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Genome-wide association studies (GWASs) have focused primarily on populations of European descent, but it is essential that diverse populations become better represented. Increasing diversity among study participants will advance our understanding of genetic architecture in all populations and ensure that genetic research is broadly applicable. To facilitate and promote research in multi-ancestry and admixed cohorts, we outline key methodological considerations and highlight opportunities, challenges, solutions, and areas in need of development. Despite the perception that analyzing genetic data from diverse populations is difficult, it is scientifically and ethically imperative, and there is an expanding analytical toolbox to do it well.
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Estudio de Asociación del Genoma Completo/métodos , Técnicas de Genotipaje/métodos , Genética Humana/métodos , Exactitud de los Datos , Variación Genética , Genética de Población/métodos , Genética de Población/normas , Estudio de Asociación del Genoma Completo/normas , Técnicas de Genotipaje/normas , Genética Humana/normas , Humanos , LinajeRESUMEN
BACKGROUND: Women experience major depression and post-traumatic stress disorder (PTSD) approximately twice as often as men. Estrogen is thought to contribute to sex differences in these disorders, and reduced estrogen is also known to be a key driver of menopause symptoms such as hot flashes. Moreover, estrogen is used to treat menopause symptoms. In order to test for potential shared genetic influences between menopause symptoms and psychiatric disorders, we conducted a genome-wide association study (GWAS) of estrogen medication use (as a proxy for menopause symptoms) in the UK Biobank. METHODS: The analysis included 232 993 women aged 39-71 in the UK Biobank. The outcome variable for genetic analyses was estrogen medication use, excluding women using hormonal contraceptives. Trans-ancestry GWAS meta-analyses were conducted along with genetic correlation analyses on the European ancestry GWAS results. Hormone usage was also tested for association with depression and PTSD. RESULTS: GWAS of estrogen medication use (compared to non-use) identified a locus in the TACR3 gene, which was previously linked to hot flashes in menopause [top rs77322567, odds ratio (OR) = 0.78, p = 7.7 × 10-15]. Genetic correlation analyses revealed shared genetic influences on menopause symptoms and depression (rg = 0.231, s.e.= 0.055, p = 2.8 × 10-5). Non-genetic analyses revealed higher psychiatric symptoms scores among women using estrogen medications. CONCLUSIONS: These results suggest that menopause symptoms have a complex genetic etiology which is partially shared with genetic influences on depression. Moreover, the TACR3 gene identified here has direct clinical relevance; antagonists for the neurokinin 3 receptor (coded for by TACR3) are effective treatments for hot flashes.
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Depresión , Sofocos , Femenino , Humanos , Masculino , Sofocos/genética , Depresión/genética , Estudio de Asociación del Genoma Completo , Menopausia/genética , Estrógenos/uso terapéuticoRESUMEN
Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human 'knockout' variants in protein-coding genes.
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Exoma/genética , Variación Genética/genética , Análisis Mutacional de ADN , Conjuntos de Datos como Asunto , Humanos , Fenotipo , Proteoma/genética , Enfermedades Raras/genética , Tamaño de la MuestraRESUMEN
Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [rg ], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (rg = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (rg = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (rg = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (rgs = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors.
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Trastornos de Alimentación y de la Ingestión de Alimentos/genética , Trastornos Relacionados con Sustancias/genética , Alcoholismo/genética , Trastorno Depresivo Mayor/genética , Estudio de Asociación del Genoma Completo , Humanos , Desequilibrio de Ligamiento , Fenotipo , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Esquizofrenia/genética , Tabaquismo/genéticaRESUMEN
PURPOSE OF REVIEW: This review highlights recent research on sex- and gender-related factors in the prevalence, symptom expression, and treatment of PTSD. Further discoveries about the underlying mechanisms of sex and gender effects have the potential to shape innovative directions for research. RECENT FINDINGS: The prevalence of PTSD is substantially higher among women, but women show a modest advantage with respect to treatment response. There is evidence of greater heritability among females. Women are more likely to experience sexual and intimate violence, childhood trauma exposure, and repeated trauma exposures. Specific characteristics of social contexts act as gender-linked risks for PTSD. Among individuals diagnosed with PTSD, men and women are similar in phenotypic expression. Though research has yet to fully account for the factors that explain sex- and gender- related effects on PTSD, emerging research suggests these effects occur across multiple levels. Shared risk factors for trauma exposure and PTSD merit further investigation. Both social and biological contexts merit investigation to understand sex-linked differences in heritability.
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Trastornos por Estrés Postraumático/genética , Trastornos por Estrés Postraumático/psicología , Experiencias Adversas de la Infancia/estadística & datos numéricos , Violencia Doméstica/estadística & datos numéricos , Humanos , Prevalencia , Factores de Riesgo , Caracteres Sexuales , Factores Sexuales , Trastornos por Estrés Postraumático/terapiaRESUMEN
PURPOSE OF REVIEW: The purpose of this review is to contextualize findings from the first 25 years of PTSD genetics research, focusing on the most robust findings and interpreting results in light of principles that have emerged from modern genetics studies. RECENT FINDINGS: Genome-wide association studies (GWAS) encompassing tens of thousands of participants enabled the first molecular genetic heritability and genetic correlation estimates for PTSD in 2017. In 2018, highly promising loci for PTSD were reported, including variants in and near the CAMKV, KANSL1, and TCF4 genes. Twin studies from 25 years ago established that PTSD is genetically influenced and foreshadowed the molecular genetic findings of today. Discoveries that were impossible with smaller studies have been achieved via collaborative/team-science efforts. Most promisingly, individual genomic loci offer entirely novel clues about PTSD etiology, providing the raw material for transformative discoveries, and the future of PTSD research is bright.
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Investigación Genética , Estudio de Asociación del Genoma Completo , Trastornos por Estrés Postraumático/genética , Predisposición Genética a la Enfermedad , Genómica , HumanosRESUMEN
The original version of this article contained an error in the title. The correct title should read "Robust Findings From 25 Years of PTSD Genetics Research" as shown above. The original article has been corrected.
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Prioritizing missense variants for further experimental investigation is a key challenge in current sequencing studies for exploring complex and Mendelian diseases. A large number of in silico tools have been employed for the task of pathogenicity prediction, including PolyPhen-2, SIFT, FatHMM, MutationTaster-2, MutationAssessor, Combined Annotation Dependent Depletion, LRT, phyloP, and GERP++, as well as optimized methods of combining tool scores, such as Condel and Logit. Due to the wealth of these methods, an important practical question to answer is which of these tools generalize best, that is, correctly predict the pathogenic character of new variants. We here demonstrate in a study of 10 tools on five datasets that such a comparative evaluation of these tools is hindered by two types of circularity: they arise due to (1) the same variants or (2) different variants from the same protein occurring both in the datasets used for training and for evaluation of these tools, which may lead to overly optimistic results. We show that comparative evaluations of predictors that do not address these types of circularity may erroneously conclude that circularity confounded tools are most accurate among all tools, and may even outperform optimized combinations of tools.
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Biología Computacional/métodos , Mutación Missense , Programas Informáticos , Conjuntos de Datos como Asunto , Humanos , Internet , Reproducibilidad de los Resultados , Navegador WebRESUMEN
OBJECTIVE: Prior investigations consistently indicate that personality pathology is a risk factor for recurrence of major depressive disorder (MDD). Lack of emipircal support, however, for the Diagnostic and Statistical Manual of Mental Disorders (DSM) Fourth Edition organization of Axis II disorders supports the investigation of empirically derived factors of personality pathology as predictors of recurrence. METHOD: A sample of 130 previously depressed emerging adults (80% female; aged 18 to 21 years) were assessed for personality disorder symptoms at baseline. Participants were then followed for 18 months to identify MDD recurrence during the first 2 years of college. RESULTS: Based on a previous factor analysis of DSM personality disorder criteria, eight personality pathology factors were examined as predictors of MDD recurrence. Survival analysis indicated that factors of interpersonal hypersensitivity, antisocial conduct, and social anxiety were associated with increased risk of MDD recurrence. CONCLUSIONS: These findings suggest that an empirically based approach to personality pathology organization may yield useful predictors of MDD recurrence during emerging adulthood.
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Trastorno Depresivo Mayor/diagnóstico , Trastornos de la Personalidad/diagnóstico , Adolescente , Comorbilidad , Trastorno Depresivo Mayor/prevención & control , Trastorno Depresivo Mayor/psicología , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Análisis Factorial , Femenino , Humanos , Masculino , Determinación de la Personalidad/estadística & datos numéricos , Trastornos de la Personalidad/prevención & control , Trastornos de la Personalidad/psicología , Psicometría/estadística & datos numéricos , Psicoterapia de Grupo , Recurrencia , Factores de Riesgo , Adulto JovenRESUMEN
Females are twice as likely to experience PTSD as compared to males. Although sex differences in prevalence are well-established, little is known about why such sex differences occur. Biological factors that vary with sex, including sex hormone production, may contribute to these differences. Considerable evidence links sex hormones, such as testosterone, to PTSD risk though less is known about the shared genetic underpinnings. The objective of the present study was to test for genetic relationships between testosterone and PTSD. To do so, we used summary statistics from large, publicly available genetic consortia to conduct linkage disequilibrium score regression to estimate the genetic correlations between PTSD and testosterone in males and females, and two-sample, bi-directional Mendelian randomization to examine potential causal relationships of testosterone on PTSD and the reverse. Heritability estimates of testosterone were significantly higher in males (0.17, SE = 0.02) than females (0.11, SE = 0.01; z = 2.46, p = 00.01). The correlation between testosterone and PTSD was negative in males (rg = -0.11, SE = 0.02, p = 6.7 x 10-6), but not significant in females (rg = 0.002, SE = 0.03, p = 0.95). MR analyses found no evidence of a causal effect of testosterone on PTSD or the reverse. Findings are consistent with phenotypic literature suggesting a relationship between testosterone and PTSD that may be sex-specific. This work provides early evidence of a relationship between testosterone and PTSD genotypically and suggests an avenue for future research that will enable a better understanding of disparities in PTSD.
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Trastornos por Estrés Postraumático , Testosterona , Humanos , Trastornos por Estrés Postraumático/genética , Trastornos por Estrés Postraumático/sangre , Masculino , Testosterona/sangre , Femenino , Caracteres Sexuales , Desequilibrio de Ligamiento , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Análisis de la Aleatorización MendelianaRESUMEN
Post-traumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 new). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (for example, GRIA1, GRM8 and CACNA1E), developmental, axon guidance and transcription factors (for example, FOXP2, EFNA5 and DCC), synaptic structure and function genes (for example, PCLO, NCAM1 and PDE4B) and endocrine or immune regulators (for example, ESR1, TRAF3 and TANK). Additional top genes influence stress, immune, fear and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation.
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Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Trastornos por Estrés Postraumático , Humanos , Trastornos por Estrés Postraumático/genética , Población Blanca/genética , Neurobiología , Sitios GenéticosRESUMEN
Functional impairment is one of the most enduring, intractable consequences of psychiatric disorders and is both familial and heritable. Previous studies have suggested that variation in functional impairment can be independent of symptom severity. Here we report the first genome-wide association study (GWAS) of functional impairment in the context of major mental illness. Participants of European-American descent (N = 2,246) were included from three large treatment studies of bipolar disorder (STEP-BD) (N = 765), major depressive disorder (STAR*D) (N = 1091), and schizophrenia (CATIE) (N = 390). At study entry, participants completed the SF-12, a widely used measure of health-related quality of life. We performed a GWAS and pathway analysis of the mental and physical components of health-related quality of life across diagnosis (â¼1.6 million single nucleotide polymorphisms), adjusting for psychiatric symptom severity. Psychiatric symptom severity was a significant predictor of functional impairment, but it accounted for less than one-third of the variance across disorders. After controlling for diagnostic category and symptom severity, the strongest evidence of genetic association was between variants in ADAMTS16 and physical functioning (P = 5.87 × 10(-8) ). Pathway analysis did not indicate significant enrichment after correction for gene clustering and multiple testing. This study illustrates a phenotypic framework for examining genetic contributions to functional impairment across psychiatric disorders.
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Trastorno Bipolar/genética , Trastorno Depresivo Mayor/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Resiliencia Psicológica , Esquizofrenia/genética , Proteínas ADAM/genética , Proteínas ADAMTS , Trastorno Bipolar/fisiopatología , Trastorno Depresivo Mayor/fisiopatología , Sitios Genéticos , Humanos , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo , Esquizofrenia/fisiopatologíaRESUMEN
Noncoding variants of presumed regulatory function contribute to the heritability of neuropsychiatric disease. A total of 2,221 noncoding variants connected to risk for ten neuropsychiatric disorders, including autism spectrum disorder, attention deficit hyperactivity disorder, bipolar disorder, borderline personality disorder, major depression, generalized anxiety disorder, panic disorder, post-traumatic stress disorder, obsessive-compulsive disorder and schizophrenia, were studied in developing human neural cells. Integrating epigenomic and transcriptomic data with massively parallel reporter assays identified differentially-active single-nucleotide variants (daSNVs) in specific neural cell types. Expression-gene mapping, network analyses and chromatin looping nominated candidate disease-relevant target genes modulated by these daSNVs. Follow-up integration of daSNV gene editing with clinical cohort analyses suggested that magnesium transport dysfunction may increase neuropsychiatric disease risk and indicated that common genetic pathomechanisms may mediate specific symptoms that are shared across multiple neuropsychiatric diseases.
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Trastorno por Déficit de Atención con Hiperactividad , Trastorno del Espectro Autista , Trastorno Bipolar , Trastorno Depresivo Mayor , Trastorno Obsesivo Compulsivo , Esquizofrenia , Humanos , Trastorno del Espectro Autista/genética , Trastorno Bipolar/genética , Esquizofrenia/genética , Trastorno Obsesivo Compulsivo/genética , Trastorno Obsesivo Compulsivo/psicología , Trastorno Depresivo Mayor/genética , Trastorno por Déficit de Atención con Hiperactividad/genéticaRESUMEN
Posttraumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 novel). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (e.g., GRIA1, GRM8, CACNA1E ), developmental, axon guidance, and transcription factors (e.g., FOXP2, EFNA5, DCC ), synaptic structure and function genes (e.g., PCLO, NCAM1, PDE4B ), and endocrine or immune regulators (e.g., ESR1, TRAF3, TANK ). Additional top genes influence stress, immune, fear, and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation.
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BACKGROUND: Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs). METHODS: A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms. RESULTS: GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program. CONCLUSIONS: Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods.
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Trastornos por Estrés Postraumático , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo/métodos , Humanos , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Trastornos por Estrés Postraumático/genéticaRESUMEN
BACKGROUND: The origin of sex differences in prevalence and presentation of neuropsychiatric and behavioral traits is largely unknown. Given established genetic contributions and correlations, we tested for a sex-differentiated genetic architecture within and between traits. METHODS: Using European ancestry genome-wide association summary statistics for 20 neuropsychiatric and behavioral traits, we tested for sex differences in single nucleotide polymorphism (SNP)-based heritability and genetic correlation (rg < 1). For each trait, we computed per-SNP z scores from sex-stratified regression coefficients and identified genes with sex-differentiated effects using a gene-based approach. We calculated correlation coefficients between z scores to test for shared sex-differentiated effects. Finally, we tested for sex differences in across-trait genetic correlations. RESULTS: We observed no consistent sex differences in SNP-based heritability. Between-sex, within-trait genetic correlations were high, although <1 for educational attainment and risk-taking behavior. We identified 4 genes with significant sex-differentiated effects across 3 traits. Several trait pairs shared sex-differentiated effects. The top genes with sex-differentiated effects were enriched for multiple gene sets, including neuron- and synapse-related sets. Most between-trait genetic correlation estimates were not significantly different between sexes, with exceptions (educational attainment and risk-taking behavior). CONCLUSIONS: Sex differences in the common autosomal genetic architecture of neuropsychiatric and behavioral phenotypes are small and polygenic and unlikely to fully account for observed sex-differentiated attributes. Larger sample sizes are needed to identify sex-differentiated effects for most traits. For well-powered studies, we identified genes with sex-differentiated effects that were enriched for neuron-related and other biological functions. This work motivates further investigation of genetic and environmental influences on sex differences.
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Estudio de Asociación del Genoma Completo , Herencia Multifactorial , Femenino , Humanos , Masculino , Fenotipo , Polimorfismo de Nucleótido Simple , Caracteres SexualesRESUMEN
The classical twin design (CTD) uses observed covariances from monozygotic and dizygotic twin pairs to infer the relative magnitudes of genetic and environmental causes of phenotypic variation. Despite its wide use, it is well known that the CTD can produce biased estimates if its stringent assumptions are not met. By modeling observed covariances of twins' relatives in addition to twins themselves, extended twin family designs (ETFDs) require less stringent assumptions, can estimate many more parameters of interest, and should produce less biased estimates than the CTD. However, ETFDs are more complicated to use and interpret, and by attempting to estimate a large number of parameters, the precision of parameter estimates may suffer. This paper is a formal investigation into a simple question: Is it worthwhile to use more complex models such as ETFDs in behavioral genetics? In particular, we compare the bias, precision, and accuracy of estimates from the CTD and three increasingly complex ETFDs. We find the CTD does a decent job of estimating broad sense heritability, but CTD estimates of shared environmental effects and the relative importance of additive versus non-additive genetic variance can be biased, sometimes wildly so. Increasingly complex ETFDs, on the other hand, are more accurate and less sensitive to assumptions than simpler models. We conclude that researchers interested in characterizing the environment or the makeup of genetic variation should use ETFDs when possible.
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Proyectos de Investigación , Gemelos Dicigóticos , Gemelos Monocigóticos , Sesgo , Simulación por Computador , Familia , Salud de la Familia , Femenino , Variación Genética , Humanos , Masculino , Modelos Genéticos , Modelos Estadísticos , Fenotipo , Reproducibilidad de los ResultadosRESUMEN
Genome-wide approaches including polygenic risk scores (PRSs) are now widely used in medical research; however, few studies have been conducted in low- and middle-income countries (LMICs), especially in South America. This study was designed to test the transferability of psychiatric PRSs to individuals with different ancestral and cultural backgrounds and to provide genome-wide association study (GWAS) results for psychiatric outcomes in this sample. The PrOMIS cohort (N = 3308) was recruited from prenatal care clinics at the Instituto Nacional Materno Perinatal (INMP) in Lima, Peru. Three major psychiatric outcomes (depression, PTSD, and suicidal ideation and/or self-harm) were scored by interviewers using valid Spanish questionnaires. Illumina Multi-Ethnic Global chip was used for genotyping. Standard procedures for PRSs and GWAS were used along with extra steps to rule out confounding due to ancestry. Depression PRSs significantly predicted depression, PTSD, and suicidal ideation/self-harm and explained up to 0.6% of phenotypic variation (minimum p = 3.9 × 10-6). The associations were robust to sensitivity analyses using more homogeneous subgroups of participants and alternative choices of principal components. Successful polygenic prediction of three psychiatric phenotypes in this Peruvian cohort suggests that genetic influences on depression, PTSD, and suicidal ideation/self-harm are at least partially shared across global populations. These PRS and GWAS results from this large Peruvian cohort advance genetic research (and the potential for improved treatments) for diverse global populations.
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Conducta Autodestructiva , Trastornos por Estrés Postraumático , Depresión/genética , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Perú , Embarazo , Conducta Autodestructiva/genética , Ideación SuicidaRESUMEN
STUDY OBJECTIVES: Sleep problems are common, serving as both a predictor and symptom of posttraumatic stress disorder (PTSD), with these bidirectional relationships well established in the literature. While both sleep phenotypes and PTSD are moderately heritable, there has been a paucity of investigation into potential genetic overlap between sleep and PTSD. Here, we estimate genetic correlations between multiple sleep phenotypes (including insomnia symptoms, sleep duration, daytime sleepiness, and chronotype) and PTSD, using results from the largest genome-wide association study (GWAS) to date of PTSD, as well as publicly available GWAS results for sleep phenotypes within UK Biobank data (23 variations, encompassing four main phenotypes). METHODS: Genetic correlations were estimated utilizing linkage disequilibrium score regression (LDSC), an approach that uses GWAS summary statistics to compute genetic correlations across traits, and Mendelian randomization (MR) analyses were conducted to follow up on significant correlations. RESULTS: Significant, moderate genetic correlations were found between insomnia symptoms (rg range 0.36-0.49), oversleeping (rg range 0.32-0.44), undersleeping (rg range 0.48-0.49), and PTSD. In contrast, there were mixed results for continuous sleep duration and daytime sleepiness phenotypes, and chronotype was not correlated with PTSD. MR analyses did not provide evidence for casual effects of sleep phenotypes on PTSD. CONCLUSION: Sleep phenotypes, particularly insomnia symptoms and extremes of sleep duration, have shared genetic etiology with PTSD, but causal relationships were not identified. This highlights the importance of further investigation into the overlapping influences on these phenotypes as sample sizes increase and new methods to investigate directionality and causality become available.
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Estudio de Asociación del Genoma Completo , Trastornos por Estrés Postraumático , Humanos , Biología Molecular , Fenotipo , Sueño/genética , Trastornos por Estrés Postraumático/genéticaRESUMEN
Alcohol use disorder (AUD) and posttraumatic stress disorder (PTSD) frequently co-occur, highlighting the importance of understanding the etiology of these comorbid conditions. Although AUD and PTSD are moderately heritable with modest overlap in genetic risk as estimated from family studies, there has been a paucity of work using molecular genetic data to estimate shared genetic effects on these conditions. This study used large-scale genomewide molecular data to examine shared genetic risk for AUD, specifically alcohol dependence (AD), and PTSD through cross-trait linkage disequilibrium (LD) score regression (LDSC; also known as LDSR). Summary statistics came from the Psychiatric Genomics Consortium (PGC) PTSD Workgroup Freeze 2 European ancestry (EA) participants (N = 174,659) and AD summary statistics in EA participants (N = 38,686) came from the PGC Substance Use Disorders (SUD) Workgroup. We performed LDSC to estimate genetic correlation between AD and PTSD using HapMap3 variants and LD scores from the 1000 Genomes project. A moderate, significant correlation was observed between AD and PTSD (rg = .35, p = .02), with sex differences identified through stratified analyses. Our results are the first to demonstrate evidence of a shared molecular genetic etiology for AD and PTSD. Further research is needed to better understand possible sex differences in shared heritability and extend these results to additional populations. (PsycInfo Database Record (c) 2020 APA, all rights reserved).