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PURPOSE: Coding mutations in the Transthyretin (TTR) gene cause a hereditary form of amyloidosis characterized by a complex genotype-phenotype correlation with limited information regarding differences among worldwide populations. METHODS: We compared 676 diverse individuals carrying TTR amyloidogenic mutations (rs138065384, Phe44Leu; rs730881165, Ala81Thr; rs121918074, His90Asn; rs76992529, Val122Ile) to 12,430 non-carriers matched by age, sex, and genetically-inferred ancestry to assess their clinical presentations across 1,693 outcomes derived from electronic health records in UK biobank. RESULTS: In individuals of African descent (AFR), Val122Ile mutation was linked to multiple outcomes related to the circulatory system (fold-enrichment = 2.96, p = 0.002) with the strongest associations being cardiac congenital anomalies (phecode 747.1, p = 0.003), endocarditis (phecode 420.3, p = 0.006), and cardiomyopathy (phecode 425, p = 0.007). In individuals of Central-South Asian descent (CSA), His90Asn mutation was associated with dermatologic outcomes (fold-enrichment = 28, p = 0.001). The same TTR mutation was linked to neoplasms in European-descent individuals (EUR, fold-enrichment = 3.09, p = 0.003). In EUR, Ala81Thr showed multiple associations with respiratory outcomes related (fold-enrichment = 3.61, p = 0.002), but the strongest association was with atrioventricular block (phecode 426.2, p = 2.81 × 10- 4). Additionally, the same mutation in East Asians (EAS) showed associations with endocrine-metabolic traits (fold-enrichment = 4.47, p = 0.003). In the cross-ancestry meta-analysis, Val122Ile mutation was associated with peripheral nerve disorders (phecode 351, p = 0.004) in addition to cardiac congenital anomalies (fold-enrichment = 6.94, p = 0.003). CONCLUSIONS: Overall, these findings highlight that TTR amyloidogenic mutations present ancestry-specific and ancestry-convergent associations related to a range of health domains. This supports the need to increase awareness regarding the range of outcomes associated with TTR mutations across worldwide populations to reduce misdiagnosis and delayed diagnosis of TTR-related amyloidosis.
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Amiloidose , Pré-Albumina , Humanos , Pré-Albumina/genética , Mutação , Amiloidose/diagnóstico , Amiloidose/genética , Fenótipo , Genética PopulacionalRESUMO
Individuals suffering from chronic pain develop substance use disorders (SUDs) more often than others. Understanding the shared genetic influences underlying the comorbidity between chronic pain and SUDs will lead to a greater understanding of their biology. Genome-wide association statistics were obtained from the UK Biobank for multisite chronic pain (MCP, Neffective = 387,649) and from the Million Veteran Program and the Psychiatric Genomics Consortium meta-analyses for alcohol use disorder (AUD, Neffective = 296,974), cannabis use disorder (CanUD, Neffective = 161,053), opioid use disorder (OUD, Neffective = 57,120), and problematic tobacco use (PTU, Neffective = 270,120). SNP-based heritability was estimated for each of the traits and genetic correlation (rg) analyses were performed to assess MCP-SUD pleiotropy. Bidirectional Mendelian Randomization analyses evaluated possible causal relationships. Finally, to identify and characterize individual loci, we performed a genome-wide pleiotropy analysis and a brain-wide analysis using imaging phenotypes available from the UK Biobank. MCP was positively genetically correlated with AUD (rg = 0.26, p = 7.55 × 10-18), CanUD (rg = 0.37, p = 8.21 × 10-37), OUD (rg = 0.20, p = 1.50 × 10-3), and PTU (rg = 0.29, p = 8.53 × 10-12). Although the MR analyses supported bi-directional relationships, MCP had larger effects on AUD (pain-exposure: beta = 0.18, p = 8.21 × 10-4; pain-outcome: beta = 0.07, p = 0.018), CanUD (pain-exposure: beta = 0.58, p = 2.70 × 10-6; pain-outcome: beta = 0.05, p = 0.014) and PTU (pain-exposure: beta = 0.43, p = 4.16 × 10-8; pain-outcome: beta = 0.09, p = 3.05 × 10-6) than the reverse. The genome-wide analysis identified two SNPs pleiotropic between MCP and all SUD investigated: IHO1 rs7652746 (ppleiotropy = 2.69 × 10-8), and CADM2 rs1248857 (ppleiotropy = 1.98 × 10-5). In the brain-wide analysis, rs7652746 was associated with multiple cerebellum and amygdala imaging phenotypes. When analyzing MCP pleiotropy with each SUD separately, we found 25, 22, and 4 pleiotropic variants for AUD, CanUD, and OUD, respectively. To our knowledge, this is the first large-scale study to provide evidence of potential causal relationships and shared genetic mechanisms underlying MCP-SUD comorbidity.
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Hearing difficulty (HD) is one of the major health burdens in older adults. While aging-related changes in the peripheral auditory system play an important role, genetic variation associated with brain structure and function could also be involved in HD predisposition. We analyzed a large-scale HD genome-wide association study (GWAS; Ntotal = 501,825, 56% females) and GWAS data related to 3,935 brain imaging-derived phenotypes (IDPs) assessed in up to 33,224 individuals (52% females) using multiple magnetic resonance imaging modalities. To investigate HD pleiotropy with brain structure and function, we conducted genetic correlation, latent causal variable, Mendelian randomization, and multivariable generalized linear regression analyses. Additionally, we performed local genetic correlation and multi-trait colocalization analyses to identify genomic regions and loci implicated in the pleiotropic mechanisms shared between HD and brain IDPs. We observed a widespread genetic correlation of HD with 120 IDPs in females, 89 IDPs in males, and 171 IDPs in the sex-combined analysis. The latent causal variable analysis showed that some of these genetic correlations could be due to cause-effect relationships. For seven correlations, the causal effects were also confirmed by the Mendelian randomization approach: vessel volumeâHD in the sex-combined analysis; hippocampus volumeâHD, cerebellum grey matter volumeâHD, primary visual cortex volumeâHD, and HDâfluctuation amplitudes of node 46 in resting-state functional MRI dimensionality 100 in females; global mean thicknessâHD and HDâmean orientation dispersion index in superior corona radiata in males. The local genetic correlation analysis identified 13 pleiotropic regions between HD and these seven IDPs. We also observed a colocalization signal for the rs13026575 variant between HD, primary visual cortex volume, and SPTBN1 transcriptomic regulation in females. Brain structure and function may have a role in the sex differences in HD predisposition via possible cause-effect relationships and shared regulatory mechanisms.
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BACKGROUND: There is still a limited understanding of the dynamics contributing to the comorbidity of COVID-19 and anxiety outcomes. METHODS: To dissect the pleiotropic mechanisms contributing to COVID-19/anxiety comorbidity, we used genome-wide data from UK Biobank (up to 420,531 participants), FinnGen Project (up to 329,077 participants), Million Veteran Program (175,163 participants), and COVID-19 Host Genetics Initiative (up to 122,616 cases and 2,475,240 controls). Specifically, we assessed global and local genetic correlation and genetically inferred effects linking COVID-19 outcomes (infection, hospitalization, and severe respiratory symptoms) to anxiety disorders and symptoms. RESULTS: We observed a strong genetic correlation of anxiety disorder with COVID-19 positive status (rg = 0.35, p = 2×10-4) and COVID-19 hospitalization (rg = 0.31, p = 7.2×10-4). Among anxiety symptoms, "Tense, sore, or aching muscles during worst period of anxiety" was genetically correlated with COVID-19 positive status (rg = 0.33, p = 0.001), while "Frequent trouble falling or staying asleep during worst period of anxiety" was genetically correlated with COVID-19 hospitalization (rg = 0.24, p = 0.004). Through a latent causal variable analysis, we observed that COVID-19 outcomes have statistically significant genetic causality proportion (gcp) on anxiety symptoms (e.g., COVID-19 positive statusâ"Recent easy annoyance or irritability" âgcpâ = 0.18, p = 6.72×10-17). Conversely, anxiety disorders appear to have a possible causal effect on COVID-19 (âgcpâ = 0.38, p = 3.17×10-9). Additionally, we also identified multiple loci with evidence of local genetic correlation between anxiety and COVID-19. These appear to be related to genetic effects shared with lung function, brain morphology, alcohol and tobacco use, and hematologic parameters. CONCLUSIONS: This study provided insights into the pleiotropic mechanisms linking COVID-19 and anxiety outcomes, suggesting differences between dynamics related to anxiety disorders and those related to anxiety symptoms.
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COVID-19 , Humanos , Transtornos de Ansiedade/epidemiologia , Transtornos de Ansiedade/genética , Ansiedade/epidemiologia , Ansiedade/genética , Dor , Etanol , Estudo de Associação Genômica AmplaRESUMO
BACKGROUND: Accumulating data suggest that the structure of posttraumatic stress disorder (PTSD) symptoms may be more nuanced than proposed by prevailing nosological models. Emerging theory further suggests that an 8-factor model with separate internally- (e.g., flashbacks) and externally- (e.g., trauma cue-related emotional reactivity) generated intrusive symptoms may best represent PTSD symptoms. To date, however, scarce research has evaluated the fit of this model and whether index traumas are differentially associated with it in populations at high risk for trauma exposure, such as military veterans. METHODS: Data were analyzed from a nationally representative sample of 3847 trauma-exposed U.S. veterans who participated in the National Health and Resilience in Veterans Study. Confirmatory factor analyses were conducted to evaluate the fit of a novel 8-factor model of PTSD symptoms relative to 4-factor DSM-5 and empirically-supported 7-factor hybrid models. RESULTS: The 8-factor model fit the data significantly better than the 7-factor hybrid and 4-factor DSM-5 models. Combat exposure and harming others were more strongly associated with internally-generated intrusions, while interpersonal violence and disaster/accident showed stronger significant associations with externally-generated intrusions. LIMITATIONS: The 8-factor model requires validation in non-veteran and more diverse trauma-exposed populations, as well as with clinician-administered interviews. CONCLUSIONS: Results of this study provide support for a novel 8-factor model of PTSD symptoms that is characterized by separate internally- and externally-generated intrusions. They also suggest that certain index traumas may lead to differential expression of these symptoms.
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Transtornos de Estresse Pós-Traumáticos , Veteranos , Humanos , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Transtornos de Estresse Pós-Traumáticos/diagnóstico , Emoções , Manual Diagnóstico e Estatístico de Transtornos Mentais , Análise FatorialRESUMO
BACKGROUND AND HYPOTHESIS: Individuals with schizophrenia (SCZ) suffer from comorbidities that substantially reduce their life expectancy. Socioeconomic inequalities could contribute to many of the negative health outcomes associated with SCZ. STUDY DESIGN: We investigated genome-wide datasets related to SCZ (52 017 cases and 75 889 controls) from the Psychiatric Genomics Consortium, household income (HI; Nâ =â 361 687) from UK Biobank, and 2202 medical endpoints assessed in up to 342 499 FinnGen participants. A phenome-wide genetic correlation analysis of SCZ and HI was performed, also assessing whether SCZ genetic correlations were influenced by the HI effect on SCZ. Additionally, SCZ and HI direct effects on medical endpoints were estimated using multivariable Mendelian randomization (MR). STUDY RESULTS: SCZ and HI showed overlapping genetic correlations with 70 traits (Pâ <â 2.89â ×â 10-5), including mental health, substance use, gastrointestinal illnesses, reproductive outcomes, liver diseases, respiratory problems, and musculoskeletal phenotypes. SCZ genetic correlations with these traits were not affected by the HI effect on SCZ. Considering Bonferroni multiple testing correction (Pâ <â 7.14â ×â 10-4), MR analysis indicated that SCZ and HI may affect medical abortion (SCZ ORâ =â 1.07; HI ORâ =â 0.78), panic disorder (SCZ ORâ =â 1.20; HI ORâ =â 0.60), personality disorders (SCZ ORâ =â 1.31; HI ORâ =â 0.67), substance use (SCZ ORâ =â 1.2; HI ORâ =â 0.68), and adjustment disorders (SCZ ORâ =â 1.18; HI ORâ =â 0.78). Multivariable MR analysis confirmed that SCZ effects on these outcomes were independent of HI. CONCLUSIONS: The effect of SCZ genetic liability on mental and physical health may not be strongly affected by socioeconomic differences. This suggests that SCZ-specific strategies are needed to reduce negative health outcomes affecting patients and high-risk individuals.
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To investigate the pleiotropic mechanisms linking brain structure and function to alcohol drinking and tobacco smoking, we integrated genome-wide data generated by the GWAS and Sequencing Consortium of Alcohol and Nicotine use (GSCAN; up to 805,431 participants) with information related to 3,935 brain imaging-derived phenotypes (IDPs) available from UK Biobank (N=33,224). We observed global genetic correlation of smoking behaviors with white matter hyperintensities, the morphology of the superior longitudinal fasciculus, and the mean thickness of pole-occipital. With respect to the latter brain IDP, we identified a local genetic correlation with age at which the individual began smoking regularly (hg38 chr2:35,895,678-36,640,246: rho=1, p=1.01×10 -5 ). This region has been previously associated with smoking initiation, educational attainment, chronotype, and cortical thickness. Our genetically informed causal inference analysis using both latent causal variable approach and Mendelian randomization linked the activity of prefrontal and premotor cortex and that of superior and inferior precentral sulci, and cingulate sulci to the number of alcoholic drinks per week (genetic causality proportion, gcp=0.38, p=8.9×10 -4 , rho=-0.18±0.07; inverse variance weighting, IVW beta=-0.04, 95%CI=-0.07 - -0.01). This relationship could be related to the role of these brain regions in the modulation of reward-seeking motivation and the processing of social cues. Overall, our brain-wide investigation highlighted that different pleiotropic mechanisms likely contribute to the relationship of brain structure and function with alcohol drinking and tobacco smoking, suggesting decision-making activities and chemosensory processing as modulators of propensity towards alcohol and tobacco consumption.
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Bipolar disorder (BD) and schizophrenia (SZ) are associated with higher odds of suicide attempt (SA). In this study, we aimed to explore the effect of BD and SZ genetic liabilities on SA, also considering the contribution of behavioral traits, socioeconomic factors, and substance use disorders. Leveraging large-scale genome-wide association data from the Psychiatric Genomics Consortium (PGC) and the UK Biobank (UKB), we conducted a two-sample Mendelian randomization (MR) analysis to evaluate the putative causal effect of BD (41,917 cases, 371,549 controls) and SZ (53,386 cases, 77,258 controls) on SA (26,590 cases, 492,022 controls). Then, we assessed the putative causal effect of BD and SZ on behavioral traits, socioeconomic factors, and substance use disorders. Considering the associations identified, we evaluated the direct causal effect of behavioral traits, socioeconomic factors, and substance use disorders on SA using a multivariable MR approach. The genetic liabilities to BD and SZ were associated with higher odds of SA (BD odds ratio (OR) = 1.24, p = 3.88 × 10-12; SZ OR = 1.09, p = 2.44 × 10-20). However, while the effect of mental distress (OR = 1.17, p = 1.02 × 10-4) and risk-taking (OR = 1.52, p = 0.028) on SA was independent of SZ genetic liability, the BD-SA relationship appeared to account for the effect of these risk factors. Similarly, the association with loneliness on SA was null after accounting for the effect of SZ genetic liability. These findings highlight the complex interplay between genetic risk of psychiatric disorders and behavioral traits in the context of SA, suggesting the need for a comprehensive mental health assessment for high-risk individuals.
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Transtorno Bipolar , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Esquizofrenia , Tentativa de Suicídio , Humanos , Esquizofrenia/genética , Esquizofrenia/epidemiologia , Transtorno Bipolar/genética , Transtorno Bipolar/epidemiologia , Transtorno Bipolar/psicologia , Tentativa de Suicídio/estatística & dados numéricos , Tentativa de Suicídio/psicologia , Predisposição Genética para Doença/genética , Transtornos Relacionados ao Uso de Substâncias/genética , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Transtornos Relacionados ao Uso de Substâncias/psicologia , Fatores Socioeconômicos , Masculino , Polimorfismo de Nucleotídeo Único , FemininoRESUMO
Emerging evidence indicates that more nuanced models of posttraumatic stress disorder (PTSD) may better capture the condition's symptom structure. Recent theoretical and empirical work suggest that an 8-factor model of PTSD with separate internally- (e.g. flashbacks) and externally- (e.g. trauma-cue related physiological reactivity) generated intrusive symptom clusters may advance understanding of PTSD and its treatment and course. However, the model's functional and clinical significance still requires evaluation. To this end, we analyzed data from the National Health and Resilience in Veterans Study, a nationally representative sample of 3847 trauma-exposed U.S. military veterans. Multivariable regressions were performed to assess the relationship between the 8 PTSD symptom clusters, assessed using the PTSD Checklist for DSM-5, and clinical and functional measures. Results revealed that externally-generated intrusions were associated with higher odds of current depression and anxiety and worse mental, cognitive, and psychosocial functioning. Anhedonia (e.g., loss of interest in enjoyable activities) symptoms were associated with all the correlates tested, while negative affect (e.g., having strong negative feelings such as fear) symptoms were associated with all measures except depression. Avoidance symptoms were associated with lower odds of current anxiety while externalizing behavior symptoms were linked to higher odds of suicidal ideation. Anxious arousal symptoms were associated with lower odds of suicidal ideation but higher odds of PTSD-related impairment/distress, while dysphoric arousal symptoms were associated with higher odds of current depression, PTSD-related impairment/distress and worse mental and cognitive functioning. Results suggest that a more nuanced 8-factor model of PTSD symptoms may help inform understanding of the clinical and functional correlates of this multi-faceted disorder.
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Resiliência Psicológica , Transtornos de Estresse Pós-Traumáticos , Veteranos , Humanos , Veteranos/psicologia , Transtornos de Estresse Pós-Traumáticos/psicologia , Síndrome , Ansiedade/diagnósticoRESUMO
To investigate assortative mating (AM), participation bias and socioeconomic status (SES) with respect to the genetics of behavioural and psychiatric traits, we estimated AM signatures using gametic phase disequilibrium and within-spouses and within-siblings polygenic risk score correlation analyses, also performing a SES conditional analysis. The cross-method meta-analysis identified AM genetic signatures for multiple alcohol-related phenotypes, bipolar disorder, major depressive disorder, schizophrenia and Tourette syndrome. Here, after SES conditioning, we observed changes in the AM genetic signatures for maximum habitual alcohol intake, frequency of drinking alcohol and Tourette syndrome. We also observed significant gametic phase disequilibrium differences between UK Biobank mental health questionnaire responders versus non-responders for major depressive disorder and alcohol use disorder. These results highlight the impact of AM, participation bias and SES on the polygenic risk of behavioural and psychiatric traits, particularly in alcohol-related traits.
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Herança Multifatorial , Classe Social , Humanos , Herança Multifatorial/genética , Masculino , Feminino , Consumo de Bebidas Alcoólicas/genética , Consumo de Bebidas Alcoólicas/epidemiologia , Transtornos Mentais/genética , Transtornos Mentais/epidemiologia , Predisposição Genética para DoençaRESUMO
Hair colour variation is influenced by hundreds of positions across the human genome but this genetic contribution has only been narrowly explored. Genome-wide association studies identified single nucleotide polymorphisms (SNPs) influencing hair colour but the biology underlying these associations is challenging to interpret. We report 16 tandem repeats (TRs) with effects on different models of hair colour plus two TRs associated with hair colour in diverse ancestry groups. Several of these TRs expand or contract amino acid coding regions of their localized protein such that structure, and by extension function, may be altered. We also demonstrate that independent of SNP variation, these TRs can be used to great an additive polygenic score that predicts darker hair colour. This work adds to the growing body of evidence regarding TR influence on human traits with relatively large and independent effects relative to surrounding SNP variation.
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INTRODUCTION: While higher socioeconomic factors (SEF) and cognitive performance (CP) have been associated with reduced Alzheimer's disease (AD) risk, recent evidence highlighted that these factors may have opposite effects on family history of AD (FHAD). METHODS: Leveraging data from the UK Biobank (N=448,100) and the All of Us Research Program (N=240,319), we applied generalized linear regression models, polygenic risk scoring (PRS), and one-sample Mendelian randomization (MR) to test the sex-specific SEF and CP associations with AD and FHAD. RESULTS: Observational and genetically informed analyses highlighted that higher SEF and CP were associated with reduced AD and sibling-FHAD, while these factors were associated with increased parent-FHAD. We also observed that population minorities may present different patterns with respect to sibling-FHAD vs. parent-FHAD. Sex differences in FHAD associations were identified in ancestry-specific and SEF PRS and MR results. DISCUSSION: This study contributes to understanding the sex-specific relationships linking SEF and CP to FHAD, highlighting the potential role of reporting, recall, and surviving-related dynamics.
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Background and Aims: Experiencing a traumatic event may lead to Posttraumatic Stress Disorder (PTSD), including symptoms such as flashbacks and hyperarousal. Individuals suffering from PTSD are at increased risk of cardiovascular disease (CVD), but it is unclear why. This study assesses shared genetic liability and potential causal pathways between PTSD and CVD. Methods: We leveraged summary-level data of genome-wide association studies (PTSD: N= 1,222,882; atrial fibrillation (AF): N=482,409; coronary artery disease (CAD): N=1,165,690; hypertension: N=458,554; heart failure (HF): N=977,323). First, we estimated genetic correlations and utilized genomic structural equation modeling to identify a common genetic factor for PTSD and CVD. Next, we assessed biological, behavioural, and psychosocial factors as potential mediators. Finally, we employed multivariable Mendelian randomization to examine causal pathways between PTSD and CVD, incorporating the same potential mediators. Results: Significant genetic correlations were found between PTSD and CAD, HT, and HF (rg =0.21-0.32, p≤ 3.08 · 10-16), but not between PTSD and AF. Insomnia, smoking, alcohol dependence, waist-to-hip ratio, and inflammation (IL6, C-reactive protein) partly mediated these associations. Mendelian randomization indicated that PTSD causally increases CAD (IVW OR=1.53, 95% CIs=1.19-1.96, p=0.001), HF (OR=1.44, CIs=1.08-1.92, p=0.012), and to a lesser degree hypertension (OR=1.25, CIs=1.05-1.49, p=0.012). While insomnia, smoking, alcohol, and inflammation were important mediators, independent causal effects also remained. Conclusions: In addition to shared genetic liability between PTSD and CVD, we present strong evidence for causal effects of PTSD on CVD. Crucially, we implicate specific lifestyle and biological mediators (insomnia, substance use, inflammation) which has important implications for interventions to prevent CVD in PTSD patients.
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What distinguishes vulnerability and resilience to posttraumatic stress disorder (PTSD) remains unclear. Levering traumatic experiences reporting, genetic data, and electronic health records (EHR), we investigated and predicted the clinical comorbidities (co-phenome) of PTSD vulnerability and resilience in the UK Biobank (UKB) and All of Us Research Program (AoU), respectively. In 60,354 trauma-exposed UKB participants, we defined PTSD vulnerability and resilience considering PTSD symptoms, trauma burden, and polygenic risk scores. EHR-based phenome-wide association studies (PheWAS) were conducted to dissect the co-phenomes of PTSD vulnerability and resilience. Significant diagnostic endpoints were applied as weights, yielding a phenotypic risk score (PheRS) to conduct PheWAS of PTSD vulnerability and resilience PheRS in up to 95,761 AoU participants. EHR-based PheWAS revealed three significant phenotypes positively associated with PTSD vulnerability (top association "Sleep disorders") and five outcomes inversely associated with PTSD resilience (top association "Irritable Bowel Syndrome"). In the AoU cohort, PheRS analysis showed a partial inverse relationship between vulnerability and resilience with distinct comorbid associations. While PheRSvulnerability associations were linked to multiple phenotypes, PheRSresilience showed inverse relationships with eye conditions. Our study unveils phenotypic differences in PTSD vulnerability and resilience, highlighting that these concepts are not simply the absence and presence of PTSD.
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Registros Eletrônicos de Saúde , Resiliência Psicológica , Transtornos de Estresse Pós-Traumáticos , Humanos , Transtornos de Estresse Pós-Traumáticos/genética , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Registros Eletrônicos de Saúde/estatística & dados numéricos , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Idoso , Predisposição Genética para Doença , Fenótipo , Transtornos do Sono-Vigília/epidemiologia , Comorbidade , Herança Multifatorial , Reino Unido/epidemiologia , Estudo de Associação Genômica AmplaRESUMO
We leveraged information from more than 1.2 million participants to investigate the genetics of anxiety disorders across five continental ancestral groups. Ancestry-specific and cross-ancestry genome-wide association studies identified 51 anxiety-associated loci, 39 of which are novel. Additionally, polygenic risk scores derived from individuals of European descent were associated with anxiety in African, Admixed-American, and East Asian groups. The heritability of anxiety was enriched for genes expressed in the limbic system, the cerebral cortex, the cerebellum, the metencephalon, the entorhinal cortex, and the brain stem. Transcriptome- and proteome-wide analyses highlighted 115 genes associated with anxiety through brain-specific and cross-tissue regulation. We also observed global and local genetic correlations with depression, schizophrenia, and bipolar disorder and putative causal relationships with several physical health conditions. Overall, this study expands the knowledge regarding the genetic risk and pathogenesis of anxiety disorders, highlighting the importance of investigating diverse populations and integrating multi-omics information.
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Observational studies suggest that posttraumatic stress disorder (PTSD) increases risk for various autoimmune diseases. Insights into shared biology and causal relationships between these diseases may inform intervention approaches to PTSD and co-morbid autoimmune conditions. We investigated the shared genetic contributions and causal relationships between PTSD, 18 autoimmune diseases, and 3 immune/inflammatory biomarkers. Univariate MiXeR was used to contrast the genetic architectures of phenotypes. Genetic correlations were estimated using linkage disequilibrium score regression. Bi-directional, two-sample Mendelian randomization (MR) was performed using independent, genome-wide significant single nucleotide polymorphisms; inverse variance weighted and weighted median MR estimates were evaluated. Sensitivity analyses for uncorrelated (MR PRESSO) and correlated horizontal pleiotropy (CAUSE) were also performed. PTSD was considerably more polygenic (10,863 influential variants) than autoimmune diseases (median 255 influential variants). However, PTSD evidenced significant genetic correlation with nine autoimmune diseases and three inflammatory biomarkers. PTSD had putative causal effects on autoimmune thyroid disease (p = 0.00009) and C-reactive protein (CRP) (p = 4.3 × 10-7). Inferences were not substantially altered by sensitivity analyses. Additionally, the PTSD-autoimmune thyroid disease association remained significant in multivariable MR analysis adjusted for genetically predicted inflammatory biomarkers as potential mechanistic pathway variables. No autoimmune disease had a significant causal effect on PTSD (all p values > 0.05). Although causal effect models were supported for associations of PTSD with CRP, shared pleiotropy was adequate to explain a putative causal effect of CRP on PTSD (p = 0.18). In summary, our results suggest a significant genetic overlap between PTSD, autoimmune diseases, and biomarkers of inflammation. PTSD has a putative causal effect on autoimmune thyroid disease, consistent with existing epidemiologic evidence. A previously reported causal effect of CRP on PTSD is potentially confounded by shared genetics. Together, results highlight the nuanced links between PTSD, autoimmune disorders, and associated inflammatory signatures, and suggest the importance of targeting related pathways to protect against disease and disability.
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Doenças Autoimunes , Doença de Hashimoto , Transtornos de Estresse Pós-Traumáticos , Humanos , Transtornos de Estresse Pós-Traumáticos/genética , Fenótipo , Proteína C-Reativa , Doenças Autoimunes/genética , Biomarcadores , Estudo de Associação Genômica AmplaRESUMO
We characterized the genetic architecture of the attention-deficit hyperactivity disorder-substance use disorder (ADHD-SUD) relationship by investigating genetic correlation, causality, pleiotropy, and common polygenic risk. Summary statistics from genome-wide association studies (GWAS) were used to investigate ADHD (Neff = 51,568), cannabis use disorder (CanUD, Neff = 161,053), opioid use disorder (OUD, Neff = 57,120), problematic alcohol use (PAU, Neff = 502,272), and problematic tobacco use (PTU, Neff = 97,836). ADHD, CanUD, and OUD GWAS meta-analyses included cohorts with case definitions based on different diagnostic criteria. PAU GWAS combined information related to alcohol use disorder, alcohol dependence, and the items related to alcohol problematic consequences assessed by the alcohol use disorders identification test. PTU GWAS was generated a multi-trait analysis including information regarding Fagerström Test for Nicotine Dependence and cigarettes per day. Linkage disequilibrium score regression analyses indicated positive genetic correlation with CanUD, OUD, PAU, and PTU. Genomic structural equation modeling showed that these genetic correlations were related to two latent factors: one including ADHD, CanUD, and PTU and the other with OUD and PAU. The evidence of a causal effect of PAU and PTU on ADHD was stronger than the reverse in the two-sample Mendelian randomization analysis. Conversely, similar strength of evidence was found between ADHD and CanUD. CADM2 rs62250713 was a pleiotropic SNP between ADHD and all SUDs. We found seven, one, and twenty-eight pleiotropic variants between ADHD and CanUD, PAU, and PTU, respectively. Finally, OUD, CanUD, and PAU PRS were associated with increased odds of ADHD. Our findings demonstrated the contribution of multiple pleiotropic mechanisms to the comorbidity between ADHD and SUDs.
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Alcoolismo , Transtorno do Deficit de Atenção com Hiperatividade , Transtornos Relacionados ao Uso de Opioides , Transtornos Relacionados ao Uso de Substâncias , Humanos , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Alcoolismo/epidemiologia , Alcoolismo/genética , Estudo de Associação Genômica Ampla , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Transtornos Relacionados ao Uso de Substâncias/genética , Transtornos Relacionados ao Uso de Substâncias/complicações , Comorbidade , Transtornos Relacionados ao Uso de Opioides/complicaçõesRESUMO
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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Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Transtornos de Estresse Pós-Traumáticos , Humanos , Transtornos de Estresse Pós-Traumáticos/genética , População Branca/genética , Neurobiologia , Loci GênicosRESUMO
One of the justifiable criticisms of human genetic studies is the underrepresentation of participants from diverse populations. Lack of inclusion must be addressed at-scale to identify causal disease factors and understand the genetic causes of health disparities. We present genome-wide associations for 2068 traits from 635,969 participants in the Department of Veterans Affairs Million Veteran Program, a longitudinal study of diverse United States Veterans. Systematic analysis revealed 13,672 genomic risk loci; 1608 were only significant after including non-European populations. Fine-mapping identified causal variants at 6318 signals across 613 traits. One-third (n = 2069) were identified in participants from non-European populations. This reveals a broadly similar genetic architecture across populations, highlights genetic insights gained from underrepresented groups, and presents an extensive atlas of genetic associations.
Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Locos de Características Quantitativas , Veteranos , Humanos , Masculino , Variação Genética , Estudos Longitudinais , Polimorfismo de Nucleotídeo Único , Estados Unidos , United States Department of Veterans Affairs , FemininoRESUMO
The human subcortex is involved in memory and cognition. Structural and functional changes in subcortical regions is implicated in psychiatric conditions. We performed an association study of subcortical volumes using 15,941 tandem repeats (TRs) derived from whole exome sequencing (WES) data in 16,527 unrelated European ancestry participants. We identified 17 loci, most of which were associated with accumbens volume, and nine of which had fine-mapping probability supporting their causal effect on subcortical volume independent of surrounding variation. The most significant association involved NTN1 -[GCGG] N and increased accumbens volume (ß=5.93, P=8.16x10 -9 ). Three exonic TRs had large effects on thalamus volume ( LAT2 -[CATC] N ß=-949, P=3.84x10 -6 and SLC39A4 -[CAG] N ß=-1599, P=2.42x10 -8 ) and pallidum volume ( MCM2 -[AGG] N ß=-404.9, P=147x10 -7 ). These genetic effects were consistent measurements of per-repeat expansion/contraction effects on organism fitness. With 3-dimensional modeling, we reinforced these effects to show that the expanded and contracted LAT2 -[CATC] N repeat causes a frameshift mutation that prevents appropriate protein folding. These TRs also exhibited independent effects on several psychiatric symptoms, including LAT2 -[CATC] N and the tiredness/low energy symptom of depression (ß=0.340, P=0.003). These findings link genetic variation to tractable biology in the brain and relevant psychiatric symptoms. We also chart one pathway for TR prioritization in future complex trait genetic studies.