RESUMEN
Importance: Observational studies suggest that major psychiatric disorders and substance use behaviors reduce longevity, making it difficult to disentangle their relationships with aging-related outcomes. Objective: To evaluate the associations between the genetic liabilities for major psychiatric disorders, substance use behaviors (smoking and alcohol consumption), and longevity. Design, Settings, and Participants: This 2-sample mendelian randomization (MR) study assessed associations between psychiatric disorders, substance use behaviors, and longevity using single-variable and multivariable models. Multiomics analyses were performed elucidating transcriptomic underpinnings of the MR associations and identifying potential proteomic therapeutic targets. This study sourced summary-level genome-wide association study (GWAS) data, gene expression, and proteomic data from cohorts of European ancestry. Analyses were performed from May 2022 to November 2023. Exposures: Genetic susceptibility for major depression (n = 500â¯199), bipolar disorder (n = 413â¯466), schizophrenia (n = 127â¯906), problematic alcohol use (n = 435â¯563), weekly alcohol consumption (n = 666â¯978), and lifetime smoking index (n = 462â¯690). Main Outcomes and Measures: The main outcome encompassed aspects of health span, lifespan, and exceptional longevity. Additional outcomes were epigenetic age acceleration (EAA) clocks. Results: Findings from multivariable MR models simultaneously assessing psychiatric disorders and substance use behaviorsm suggest a negative association between smoking and longevity in cohorts of European ancestry (n = 709â¯709; 431â¯503 [60.8%] female; ß, -0.33; 95% CI, -0.38 to -0.28; P = 4.59 × 10-34) and with increased EAA (n = 34â¯449; 18â¯017 [52.3%] female; eg, PhenoAge: ß, 1.76; 95% CI, 0.72 to 2.79; P = 8.83 × 10-4). Transcriptomic imputation and colocalization identified 249 genes associated with smoking, including 36 novel genes not captured by the original smoking GWAS. Enriched pathways included chromatin remodeling and telomere assembly and maintenance. The transcriptome-wide signature of smoking was inversely associated with longevity, and estimates of individual smoking-associated genes, eg, XRCC3 and PRMT6, aligned with the smoking-longevity MR analyses, suggesting underlying transcriptomic mediators. Cis-instrument MR prioritized brain proteins associated with smoking behavior, including LY6H (ß, 0.02; 95% CI, 0.01 to 0.03; P = 2.37 × 10-6) and RIT2 (ß, 0.02; 95% CI, 0.01 to 0.03; P = 1.05 × 10-5), which had favorable adverse-effect profiles across 367 traits evaluated in phenome-wide MR. Conclusions: The findings suggest that the genetic liability of smoking, but not of psychiatric disorders, is associated with longevity. Transcriptomic associations offer insights into smoking-related pathways, and identified proteomic targets may inform therapeutic development for smoking cessation strategies.
RESUMEN
Alcohol Use Disorder (AUD) is a persistent condition linked to neuroinflammation, neuronal oxidative stress, and neurodegenerative processes. While the inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has demonstrated effectiveness in reducing liver inflammation associated with alcohol, its impact on the brain remains largely unexplored. This study aimed to assess the effects of alirocumab, a monoclonal antibody targeting PCSK9 to lower systemic low-density lipoprotein cholesterol (LDL-C), on central nervous system (CNS) pathology in a rat model of chronic alcohol exposure. Alirocumab (50 mg/kg) or vehicle was administered weekly for six weeks in 32 male rats subjected to a 35 % ethanol liquid diet or a control liquid diet (n = 8 per group). The study evaluated PCSK9 expression, LDL receptor (LDLR) expression, oxidative stress, and neuroinflammatory markers in brain tissues. Chronic ethanol exposure increased PCSK9 expression in the brain, while alirocumab treatment significantly upregulated neuronal LDLR and reduced oxidative stress in neurons and brain vasculature (3-NT, p22phox). Alirocumab also mitigated ethanol-induced microglia recruitment in the cortex and hippocampus (Iba1). Additionally, alirocumab decreased the expression of pro-inflammatory cytokines and chemokines (TNF, CCL2, CXCL3) in whole brain tissue and attenuated the upregulation of adhesion molecules in brain vasculature (ICAM1, VCAM1, eSelectin). This study presents novel evidence that alirocumab diminishes oxidative stress and modifies neuroimmune interactions in the brain elicited by chronic ethanol exposure. Further investigation is needed to elucidate the mechanisms by which PCSK9 signaling influences the brain in the context of chronic ethanol exposure.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Encéfalo , Etanol , Neuronas , Estrés Oxidativo , Inhibidores de PCSK9 , Proproteína Convertasa 9 , Animales , Estrés Oxidativo/efectos de los fármacos , Masculino , Ratas , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Inhibidores de PCSK9/farmacología , Proproteína Convertasa 9/metabolismo , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Anticuerpos Monoclonales Humanizados/farmacología , Alcoholismo/metabolismo , Alcoholismo/tratamiento farmacológico , Microglía/metabolismo , Microglía/efectos de los fármacos , Receptores de LDL/metabolismo , Ratas Sprague-Dawley , Modelos Animales de EnfermedadAsunto(s)
Inhibidores de Hidroximetilglutaril-CoA Reductasas , Inhibidores de PCSK9 , Humanos , Pueblos del Este de Asia , Corazón , Hidroximetilglutaril-CoA Reductasas/genética , Análisis de la Aleatorización Mendeliana , Proproteína Convertasa 9/genética , Pueblo Europeo , Inhibidores de PCSK9/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéuticoRESUMEN
BACKGROUND & AIMS: Observational studies have linked lipid-lowering drug targets pro-protein convertase subtilisin/kexin 9 (PCSK9) and HMG-CoA reductase (HMGCR) with adverse liver outcomes; however, liver disease incidence varies across diverse populations, and the long-term hepatic impact of these lipid-lowering drugs among non-white Europeans remains largely unknown. METHODS: We use single nucleotide polymorphisms (SNPs) in PCSK9 and HMGCR loci from genome-wide association study data of low-density lipoprotein cholesterol in 4 populations (East Asian [EAS], South Asian [SAS], African [AFR], and European [EUR]) to perform drug-target Mendelian randomization investigating relationships between PCSK9 and HMGCR inhibition and alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), and bilirubin. RESULTS: Analyses of PCSK9 instruments, including functional variants R46L and E670G, failed to find evidence for relationships of low-density lipoprotein cholesterol lowering via PCSK9 variants and adverse effects on ALT, AST, GGT, or ALP among the cohorts. PCSK9 inhibition was associated with increased direct bilirubin levels in EUR (ß = 0.089; P value = 5.69 × 10-6) and, nominally, in AFR (ß = 0.181; P value = .044). HMGCR inhibition was associated with reduced AST in SAS (ß = -0.705; P value = .005) and, nominally, reduced AST in EAS (ß = -0.096; P value = .03), reduced ALP in EUR (ß = -2.078; P value = .014), and increased direct bilirubin in EUR (ß = 0.071; P value = .032). Sensitivity analyses using genetic instruments derived from circulating PCSK9 protein levels, tissue-specific PCSK9 expression, and HMGCR expression were in alignment, strengthening causal inference. CONCLUSIONS: We did not find ALT, AST, GGT, or ALP associated with genetically proxied PCSK9 and HMGCR inhibition across ancestries. We identified possible relationships in several ancestries between PCSK9 and increased direct and total bilirubin and between HMGCR and reduced AST. These findings support long-term safety profiles and low hepatotoxic risk of PCSK9 and HMGCR inhibition in diverse populations.
Asunto(s)
Proproteína Convertasa 9 , Subtilisina , Humanos , Proproteína Convertasa 9/genética , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Hígado , Bilirrubina , Lipoproteínas LDL , Colesterol , Lípidos , Hidroximetilglutaril-CoA Reductasas/genéticaRESUMEN
The concept of aging is complex, including many related phenotypes such as healthspan, lifespan, extreme longevity, frailty and epigenetic aging, suggesting shared biological underpinnings; however, aging-related endpoints have been primarily assessed individually. Using data from these traits and multivariate genome-wide association study methods, we modeled their underlying genetic factor ('mvAge'). mvAge (effective n = ~1.9 million participants of European ancestry) identified 52 independent variants in 38 genomic loci. Twenty variants were novel (not reported in input genome-wide association studies). Transcriptomic imputation identified age-relevant genes, including VEGFA and PHB1. Drug-target Mendelian randomization with metformin target genes showed a beneficial impact on mvAge (P value = 8.41 × 10-5). Similarly, genetically proxied thiazolidinediones (P value = 3.50 × 10-10), proprotein convertase subtilisin/kexin 9 inhibition (P value = 1.62 × 10-6), angiopoietin-like protein 4, beta blockers and calcium channel blockers also had beneficial Mendelian randomization estimates. Extending the drug-target Mendelian randomization framework to 3,947 protein-coding genes prioritized 122 targets. Together, these findings will inform future studies aimed at improving healthy aging.
Asunto(s)
Estudio de Asociación del Genoma Completo , Envejecimiento Saludable , Fenotipo , LongevidadRESUMEN
Biological aging is accompanied by increasing morbidity, mortality, and healthcare costs; however, its molecular mechanisms are poorly understood. Here, we use multi-omic methods to integrate genomic, transcriptomic, and metabolomic data and identify biological associations with four measures of epigenetic age acceleration and a human longevity phenotype comprising healthspan, lifespan, and exceptional longevity (multivariate longevity). Using transcriptomic imputation, fine-mapping, and conditional analysis, we identify 22 high confidence associations with epigenetic age acceleration and seven with multivariate longevity. FLOT1, KPNA4, and TMX2 are novel, high confidence genes associated with epigenetic age acceleration. In parallel, cis-instrument Mendelian randomization of the druggable genome associates TPMT and NHLRC1 with epigenetic aging, supporting transcriptomic imputation findings. Metabolomics Mendelian randomization identifies a negative effect of non-high-density lipoprotein cholesterol and associated lipoproteins on multivariate longevity, but not epigenetic age acceleration. Finally, cell-type enrichment analysis implicates immune cells and precursors in epigenetic age acceleration and, more modestly, multivariate longevity. Follow-up Mendelian randomization of immune cell traits suggests lymphocyte subpopulations and lymphocytic surface molecules affect multivariate longevity and epigenetic age acceleration. Our results highlight druggable targets and biological pathways involved in aging and facilitate multi-omic comparisons of epigenetic clocks and human longevity.
Asunto(s)
Longevidad , Multiómica , Humanos , Longevidad/genética , Epigénesis Genética , Envejecimiento/genética , Fenotipo , Lipoproteínas/genética , Metilación de ADN/genética , Ubiquitina-Proteína Ligasas/genética , alfa Carioferinas/genéticaRESUMEN
BACKGROUND: Stress contributes to premature aging and susceptibility to alcohol use disorder (AUD), and AUD itself is a factor in premature aging; however, the interrelationships of stress, AUD, and premature aging are poorly understood. METHODS: We constructed a composite score of stress from 13 stress-related outcomes in a discovery cohort of 317 individuals with AUD and control subjects. We then developed a novel methylation score of stress (MS stress) as a proxy of composite score of stress comprising 211 CpGs selected using a penalized regression model. The effects of MS stress on health outcomes and epigenetic aging were assessed in a sample of 615 patients with AUD and control subjects using epigenetic clocks and DNA methylation-based telomere length. Statistical analysis with an additive model using MS stress and a MS for alcohol consumption (MS alcohol) was conducted. Results were replicated in 2 independent cohorts (Generation Scotland, N = 7028 and the Grady Trauma Project, N = 795). RESULTS: Composite score of stress and MS stress were strongly associated with heavy alcohol consumption, trauma experience, epigenetic age acceleration (EAA), and shortened DNA methylation-based telomere length in AUD. Together, MS stress and MS alcohol additively showed strong stepwise increases in EAA. Replication analyses showed robust association between MS stress and EAA in the Generation Scotland and Grady Trauma Project cohorts. CONCLUSIONS: A methylation-derived score tracking stress exposure is associated with various stress-related phenotypes and EAA. Stress and alcohol have additive effects on aging, offering new insights into the pathophysiology of premature aging in AUD and, potentially, other aspects of gene dysregulation in this disorder.
Asunto(s)
Envejecimiento Prematuro , Alcoholismo , Humanos , Alcoholismo/genética , Envejecimiento Prematuro/genética , Consumo de Bebidas Alcohólicas/genética , Metilación de ADN , Epigénesis GenéticaRESUMEN
Background PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors are important therapeutic options for reducing cardiovascular disease risk; however, questions remain regarding potential differences in the neuropsychiatric impact of long-term PCSK9 inhibition between men and women. Methods and Results Using PCSK9 gene single-nucleotide polymorphisms from European ancestry-based genome-wide association studies of low-density lipoprotein cholesterol (N=1 320 016), circulating PCSK9 protein levels (N=10 186), tissue-specific PCSK9 gene expression, sex-specific genome-wide association studies of anxiety, depression, cognition, insomnia, and dementia (ranging from 54 321 to 194 174), we used drug-target inverse variance-weighted Mendelian randomization (MR) and complementary MR methods (MR Egger, weighted median, and weighted mode) to investigate potential neuropsychiatric consequences of genetically proxied PCSK9 inhibition in men and women. We failed to find evidence surpassing correction for multiple comparisons of relationships between genetically proxied PCSK9 inhibition and the risk for the 12 neuropsychiatric end points in either men or women. Drug-target analyses were generally well-powered to detect effect estimates at several hypothesized thresholds for both combined-sex and sex-specific end points, especially analyses using PCSK9 instruments derived from protein and expression quantitative trait loci. Further, MR estimates across complementary MR methods and additional models using genetic instruments derived from circulating PCSK9 protein levels and tissue-specific PCSK9 expression were in alignment, strengthening causal inference. Conclusions Genetically proxied PCSK9 inhibition showed a neutral neuropsychiatric side effect profile with no major sex-specific differences. Given statistical power considerations, replication with larger samples, as well as data from other ancestral populations, are necessary. These findings may have important clinical implications for lipid-lowering drug-prescribing practices and side effect monitoring of approved and future PCSK9 therapies.
Asunto(s)
Trastornos del Conocimiento , Demencia , Trastornos del Humor , Proproteína Convertasa 9 , Femenino , Humanos , Masculino , Cognición , Trastornos del Conocimiento/genética , Demencia/genética , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Trastornos del Humor/genética , Proproteína Convertasa 9/genética , Proproteína Convertasa 9/metabolismoRESUMEN
BACKGROUND: Lipid-lowering therapy with statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition are effective strategies in reducing cardiovascular disease risk; however, concerns remain about potential long-term adverse neurocognitive effects. OBJECTIVES: This genetics-based study aimed to evaluate the relationships of long-term PCSK9 inhibition and statin use on neurocognitive outcomes. METHODS: We extracted single-nucleotide polymorphisms in 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and PCSK9 from predominantly European ancestry-based genome-wide association studies summary-level statistics of low-density lipoprotein cholesterol and performed drug-target Mendelian randomization, proxying the potential neurocognitive impact of drug-based PCSK9 and HMGCR inhibition using a range of outcomes to capture the complex facets of cognition and dementia. RESULTS: Using data from a combined sample of â¼740,000 participants, we observed a neutral cognitive profile related to genetic PCSK9 inhibition, with no significant effects on cognitive performance, memory performance, or cortical surface area. Conversely, we observed several adverse associations for HMGCR inhibition with lowered cognitive performance (beta: -0.082; 95% CI: -0.16 to -0.0080; P = 0.03), reaction time (beta = 0.00064; 95% CI: 0.00030-0.00098; P = 0.0002), and cortical surface area (beta = -0.18; 95% CI: -0.35 to -0.014; P = 0.03). Neither PCSK9 nor HMGCR inhibition impacted biomarkers of Alzheimer's disease progression or Lewy body dementia risk. Consistency of findings across Mendelian randomization methods accommodating different assumptions about genetic pleiotropy strengthens causal inference. CONCLUSIONS: Using a wide range of cognitive function and dementia endpoints, we failed to find genetic evidence of an adverse PCSK9-related impact, suggesting a neutral cognitive profile. In contrast, we observed adverse neurocognitive effects related to HMGCR inhibition, which may well be outweighed by the cardiovascular benefits of statin use, but nonetheless may warrant pharmacovigilance.
Asunto(s)
Enfermedad de Alzheimer , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Acilcoenzima A , Enfermedad de Alzheimer/genética , Cognición , Estudio de Asociación del Genoma Completo , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Análisis de la Aleatorización Mendeliana , Proproteína Convertasa 9/genéticaRESUMEN
Chronic heavy alcohol consumption is associated with increased mortality and morbidity and often leads to premature aging; however, the mechanisms of alcohol-associated cellular aging are not well understood. In this study, we used DNA methylation derived telomere length (DNAmTL) as a novel approach to investigate the role of alcohol use on the aging process. DNAmTL was estimated by 140 cytosine phosphate guanines (CpG) sites in 372 individuals with alcohol use disorder (AUD) and 243 healthy controls (HC) and assessed using various endophenotypes and clinical biomarkers. Validation in an independent sample of DNAmTL on alcohol consumption was performed (N = 4219). Exploratory genome-wide association studies (GWAS) on DNAmTL were also performed to identify genetic variants contributing to DNAmTL shortening. Top GWAS findings were analyzed using in-silico expression quantitative trait loci analyses and related to structural MRI hippocampus volumes of individuals with AUD. DNAmTL was 0.11-kilobases shorter per year in AUD compared to HC after adjustment for age, sex, race, and blood cell composition (p = 4.0 × 10-12). This association was partially attenuated but remained significant after additionally adjusting for BMI, and smoking status (0.06 kilobases shorter per year, p = 0.002). DNAmTL shortening was strongly associated with chronic heavy alcohol use (ps < 0.001), elevated gamma-glutamyl transferase (GGT), and aspartate aminotransferase (AST) (ps < 0.004). Comparison of DNAmTL with PCR-based methods of assessing TL revealed positive correlations (R = 0.3, p = 2.2 × 10-5), highlighting the accuracy of DNAmTL as a biomarker. The GWAS meta-analysis identified a single nucleotide polymorphism (SNP), rs4374022 and 18 imputed ones in Thymocyte Expressed, Positive Selection Associated 1(TESPA1), at the genome-wide level (p = 3.75 × 10-8). The allele C of rs4374022 was associated with DNAmTL shortening, lower hippocampus volume (p < 0.01), and decreased mRNA expression in hippocampus tissue (p = 0.04). Our study demonstrates DNAmTL-related aging acceleration in AUD and suggests a functional role for TESPA1 in regulating DNAmTL length, possibly via the immune system with subsequent biological effects on brain regions negatively affected by alcohol and implicated in aging.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Envejecimiento , Alcoholismo , Acortamiento del Telómero , Humanos , Consumo de Bebidas Alcohólicas/genética , Alcoholismo/genética , Metilación de ADN/genética , Estudio de Asociación del Genoma Completo , Telómero/genética , Proteínas Adaptadoras Transductoras de Señales/genéticaRESUMEN
Alcohol misuse is common in many societies worldwide and is associated with extensive morbidity and mortality, often leading to alcohol use disorders (AUD) and alcohol-related end-organ damage. The underlying mechanisms contributing to the development of AUD are largely unknown; however, growing evidence suggests that alcohol consumption is strongly associated with alterations in DNA methylation. Identification of alcohol-associated methylomic variation might provide novel insights into pathophysiology and novel treatment targets for AUD. Here we performed the largest single-cohort epigenome-wide association study (EWAS) of alcohol consumption to date (N = 8161) and cross-validated findings in AUD populations with relevant endophenotypes, as well as alcohol-related animal models. Results showed 2504 CpGs significantly associated with alcohol consumption (Bonferroni p value < 6.8 × 10-8) with the five leading probes located in SLC7A11 (p = 7.75 × 10-108), JDP2 (p = 1.44 × 10-56), GAS5 (p = 2.71 × 10-47), TRA2B (p = 3.54 × 10-42), and SLC43A1 (p = 1.18 × 10-40). Genes annotated to associated CpG sites are implicated in liver and brain function, the cellular response to alcohol and alcohol-associated diseases, including hypertension and Alzheimer's disease. Two-sample Mendelian randomization confirmed the causal relationship of consumption on AUD risk (inverse variance weighted (IVW) p = 5.37 × 10-09). A methylation-based predictor of alcohol consumption was able to discriminate AUD cases in two independent cohorts (p = 6.32 × 10-38 and p = 5.41 × 10-14). The top EWAS probe cg06690548, located in the cystine/glutamate transporter SLC7A11, was replicated in an independent cohort of AUD and control participants (N = 615) and showed strong hypomethylation in AUD (p < 10-17). Decreased CpG methylation at this probe was consistently associated with clinical measures including increased heavy drinking days (p < 10-4), increased liver function enzymes (GGT (p = 1.03 × 10-21), ALT (p = 1.29 × 10-6), and AST (p = 1.97 × 10-8)) in individuals with AUD. Postmortem brain analyses documented increased SLC7A11 expression in the frontal cortex of individuals with AUD and animal models showed marked increased expression in liver, suggesting a mechanism by which alcohol leads to hypomethylation-induced overexpression of SLC7A11. Taken together, our EWAS discovery sample and subsequent validation of the top probe in AUD suggest a strong role of abnormal glutamate signaling mediated by methylomic variation in SLC7A11. Our data are intriguing given the prominent role of glutamate signaling in brain and liver and might provide an important target for therapeutic intervention.
Asunto(s)
Alcoholismo , Sistema de Transporte de Aminoácidos y+ , Epigenoma , Consumo de Bebidas Alcohólicas/genética , Alcoholismo/genética , Sistema de Transporte de Aminoácidos X-AG , Sistema de Transporte de Aminoácidos y+/genética , Sistema de Transporte de Aminoácidos y+/metabolismo , Cistina/genética , Metilación de ADN/genética , Estudio de Asociación del Genoma Completo/métodos , Glutamatos/genética , HumanosRESUMEN
Substance use disorders (SUDs) are moderately to highly heritable and are in part cross-transmitted genetically, as observed in twin and family studies. We performed exome-focused genotyping to examine the cross-transmission of four SUDs: alcohol use disorder (AUD, n = 4487); nicotine use disorder (NUD, n = 4394); cannabis use disorder (CUD, n = 954); and nonmedical prescription opioid use disorder (NMPOUD, n = 346) within a large nationally representative sample (n = 36,309), the National Epidemiologic Survey on Alcohol and Related Conditions-III (NESARC-III). All diagnoses were based on in-person structured psychiatric interview (AUDADIS-5). SUD cases were compared alone and together to 3959 "super controls" who had neither a SUD nor a psychiatric disorder using an exome-focused array assaying 363,496 SNPs, yielding a representative view of within-disorder and cross-disorder genetic influences on SUDs. The 29 top susceptibility genes for one or more SUDs overlapped highly with genes previously implicated by GWAS of SUD. Polygenic scores (PGS) were computed within the European ancestry (EA) component of the sample (n = 12,505) using summary statistics from each of four clinically distinct SUDs compared to the 3959 "super controls" but then used for two distinctly different purposes: to predict SUD severity (mild, moderate, or severe) and to predict each of the other 3 SUDs. Our findings based on PGS highlight shared and unshared genetic contributions to the pathogenesis of SUDs, confirming the strong cross-inheritance of AUD and NUD as well as the distinctiveness of inheritance of opioid use disorder.
Asunto(s)
Trastornos Relacionados con Alcohol , Alcoholismo , Trastornos Relacionados con Opioides , Trastornos Relacionados con Sustancias , Tabaquismo , Consumo de Bebidas Alcohólicas , Alcoholismo/psicología , Comorbilidad , Humanos , Trastornos Relacionados con Opioides/epidemiología , Trastornos Relacionados con Opioides/genética , Trastornos Relacionados con Sustancias/epidemiología , Trastornos Relacionados con Sustancias/genética , Trastornos Relacionados con Sustancias/psicología , Tabaquismo/psicologíaRESUMEN
BACKGROUND: Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. RESULTS: Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. CONCLUSION: This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.
Asunto(s)
Envejecimiento/genética , Metilación de ADN , Epigénesis Genética , Sitios Genéticos , Herencia Multifactorial , Adiposidad/genética , Adiposidad/inmunología , Envejecimiento/inmunología , Biomarcadores/metabolismo , Proteína C-Reactiva/genética , Proteína C-Reactiva/inmunología , Islas de CpG , Escolaridad , Marcadores Genéticos , Genoma Humano , Estudio de Asociación del Genoma Completo , Granulocitos/citología , Granulocitos/inmunología , Humanos , Inmunidad Innata , Metabolismo de los Lípidos/genética , Metabolismo de los Lípidos/inmunología , Inhibidor 1 de Activador Plasminogénico/genética , Inhibidor 1 de Activador Plasminogénico/inmunologíaRESUMEN
Alcohol use disorder (AUD) is a major contributor to morbidity and mortality worldwide. Although there is a heritable component, the etiology of AUD is complex and can involve environmental exposures like trauma and can be associated with many different patterns of alcohol consumption. Epigenetic modifications, which can mediate the influence of genetic variants and environmental variables on gene expression, have emerged as an important area of AUD research. Over the past decade, the number of studies investigating AUD and DNA methylation, a form of epigenetic modification, has grown rapidly. Yet we are still far from understanding how DNA methylation contributes to or reflects aspects of AUD. In this paper, we reviewed studies of DNA methylation and AUD and discussed how the field has evolved. We found that global DNA and candidate DNA methylation studies did not produce replicable results. To assess whether findings of epigenome-wide association studies (EWAS) were replicated, we aggregated significant findings across studies and identified 184 genes and 15 gene ontological pathways that were differentially methylated in at least two studies and four genes and three gene ontological pathways that were differentially methylated in three studies. These genes and pathways repeatedly found enrichment of immune processes, which is in line with recent developments suggesting that the immune system may be altered in AUD. Finally, we assess the current limitations of studies of DNA methylation and AUD and make recommendations on how to design future studies to resolve outstanding questions.
Asunto(s)
Alcoholismo/genética , Metilación de ADN/fisiología , Epigénesis Genética , Perfilación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Humanos , Fenotipo , Regiones Promotoras Genéticas/fisiologíaRESUMEN
Observational studies suggest that lower educational attainment (EA) may be associated with risky alcohol use behaviors; however, these findings may be biased by confounding and reverse causality. We performed two-sample Mendelian randomization (MR) using summary statistics from recent genome-wide association studies (GWAS) with >780,000 participants to assess the causal effects of EA on alcohol use behaviors and alcohol dependence (AD). Fifty-three independent genome-wide significant SNPs previously associated with EA were tested for association with alcohol use behaviors. We show that while genetic instruments associated with increased EA are not associated with total amount of weekly drinks, they are associated with reduced frequency of binge drinking ≥6 drinks (ßIVW = -0.198, 95% CI, -0.297 to -0.099, PIVW = 9.14 × 10-5), reduced total drinks consumed per drinking day (ßIVW = -0.207, 95% CI, -0.293 to -0.120, PIVW = 2.87 × 10-6), as well as lower weekly distilled spirits intake (ßIVW = -0.148, 95% CI, -0.188 to -0.107, PIVW = 6.24 × 10-13). Conversely, genetic instruments for increased EA were associated with increased alcohol intake frequency (ßIVW = 0.331, 95% CI, 0.267-0.396, PIVW = 4.62 × 10-24), and increased weekly white wine (ßIVW = 0.199, 95% CI, 0.159-0.238, PIVW = 7.96 × 10-23) and red wine intake (ßIVW = 0.204, 95% CI, 0.161-0.248, PIVW = 6.67 × 10-20). Genetic instruments associated with increased EA reduced AD risk: an additional 3.61 years schooling reduced the risk by ~50% (ORIVW = 0.508, 95% CI, 0.315-0.819, PIVW = 5.52 × 10-3). Consistency of results across complementary MR methods accommodating different assumptions about genetic pleiotropy strengthened causal inference. Our findings suggest EA may have important effects on alcohol consumption patterns and may provide potential mechanisms explaining reported associations between EA and adverse health outcomes.
Asunto(s)
Alcoholismo , Estudio de Asociación del Genoma Completo , Consumo de Bebidas Alcohólicas/genética , Alcoholismo/genética , Escolaridad , Humanos , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
Alcohol use disorder (AUD) is a chronic debilitating disorder with limited treatment options and poorly defined pathophysiology. There are substantial genetic and epigenetic components; however, the underlying mechanisms contributing to AUD remain largely unknown. We conducted the largest DNA methylation epigenome-wide association study (EWAS) analyses currently available for AUD (total N = 625) and employed a top hit replication (N = 4798) using a cross-tissue/cross-phenotypic approach with the goal of identifying novel epigenetic targets relevant to AUD. Results show that a network of differentially methylated regions in glucocorticoid signaling and inflammation-related genes were associated with alcohol use behaviors. A top probe consistently associated across all cohorts was located in the long non-coding RNA growth arrest specific five gene (GAS5) (p < 10-24). GAS5 has been implicated in regulating transcriptional activity of the glucocorticoid receptor and has multiple functions related to apoptosis, immune function and various cancers. Endophenotypic analyses using peripheral cortisol levels and neuroimaging paradigms showed that methylomic variation in GAS5 network-related probes were associated with stress phenotypes. Postmortem brain analyses documented increased GAS5 expression in the amygdala of individuals with AUD. Our data suggest that alcohol use is associated with differential methylation in the glucocorticoid system that might influence stress and inflammatory reactivity and subsequently risk for AUD.
Asunto(s)
Alcoholismo , Glucocorticoides , Consumo de Bebidas Alcohólicas/genética , Alcoholismo/genética , Metilación de ADN/genética , Epigénesis Genética/genética , Epigenoma , Estudio de Asociación del Genoma Completo , Humanos , Transducción de Señal/genéticaRESUMEN
Alcohol withdrawal syndrome (AWS) is a serious medical condition of high variability in alcohol use disorder (AUD) after drinking cessation. Identification of clinical biomarkers capable of detecting severe AWS is needed. While alcohol consumption and withdrawal are linked with lipid profile dysregulation, the relationship between lipid levels (high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], and triglycerides) and AWS is unknown. Therefore, this study investigated whether HDL-C, LDL-C, and triglycerides conferred risk for moderate-to-severe AWS symptoms in treatment-seeking individuals (n = 732) admitted to the National Institute on Alcohol Abuse and Alcoholism (NIAAA) alcohol treatment program. Lipid levels were measured upon admission, and the Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar) assessed AWS severity for generating a three-level AWS typology (none-to-mild, moderate, and severe). Multivariable multinomial logistic regression examined whether lipid levels were associated with risk for moderate-to-severe AWS. We found significant predictive relationships between AWS and HDL-C, LDL-C, and triglycerides. While extremely high HDL-C (≥100 mg/dL) conferred the highest odds for moderate (4.405, 95% CI, 2.572-7.546, p < 0.001) and severe AWS (5.494, 95% CI, 3.541-8.523, p < 0.001), the lowest odds ratios for moderate AWS (0.493, 95% CI, 0.248-0.981, p = 0.044) and severe AWS (0.303, 95% CI, 0.223-0.411, p < 0.001) were associated with high LDL-C (≥160 mg/dL). The present study demonstrates that altered lipid levels, measured upon admission for inpatient AUD treatment, may help to predict which individuals are at risk for medically relevant moderate-to-severe AWS. This suggests that further research into the role of lipid biomarkers in AWS may be beneficial for identifying biologically determined risk profiles in AUD.
Asunto(s)
Alcoholismo/sangre , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Síndrome de Abstinencia a Sustancias/sangre , Triglicéridos/sangre , Adulto , Femenino , Hospitalización , Humanos , Masculino , Persona de Mediana Edad , Síndrome de Abstinencia a Sustancias/diagnósticoRESUMEN
AIM: High-intensity binge drinking (HIBD), defined as two or more times the gender-specific binge threshold, is rapidly increasing in the USA; however, the underlying contributing factors are poorly understood. This study investigated the relationship of adverse childhood experiences (ACEs) and HIBD. METHODS: Two independent, cross-sectional samples were analysed: (a) past 12-month drinkers in the National Epidemiological Survey on Alcohol and Related Conditions-III (NESARC-III; n = 25,552) and (b) the National Institute on Alcohol Abuse and Alcoholism (NIAAA) clinical sample (n = 1303). Multinomial logistic regressions were utilized to estimate adjusted odds ratios (AORs) of ACEs on HIBD. Mediation analysis was performed to examine the relationship between the past 12-month psychiatric disorders, ACEs, and HIBD. RESULTS: In the NESARC-III sample, prevalence of ACEs increased across all binge levels with the highest prevalence in extreme HIBD; ACEs were associated with higher odds for HIBD (level II, odds ratio (OR) = 1.2-1.4; P = 0.03-0.001; level III, OR = 1.3-1.9; P < 0.001). Prevalence of DSM-5 diagnoses also increased across all binge levels. Substance use disorders (SUD), mood, personality and post-traumatic stress disorders (PTSD) conferred the highest odds with extreme HIBD (SUD: OR = 21.32; mood: 1.73; personality: 2.84; PTSD: 1.97; all Ps < 0.001). Mediation analyses showed that the association between ACEs and HIBD was fully mediated through SUD (proportion mediated: 70-90%) and partially through other psychiatric disorders (20-80%). In the NIAAA sample, ACEs were 2-5 times more prevalent in extreme HIBD with higher odds (ORs = 3-8, P < 0.001) compared with non-bingers. CONCLUSION: ACEs were associated with significantly increased odds of HIBD and the relationship may be mediated by psychiatric disorders.
Asunto(s)
Adultos Sobrevivientes del Maltrato a los Niños/psicología , Consumo Excesivo de Bebidas Alcohólicas/epidemiología , Trastornos Mentales/epidemiología , Adulto , Comorbilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estados Unidos/epidemiologíaRESUMEN
Background: Cardiomyopathy is a major cause of death in patients with systemic transthyretin amyloidosis. Long term effect of therapy designed to inhibit hepatic production of the amyloid precursor has not been established in cardiomyopathy. The purpose of this study was to evaluate the long term safety and efficacy of transthyretin specific antisense oligonucleotide therapy, inotersen, in transthyretin cardiomyopathy.Methods: Patients with hereditary or wildtype transthyretin cardiomyopathy (NYHA I-III) with an LV wall thickness [Formula: see text]1.3 cm and clinical evidence of congestive heart failure were eligible for this single centre, open label protocol. Safety and cardiac structural and functional parameters were prospectively studied.Results: As of October 2018, 33 subjects have entered the study. Twenty have completed 1 year, 16 have completed 2 years, and 14 have completed three years. At the 2 year time point, mean LV mass decreased by 8.4% as measured by MRI, and exercise tolerance increased by 20.2 metres as measured by 6 minute walk test. Further positive indicators were noted at 3 years, with LV mass decreasing by 11.4% and 6MWT increasing by 16.2 metres.Conclusion: Long term treatment of amyloid cardiomyopathy with inotersen is safe and effective in inhibiting progression and potentially reversing amyloid burden.
Asunto(s)
Neuropatías Amiloides Familiares/tratamiento farmacológico , Cardiomiopatías/tratamiento farmacológico , Oligonucleótidos/administración & dosificación , Anciano , Neuropatías Amiloides Familiares/complicaciones , Neuropatías Amiloides Familiares/diagnóstico por imagen , Cardiomiopatías/diagnóstico por imagen , Cardiomiopatías/etiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oligonucleótidos/efectos adversosRESUMEN
To investigate the potential role of alcohol use disorder (AUD) in aging processes, we employed Levine's epigenetic clock (DNAm PhenoAge) to estimate DNA methylation age in 331 individuals with AUD and 201 healthy controls (HC). We evaluated the effects of heavy, chronic alcohol consumption on epigenetic age acceleration (EAA) using clinical biomarkers, including liver function test enzymes (LFTs) and clinical measures. To characterize potential underlying genetic variation contributing to EAA in AUD, we performed genome-wide association studies (GWAS) on EAA, including pathway analyses. We followed up on relevant top findings with in silico expression quantitative trait loci (eQTL) analyses for biological function using the BRAINEAC database. There was a 2.22-year age acceleration in AUD compared to controls after adjusting for gender and blood cell composition (p = 1.85 × 10-5). This association remained significant after adjusting for race, body mass index, and smoking status (1.38 years, p = 0.02). Secondary analyses showed more pronounced EAA in individuals with more severe AUD-associated phenotypes, including elevated gamma-glutamyl transferase (GGT) and alanine aminotransferase (ALT), and higher number of heavy drinking days (all ps < 0.05). The genome-wide meta-analysis of EAA in AUD revealed a significant single nucleotide polymorphism (SNP), rs916264 (p = 5.43 × 10-8), in apolipoprotein L2 (APOL2) at the genome-wide level. The minor allele A of rs916264 was associated with EAA and with increased mRNA expression in hippocampus (p = 0.0015). Our data demonstrate EAA in AUD and suggest that disease severity further accelerates epigenetic aging. EAA was associated with genetic variation in APOL2, suggesting potential novel biological mechanisms for age acceleration in AUD.