-AD = + 0.47, P = 6.6 × 10-10). AC-quantity showed positive genetic correlation with both AD (rgAD-AC quantity = + 0.75, P = 1.8 × 10-14) and MD (rgMD-AC quantity = + 0.14, P = 2.9 × 10-7), while there was negative correlation of AC-frequency with MD (rgMD-AC frequency = -0.17, P = 1.5 × 10-10) and a non-significant result with AD. MR analyses confirmed the presence of pleiotropy among these four traits. However, the MD-AD results reflect a mediated-pleiotropy mechanism (i.e. causal relationship) with an effect of MD on AD (beta = 0.28, P = 1.29 × 10-6). There was no evidence for reverse causation. CONCLUSION: This study supports a causal role for genetic liability of MD on AD based on genetic datasets including thousands of individuals. Understanding mechanisms underlying MD-AD comorbidity addresses important public health concerns and has the potential to facilitate prevention and intervention efforts.
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Alcoolismo/genética , Alcoolismo/psicologia , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/psicologia , Genômica , Adulto , Idoso , Alcoolismo/diagnóstico , Alcoolismo/epidemiologia , Causalidade , Estudos de Coortes , Comorbidade , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/epidemiologia , Feminino , Estudos de Associação Genética , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Reino UnidoRESUMO
BACKGROUND: Migraine is a common heritable neurovascular disorder typically characterised by episodic attacks of severe pulsating headache and nausea, often accompanied by visual, auditory or other sensory symptoms. Although genome-wide association studies have identified over 40 single nucleotide polymorphisms associated with migraine, there remains uncertainty about the casual genes involved in disease pathogenesis and how their function is regulated. RESULTS: We performed an epigenome-wide association study, quantifying genome-wide patterns of DNA methylation in 67 migraine cases and 67 controls with a matching age and sex distribution. Association analyses between migraine and methylation probe expression, after adjustment for cell type proportions, indicated an excess of small P values, but there was no significant single-probe association after correction for multiple testing (P < 1.09 × 10- 7). However, utilising a 1 kb sliding window approach to combine adjacent migraine-methylation association P values, we identified 62 independent differentially methylated regions (DMRs) underlying migraine (false discovery rate < 0.05). Migraine association signals were subtle but consistent in effect direction across the length of each DMR. Subsequent analyses showed that the migraine-associated DMRs were enriched in regulatory elements of the genome and were in close proximity to genes involved in solute transportation and haemostasis. CONCLUSIONS: This study represents the first genome-wide analysis of DNA methylation in migraine. We have identified DNA methylation in the whole blood of subjects associated with migraine, highlighting novel loci that provide insight into the biological pathways and mechanisms underlying migraine pathogenesis.
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Metilação de DNA , Epigenômica , Marcadores Genéticos , Genoma Humano , Transtornos de Enxaqueca/diagnóstico , Transtornos de Enxaqueca/genética , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Criança , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/sangue , Polimorfismo de Nucleotídeo Único , Sequências Reguladoras de Ácido Nucleico , Adulto JovemRESUMO
Background Typical migraine is a frequent, debilitating and painful headache disorder with an estimated heritability of about 50%. Although genome-wide association (GWA) studies have identified over 40 single nucleotide polymorphisms associated with migraine, further research is required to determine their biological role in migraine susceptibility. Therefore, we performed a study of genome-wide gene expression in a large sample of 83 migraine cases and 83 non-migraine controls to determine whether altered expression levels of genes and pathways could provide insights into the biological mechanisms underlying migraine. Methods We assessed whole blood gene expression data for 17994 expression probes measured using IlluminaHT-12 v4.0 BeadChips. Differential expression was assessed using multivariable logistic regression. Gene expression probes with a nominal p value < 0.05 were classified as differentially expressed. We identified modules of co-regulated genes and tested them for enrichment of differentially expressed genes and functional pathways using a false discovery rate <0.05. Results Association analyses between migraine and probe expression levels, adjusted for age and gender, revealed an excess of small p values, but there was no significant single-probe association after correction for multiple testing. Network analysis of pooled expression data identified 10 modules of co-expressed genes. One module harboured a significant number of differentially expressed genes and was strongly enriched with immune-inflammatory pathways, including multiple pathways expressed in microglial cells. Conclusions These data suggest immune-inflammatory pathways play an important role in the pathogenesis, manifestation, and/or progression of migraine in some patients. Furthermore, gene-expression associations are measurable in whole blood, suggesting the analysis of blood gene expression can inform our understanding of the biological mechanisms underlying migraine, identify biomarkers, and facilitate the discovery of novel pathways and thus determine new targets for drug therapy.
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Estudo de Associação Genômica Ampla , Inflamação/genética , Transtornos de Enxaqueca/genética , Transtornos de Enxaqueca/fisiopatologia , Adolescente , Adulto , Idoso , Criança , Feminino , Perfilação da Expressão Gênica , Redes Reguladoras de Genes/genética , Humanos , Inflamação/fisiopatologia , Masculino , Pessoa de Meia-Idade , TranscriptomaRESUMO
BACKGROUND: Global gene expression analysis may be used to obtain insights into the functional processes underlying migraine. However, there is a shortage of high-quality post-mortem brain tissue samples for genetic analysis. One approach is to use a more accessible tissue as a surrogate, such as peripheral blood. PURPOSE: Discuss the benefits and caveats of blood genomic profiling in migraine and its potential application in the development of biomarkers of migraine susceptibility and outcome. Demonstrate the utility of blood-based expression profiles in migraine by analysing pilot Illumina HT-12 expression data from 76 (38 case, 38 control) whole-blood samples. CONCLUSION: Current evidence suggests peripheral blood is a biologically valid substrate for genetic studies of migraine, and may be used to identify biomarkers and therapeutic pathways. Pilot blood gene expression data confirm that expression profiles significantly differ between migraine case and non-migraine control individuals.
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Biomarcadores/sangue , Perfilação da Expressão Gênica/métodos , Transtornos de Enxaqueca/sangue , Transtornos de Enxaqueca/genética , Predisposição Genética para Doença/genética , HumanosRESUMO
Retinol is a fat-soluble vitamin that plays an essential role in many biological processes throughout the human lifespan. Here, we perform the largest genome-wide association study (GWAS) of retinol to date in up to 22,274 participants. We identify eight common variant loci associated with retinol, as well as a rare-variant signal. An integrative gene prioritisation pipeline supports novel retinol-associated genes outside of the main retinol transport complex (RBP4:TTR) related to lipid biology, energy homoeostasis, and endocrine signalling. Genetic proxies of circulating retinol were then used to estimate causal relationships with almost 20,000 clinical phenotypes via a phenome-wide Mendelian randomisation study (MR-pheWAS). The MR-pheWAS suggests that retinol may exert causal effects on inflammation, adiposity, ocular measures, the microbiome, and MRI-derived brain phenotypes, amongst several others. Conversely, circulating retinol may be causally influenced by factors including lipids and serum creatinine. Finally, we demonstrate how a retinol polygenic score could identify individuals more likely to fall outside of the normative range of circulating retinol for a given age. In summary, this study provides a comprehensive evaluation of the genetics of circulating retinol, as well as revealing traits which should be prioritised for further investigation with respect to retinol related therapies or nutritional intervention.
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Estudo de Associação Genômica Ampla , Vitamina A , Humanos , Fenótipo , Obesidade , Adiposidade , Análise da Randomização Mendeliana/métodos , Proteínas Plasmáticas de Ligação ao RetinolRESUMO
Obsessive-compulsive disorder (OCD) affects ~1% of the population and exhibits a high SNP-heritability, yet previous genome-wide association studies (GWAS) have provided limited information on the genetic etiology and underlying biological mechanisms of the disorder. We conducted a GWAS meta-analysis combining 53,660 OCD cases and 2,044,417 controls from 28 European-ancestry cohorts revealing 30 independent genome-wide significant SNPs and a SNP-based heritability of 6.7%. Separate GWAS for clinical, biobank, comorbid, and self-report sub-groups found no evidence of sample ascertainment impacting our results. Functional and positional QTL gene-based approaches identified 249 significant candidate risk genes for OCD, of which 25 were identified as putatively causal, highlighting WDR6, DALRD3, CTNND1 and genes in the MHC region. Tissue and single-cell enrichment analyses highlighted hippocampal and cortical excitatory neurons, along with D1- and D2-type dopamine receptor-containing medium spiny neurons, as playing a role in OCD risk. OCD displayed significant genetic correlations with 65 out of 112 examined phenotypes. Notably, it showed positive genetic correlations with all included psychiatric phenotypes, in particular anxiety, depression, anorexia nervosa, and Tourette syndrome, and negative correlations with a subset of the included autoimmune disorders, educational attainment, and body mass index.. This study marks a significant step toward unraveling its genetic landscape and advances understanding of OCD genetics, providing a foundation for future interventions to address this debilitating disorder.
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BACKGROUND: Traumatic experiences are associated with increased risk for major depressive disorder (MDD). This study sought to determine the extent that trauma exposure, depression polygenic risk scores (PRS), and their interaction are associated with MDD and individual depression symptoms. METHODS: Data from 102,182 individuals from the large-scale UK Biobank population cohort was analysed. A series of regression analyses were conducted to estimate the association between trauma, depression PRS and 1) current depression, 2) lifetime MDD case-control status, 3) nine individual current depressive symptoms, and 4) thirteen individual symptoms experienced during a major depressive episode. Additive and multiplicative PRS-by-trauma interactions were also assessed. RESULTS: Trauma and depression PRS were significantly associated with both current depression and lifetime MDD. A positive, additive interaction effect was observed on depression, but multiplicative interactions were not significant. Trauma exposure and depression PRS were associated with specific patterns of depression symptoms; Trauma was associated with low self-esteem, suicidal ideation, and atypical (but not typical) neurovegetative symptoms. Additive interaction effects were observed on six out of nine current depressive symptoms. CONCLUSIONS: Trauma exposure and genetic predisposition to depression may lead to particular symptomatology, which may contribute to the extreme clinical heterogeneity observed in individuals with major depression.
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Transtorno Depressivo Maior , Humanos , Transtorno Depressivo Maior/diagnóstico , Depressão , Predisposição Genética para Doença , Fatores de Risco , Análise de Regressão , Estudo de Associação Genômica AmplaRESUMO
Anxiety disorders are a group of prevalent and heritable neuropsychiatric diseases. We previously conducted a genome-wide association study (GWAS) which identified genomic loci associated with anxiety; however, the biological consequences underlying the genetic associations are largely unknown. Integrating GWAS and functional genomic data may improve our understanding of the genetic effects on intermediate molecular phenotypes such as gene expression. This can provide an opportunity for the discovery of drug targets for anxiety via drug repurposing. We used the GWAS summary statistics to determine putative causal genes for anxiety using MAGMA and colocalization analyses. A transcriptome-wide association study was conducted to identify genes with differential genetically regulated levels of gene expression in human brain tissue. The genes were integrated with a large drug-gene expression database (Connectivity Map), discovering compounds that are predicted to "normalise" anxiety-associated expression changes. The study identified 64 putative causal genes associated with anxiety (35 genes upregulated; 29 genes downregulated). Drug mechanisms adrenergic receptor agonists, sigma receptor agonists, and glutamate receptor agonists gene targets were enriched in anxiety-associated genetic signal and exhibited an opposing effect on the anxiety-associated gene expression signature. The significance of the project demonstrated genetic links for novel drug candidates to potentially advance anxiety therapeutics.
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Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Reposicionamento de Medicamentos , Transcriptoma , Ansiedade/tratamento farmacológico , Ansiedade/genética , Transtornos de Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
There are universal concerns about youth health and recognition of the potential of school health services but little consensus internationally as to how these are best configured. Limited information about nursing services in New Zealand secondary schools, changing patterns of youth health needs and expanding roles for nurses in primary health care indicated a need to research school nursing services. This study found that within New Zealand schools there was wide variation in the types of health services and their funding; that nurses are well qualified and highly experienced, although some lack clinical supervision; that students present most commonly for sexual health and injuries or sickness; and that they choose school health services for accessibility and confidentiality. It concludes that one way forward would be to develop a national-level policy for nurse-led school health centers, with appropriate funding, that allows for local flexibility and includes a career pathway for school nurses.
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Educação em Saúde/organização & administração , Serviços de Saúde Escolar/organização & administração , Serviços de Enfermagem Escolar/organização & administração , Adolescente , Adulto , Criança , Intervalos de Confiança , Estudos Transversais , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Nova Zelândia , Papel do Profissional de Enfermagem , Razão de Chances , Formulação de Políticas , Fatores de Risco , População Rural , Fatores Socioeconômicos , Inquéritos e Questionários , Gestão da Qualidade Total , População Urbana , Adulto JovemRESUMO
Genome-wide association studies have identified hundreds of robust genetic associations underlying psychiatric disorders and provided important biological insights into disease onset and progression. There is optimism that genetic findings will pave the way to precision psychiatry by facilitating the development of more effective treatments and the identification of groups of patients that these treatments should be targeted toward. However, there are several challenges that must be addressed before genetic findings can be translated into the clinic. In this Perspective, we highlight ten challenges for the field of psychiatric genetics, focused on the robust and generalizable detection of genetic risk factors, improved definition and assessment of psychopathology and achieving better clinical indicators. We discuss recent advancements in the field that will improve the explanatory and predictive power of genetic data and ultimately contribute to improving the management and treatment of patients with a psychiatric disorder.
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Transtornos Mentais , Psiquiatria , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Transtornos Mentais/genéticaRESUMO
BACKGROUND: Global genetic correlation analysis has provided valuable insight into the shared genetic basis between psychiatric and substance use disorders. However, little is known about which regions disproportionately contribute to the global correlation. METHODS: We used Local Analysis of [co]Variant Annotation to calculate bivariate local genetic correlations across 2495 approximately equal-sized, semi-independent genomic regions for 20 psychiatric and substance use phenotypes. We performed a transcriptome-wide association study using expression weights from the prefrontal cortex to identify risk genes for each phenotype, followed by probabilistic fine-mapping to prioritize credible causal genes within each bivariate locus. RESULTS: We detected 80 significant (p < 2.08 × 10-6) bivariate local genetic correlations across 61 loci. The expression effect directions for risk genes within each bivariate locus were largely consistent with the local correlation coefficients, suggesting that genetically regulated gene expression may be used in the functional interpretation of local genetic correlations. Probabilistic fine-mapping identified several genes that may drive pleiotropic mechanisms for genetically correlated phenotypes. For example, we confirmed a local genetic correlation between schizophrenia and smoking behavior at 15q25 and prioritized PSMA4 as the most credible gene candidate underlying both phenotypes. CONCLUSIONS: Our study reveals previously unreported local bivariate genetic correlations between psychiatric and substance use phenotypes, which we fine-mapped to identify shared credible causal genes underlying genetically correlated phenotypes.
Assuntos
Esquizofrenia , Transtornos Relacionados ao Uso de Substâncias , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genômica , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/genética , Transtornos Relacionados ao Uso de Substâncias/genéticaRESUMO
Genome-wide association studies (GWASs) have identified thousands of risk loci for psychiatric and substance use phenotypes, however the biological consequences of these loci remain largely unknown. We performed a transcriptome-wide association study of 10 psychiatric disorders and 6 substance use phenotypes (GWAS sample size range, N = 9725-807,553) using expression quantitative trait loci data from 532 prefrontal cortex samples. We estimated the correlation of genetically regulated expression between phenotype pairs, and compared the results with the genetic correlations. We identified 393 genes with at least one significant phenotype association, comprising 458 significant associations across 16 phenotypes. Overall, the transcriptomic correlations for phenotype pairs were significantly higher than the respective genetic correlations. For example, attention deficit hyperactivity disorder and autism spectrum disorder, both childhood developmental disorders, had significantly higher transcriptomic correlation (r = 0.84) than genetic correlation (r = 0.35). Finally, we tested the enrichment of phenotype-associated genes in gene co-expression networks built from human prefrontal cortex samples. Phenotype-associated genes were enriched in multiple gene co-expression modules and the implicated modules contained genes involved in mRNA splicing and glutamatergic receptors, among others. Together, our results highlight the utility of gene expression data in the understanding of functional gene mechanisms underlying psychiatric disorders and substance use phenotypes.