32 research outputs found
GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors
Objective: Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and crossvalidated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS metaanalysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures. Methods: This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses. Results: Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors. Conclusions: This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.</p
Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors
Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe
Pleiotropic effects of Chr15q25 nicotinic gene cluster and the relationship between smoking, cognition and ADHD
Polymorphisms in the <i>CHRNA5-CHRNA3-CHRNB4</i> gene cluster (Chr15q25) have been robustly associated with nicotine dependence, including genome-wide studies, as well as with cognitive and neuropsychological measures. In addition, cognitive processes can be influenced by nicotine use through nicotinic acetylcholine receptors (nAChRs). Here, we evaluated the effect of polymorphisms in <i>CHRNA5-CHRNA3-CHRNB4</i> gene cluster and their interaction with tobacco smoking status on cognition in patients with Attention Deficit/Hyperactivity Disorder (ADHD). Eight SNPs from the <i>CHRNA5-CHRNA3-CHRNB4</i> gene cluster were evaluated on a clinical sample of 403 adults with ADHD. Cognitive performance was assessed using the Wechsler Adult Intelligence Scale-Revised (WAIS-R). Analyses of covariance were used to assess the influence of single markers and their interaction with smoking status in the Vocabulary and Block Design subtests of WAIS-R. Correction for multiple comparisons was applied. Lifetime smoking was associated to Vocabulary subtest. The TT genotypes of CHRNA5 SNPs rs588765 and rs514743 showed a trend towards association with, respectively, higher and lower scores on the Vocabulary subtest. There was a significant interaction between intergenic SNP rs8023462 and smoking on Vocabulary scores. Our results are consistent with an influence of variants in the <i>CHRNA5</i>-<i>CHRNA3</i>-<i>CHRNB4</i> gene cluster on cognitive measures. The overall scenario suggests a pleiotropic role of Chr15q25 nicotinic gene cluster with complex influences in ADHD, tobacco smoking and cognitive performance, characteristics that can be partially interdependent and may share underlying genetic factors
A tale of agriculturalists and hunter-gatherers: Exploring the thrifty genotype hypothesis in native South Americans
Objectives: To determine genetic differences between agriculturalist and hunter-gatherer southern Native American populations for selected metabolism-related markers and to test whether Neel's thrifty genotype hypothesis (TGH) could explain the genetic patterns observed in these populations. Materials and Methods: 375 Native South American individuals from 17 populations were genotyped using six markers (APOE rs429358 and rs7412; APOA2 rs5082; CD36 rs3211883; TCF7L2 rs11196205; and IGF2BP2 rs11705701). Additionally, APOE genotypes from 39 individuals were obtained from the literature. AMOVA, main effects, and gene-gene interaction tests were performed. Results: We observed differences in allele distribution patterns between agriculturalists and hunter-gatherers for some markers. For instance, between-groups component of genetic variance (FCT) for APOE rs429358 showed strong differences in allelic distributions between hunter-gatherers and agriculturalists (p = 0.00196). Gene-gene interaction analysis indicated that the APOE E4/CD36 TT and APOE E4/IGF2BP2 A carrier combinations occur at a higher frequency in hunter-gatherers, but this combination is not replicated in archaic (Neanderthal and Denisovan) and ancient (Anzick, Saqqaq, Ust-Ishim, Mal'ta) hunter-gatherer individuals. Discussion: A complex scenario explains the observed frequencies of the tested markers in hunter-gatherers. Different factors, such as pleotropic alleles, rainforest selective pressures, and population dynamics, may be collectively shaping the observed genetic patterns. We conclude that although TGH seems a plausible hypothesis to explain part of the data, other factors may be important in our tested populations.Fil: Reales, Guillermo. Universidade Federal do Rio Grande do Sul; BrasilFil: Rovaris, Diego L.. Universidade Federal do Rio Grande do Sul; BrasilFil: Jacovas, Vanessa C.. Universidade Federal do Rio Grande do Sul; BrasilFil: Hünemeier, Tábita. Universidade de Sao Paulo; BrasilFil: Sandoval, José R.. Universidad de San Martín de Porres. Facultad de Medicina Humana; PerúFil: Salazar Granara, Alcibiades. Universidad de San Martín de Porres. Facultad de Medicina Humana; PerúFil: Demarchi, Dario. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Antropología de Córdoba. Universidad Nacional de Córdoba. Facultad de Filosofía y Humanidades. Instituto de Antropología de Córdoba; ArgentinaFil: Tarazona Santos, Eduardo. Universidade Federal de Minas Gerais; BrasilFil: Felkl, Aline B.. Universidade Federal do Rio Grande do Sul; BrasilFil: Serafini, Michele A.. Universidade Federal do Rio Grande do Sul; BrasilFil: Salzano, Francisco M.. Universidade Federal do Rio Grande do Sul; BrasilFil: Bisso Machado, Rafael. Universidad de la República; UruguayFil: Comas, David. Universitat Pompeu Fabra; EspañaFil: Paixão Côrtes, Vanessa R.. Universidade Federal da Bahia; BrasilFil: Bortolini, Maria Catira. Universidade Federal do Rio Grande do Sul; Brasi
Functional New World monkey oxytocin forms elicit an altered signaling profile and promotes parental care in rats
Should we keep on? Looking into pharmacogenomics of ADHD in adulthood from a different perspective
Leadless Pacemaker Implantation in the Emergency Bradyarrhythmia Setting: Results from a Multicenter European Registry
Background. Data on leadless pacemaker (LPM) implantation in an emergency setting are currently lacking. Objective. We aimed to investigate the feasibility of LPM implantation for emergency bradyarrhythmia, in patients referred for urgent PM implantation, in a large, multicenter, real-world cohort of LPM recipients. Methods. Two cohorts of LPM patients, stratified according to the LPM implantation scenario (patients admitted from the emergency department (ED+) vs. elective patients (ED−)) were retrieved from the iLEAPER registry. The primary outcome of the study was a comparison of the peri-procedural complications between the groups. The rates of peri-procedural characteristics (overall procedural and fluoroscopic duration) were deemed secondary outcomes. Results. A total of 1154 patients were enrolled in this project, with patients implanted due to an urgent bradyarrhythmia (ED+) representing 6.2% of the entire cohort. Slow atrial fibrillation and complete + advanced atrioventricular blocks were more frequent in the ED+ cohort (76.3% for ED+ vs. 49.7% for ED−, p = 0.025; 37.5% vs. 27.3%, p = 0.027, respectively). The overall procedural times were longer in the ED+ cohort (60 (45–80) mins vs. 50 (40–65) mins, p p p = 0.244). Conclusion. LPM implantation is a feasible procedure for the treatment of severe bradyarrhythmia in an urgent setting. Urgent LPM implantation was not correlated with an increase in the rate of major complications compared to the control group, but it was associated with longer procedural times