77 research outputs found

    Modeling the longitudinal changes of ancestry diversity in the Million Veteran Program

    No full text
    Abstract Background The Million Veteran Program (MVP) participants represent 100¬†years of US history, including significant social and demographic changes over time. Our study assessed two aspects of the MVP: (i) longitudinal changes in population diversity and (ii) how these changes can be accounted for in genome-wide association studies (GWAS). To investigate these aspects, we divided MVP participants into five birth cohorts (N-range‚ÄČ=‚ÄČ123,888 [born from 1943 to 1947] to 136,699 [born from 1948 to 1953]). Results Ancestry groups were defined by (i) HARE (harmonized ancestry and race/ethnicity) and (ii) a random-forest clustering approach using the 1000 Genomes Project and the Human Genome Diversity Project (1kGP‚ÄČ+‚ÄČHGDP) reference panels (77 world populations representing six continental groups). In these groups, we performed GWASs of height, a trait potentially affected by population stratification. Birth cohorts demonstrate important trends in ancestry diversity over time. More recent HARE-assigned Europeans, Africans, and Hispanics had lower European ancestry proportions than older birth cohorts (0.010‚ÄČ<‚ÄČCohen‚Äôs d‚ÄČ<‚ÄČ0.259, p‚ÄČ<‚ÄČ7.80‚ÄČ√ó‚ÄČ10‚ąí4). Conversely, HARE-assigned East Asians showed an increase in European ancestry proportion over time. In GWAS of height using HARE assignments, genomic inflation due to population stratification was prevalent across all birth cohorts (linkage disequilibrium score regression intercept‚ÄČ=‚ÄČ1.08‚ÄȬĪ‚ÄČ0.042). The 1kGP‚ÄČ+‚ÄČHGDP-based ancestry assignment significantly reduced the population stratification (mean intercept reduction‚ÄČ=‚ÄČ0.045‚ÄȬĪ‚ÄČ0.007, p‚ÄČ<‚ÄČ0.05) confounding in the GWAS statistics. Conclusions This study provides a characterization of ancestry diversity of the MVP cohort over time and compares two strategies to infer genetically defined ancestry groups by assessing differences in controlling population stratification in genome-wide association studies

    Genome-wide association studies and follow-up analyses (Seminari tecnològic 2023)

    Full text link

    Sex differences in the polygenic architecture of hearing problems in adults

    No full text
    BackgroundHearing problems (HP) in adults are common and are associated with several comorbid conditions. Its prevalence increases with age, reflecting the cumulative effect of environmental factors and genetic predisposition. Although several risk loci have been already identified, HP biology and epidemiology are still insufficiently investigated by large-scale genetic studies.MethodsLeveraging the UK Biobank, the Nurses' Health Studies (I and II), the Health Professionals Follow-up Study, and the Million Veteran Program, we conducted a comprehensive genome-wide investigation of HP in 748,668 adult participants (discovery N‚ÄČ=‚ÄČ501,825; replication N‚ÄČ=‚ÄČ226,043; cross-ancestry replication N‚ÄČ=‚ÄČ20,800). We leveraged the GWAS findings to characterize HP polygenic architecture, exploring sex differences, polygenic risk across ancestries, tissue-specific transcriptomic regulation, cause-effect relationships with genetically correlated traits, and gene interactions with HP environmental risk factors.ResultsWe identified 54 risk loci and demonstrated that HP polygenic risk is shared across ancestry groups. Our transcriptomic regulation analysis highlighted the potential role of the central nervous system in HP pathogenesis. The sex-stratified analyses showed several additional associations related to peripheral hormonally regulated tissues reflecting a potential role of estrogen in hearing function. This evidence was supported by the multivariate interaction analysis that showed how genes involved in brain development interact with sex, noise pollution, and tobacco smoking in relation to their HP associations. Additionally, the genetically informed causal inference analysis showed that HP is linked to many physical and mental health outcomes.ConclusionsThe results provide many novel insights into the biology and epidemiology of HP in adults. Our sex-specific analyses and transcriptomic associations highlighted molecular pathways that may be targeted for drug development or repurposing. Additionally, the potential causal relationships identified may support novel preventive screening programs to identify individuals at risk

    Additional file 1 of Denisovan and Neanderthal archaic introgression differentially impacted the genetics of complex traits in modern populations

    No full text
    Additional file 1: Table S1. Description of all phenotypes derived from each GWAS of East Asian and European individuals. Table S2. Comparison of the equivalent phenotypes derived from each GWAS of East Asian and European individuals. Table S3. Description of all phenotypes and statistics for baseline annotations derived from each GWAS of East Asian and European individuals. Table S4. Description of all phenotypes and statistics for evolutionary annotations derived from each GWAS of East Asian and European individuals with heritability z>7. Nominally significant enrichments (p < 0.05) are provided and FDR significant (q < 0.05) results are highlighted. Table S5. Traits from the UK Biobank included in the Phenome-Wide Association Study. The number of cases and controls and trait description are shown. Table S6. Significant association of Denisovan-introgressed variants with phenotypic traits from the Pan UKB in EAS. Beta value, SE, p-value, FDR q-value, gene annotation, predicted function, MAF, p value heterogeneity and q value heterogeneity are also reported. Table S7. Significant association of Neanderthal-introgressed variants with phenotypic traits from the Pan UKB in EAS. Beta value, SE, p-value, FDR q-value, gene annotation, predicted function, MAF, p value heterogeneity and q value heterogeneity are also reported. Table S8. Significant association of shared Denisovan- and Neanderthal-introgressed variants with phenotypic traits from the Pan UKB in EAS. Beta value, SE, p-value, FDR q-value, gene annotation, predicted function, MAF, p value heterogeneity and q value heterogeneity are also reported. Table S9. Significant association of Neanderthal-introgressed variants with phenotypic traits from the Pan UKB in EUR. Beta value, SE, p-value, FDR q-value, gene annotation, predicted function, MAF, p value heterogeneity and q value heterogeneity are also reported. Table S10. Significant association of Neanderthal-introgressed variants with phenotypic traits from the Pan UKB in CSA. Beta value, SE, p-value, FDR q-value, gene annotation, predicted function, MAF, p value heterogeneity and q value heterogeneity are also reported. Table S11. Significant association of Neanderthal-introgressed variants with phenotypic traits from the Pan UKB in MID. Beta value, SE, p-value, FDR q-value, gene annotation, predicted function, MAF, p value heterogeneity and q value heterogeneity are also reported. Table S12. Significant association of Denisovan-introgressed variants with phenotypic traits from the Pan UKB in CSA. Beta value, SE, p-value, FDR q-value, gene annotation, predicted function, MAF, p value heterogeneity and q value heterogeneity are also reported. Table S13. Significant association of shared Denisovan- and Neanderthal-introgressed variants with phenotypic traits from the Pan UKB in CSA. Beta value, SE, p-value, FDR q-value, gene annotation, predicted function, MAF, p value heterogeneity and q value heterogeneity are also reported. Table S14. Significant association of Neanderthal-introgressed variants with phenotypic traits from the Pan UKB in AMR. Beta value, SE, p-value, FDR q-value, gene annotation, predicted function, MAF, p value heterogeneity and q value heterogeneity are also reported. Table S15. Significant (FDR < 0.05) gene-set enrichments in the EUR PheWAS with Neanderthal-introgressed loci

    CYP2D6 Genetic Variation and Antipsychotic-Induced Weight Gain:A Systematic Review and Meta-Analysis

    Get PDF
    BACKGROUND: Antipsychotic-induced weight gain is a contributing factor in the reduced life expectancy reported amongst people with psychotic disorders. CYP2D6 is a liver enzyme involved in the metabolism of many commonly used antipsychotic medications. We investigated if CYP2D6 genetic variation influenced weight or BMI among people taking antipsychotic treatment. METHODS: We conducted a systematic review and a random effects meta-analysis of publications in Pubmed, Embase, PsychInfo, and CENTRAAL that had BMI and/or weight measurements of patients on long-term antipsychotics by their CYP2D6-defined metabolic groups (poor, intermediate, normal/extensive, and ultra-rapid metabolizers, UMs). RESULTS: Twelve studies were included in the systematic review. All cohort studies suggested that the presence of reduced-function or non-functional alleles for CYP2D6 was associated with greater antipsychotic-induced weight gain, whereas most cross-sectional studies did not find any significant associations. Seventeen studies were included in the meta-analysis with clinical data of 2,041 patients, including 93 poor metabolizers (PMs), 633 intermediate metabolizers (IMs), 1,272 normal metabolizers (NMs), and 30 UMs. Overall, we did not find associations in any of the comparisons made. The estimated pooled standardized differences for the following comparisons were (i) PM versus NM; weight = ‚Äď0.07 (95%CI: ‚Äď0.49 to 0.35, p = 0.74), BMI = 0.40 (95%CI: ‚Äď0.19 to 0.99, p = 0.19). (ii) IM versus NM; weight = 0.09 (95% CI: ‚Äď0.04 to 0.22, p = 0.16) and BMI = 0.09 (95% CI: ‚Äď0.24 to 0.41, p = 0.60). (iii) UM versus EM; weight = 0.01 (95% CI: ‚Äď0.37 to 0.40, p = 0.94) and BMI = ‚Äď0.08 (95%CI: ‚Äď0.57 to 0.42, p = 0.77). CONCLUSION: Our systematic review of cohort studies suggested that CYP2D6 poor metabolizers have higher BMI than normal metabolizers, but the data of cross-sectional studies and the meta-analysis did not show this association. Although our review and meta-analysis constitutes one of the largest studies with comprehensively genotyped samples, the literature is still limited by small numbers of participants with genetic variants resulting in poor or UMs status. We need further studies with larger numbers of extreme metabolizers to establish its clinical utility in antipsychotic treatment. CYP2D6 is a key gene for personalized prescribing in mental health

    Author Correction: Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease (Nature Communications, (2020), 11, 1, (995), 10.1038/s41467-019-14275-y)

    No full text

    Genetically regulated multi-omics study for symptom clusters of posttraumatic stress disorder highlights pleiotropy with hematologic and cardio-metabolic traits

    No full text
    Posttraumatic stress disorder (PTSD) is a psychiatric disorder that may arise in response to severe traumatic event and is diagnosed based on three main symptom clusters (reexperiencing, avoidance, and hyperarousal) per the Diagnostic Manual of Mental Disorders (version DSM-IV-TR). In this study, we characterized the biological heterogeneity of PTSD symptom clusters by performing a multi-omics investigation integrating genetically regulated gene, splicing, and protein expression in dorsolateral prefrontal cortex tissue within a sample of US veterans enrolled in the Million Veteran Program (N total‚ÄČ=‚ÄČ186,689). We identified 30 genes in 19 regions across the three PTSD symptom clusters. We found nine genes to have cell-type specific expression, and over-representation of miRNA-families - miR-148, 30, and 8. Gene-drug target prioritization approach highlighted cyclooxygenase and acetylcholine compounds. Next, we tested molecular-profile based phenome-wide impact of identified genes with respect to 1678 phenotypes derived from the Electronic Health Records of the Vanderbilt University biorepository (N‚ÄČ=‚ÄČ70,439). Lastly, we tested for local genetic correlation across PTSD symptom clusters which highlighted metabolic (e.g., obesity, diabetes, vascular health) and laboratory traits (e.g., neutrophil, eosinophil, tau protein, creatinine kinase). Overall, this study finds comprehensive genomic evidence including clinical and regulatory profiles between PTSD, hematologic and cardiometabolic traits, that support comorbidities observed in epidemiologic studies of PTSD

    Safety and cardiovascular effects of multiple-dose administration of aripiprazole and olanzapine in a randomised clinical trial

    Get PDF
    [Objective] To assess adverse events (AEs) and safety of aripiprazole (ARI) and olanzapine (OLA) treatment. [Methods] Twenty-four healthy volunteers receiving five daily oral doses of 10 mg ARI and 5 mg OLA in a crossover clinical trial were genotyped for 46 polymorphisms in 14 genes by qPCR. Drug plasma concentrations were measured by high-performance liquid chromatography tandem mass spectrometry. Blood pressure (BP) and 12-lead electrocardiogram were measured in supine position. AEs were also recorded. [Results] ARI decreased diastolic BP on the first day and decreased QTc on the third and fifth day. OLA had a systolic and diastolic BP, heart rate and QTc lowering effect on the first day. Polymorphisms in ADRA2A, COMT, DRD3 and HTR2A genes were significantly associated to these changes. The most frequent adverse drug reactions (ADRs) to ARI were somnolence, headache, insomnia, dizziness, restlessness, palpitations, akathisia and nausea while were somnolence, dizziness, asthenia, constipation, dry mouth, headache and nausea to OLA. Additionally, HTR2A, HTR2C, DRD2, DRD3, OPRM1, UGT1A1 and CYP1A2 polymorphisms had a role in the development of ADRs. [Conclusions] OLA induced more cardiovascular changes; however, more ADRs were registered to ARI. In addition, some polymorphisms may explain the difference in the incidence of these effects among subjects.D. Koller is co-financed by the H2020 Marie Sklodowska-Curie Innovative Training Network 721236 grant. M. Navares is co-financed by the ‚ÄúConsejer√≠a de Educaci√≥n, Juventud y Deporte‚ÄĚ PEJ-2018-TL/BMD-11080 grant from ‚ÄúComunidad de Madrid‚ÄĚ and ‚ÄúFondo Social Europeo‚ÄĚ.Peer reviewe

    Dataset related to article: Metabolic Effects of Aripiprazole and Olanzapine Multiple-Dose Treatment in a Randomised Crossover Clinical Trial in Healthy Volunteers: Association with Pharmacogenetics

    No full text
    The data generated or analysed during this study are obtained included in the clinical trial registry name, URL and registration number: TREATMENT-HV; EUDRACT 2018-000744-26; https://eudract.ema. europa.eu/. File1 Adverse events after the treatment with antipsychoticsShort-term treatment with aripiprazole and olanzapine had a significant influence on the metabolic parameters. However, it seems that aripiprazole provokes less severe metabolic changes.European Comission ITN Treatment H2020-MSCA-ITN-721236Peer reviewe

    Dataset related to article: Effects of aripiprazole on circadian prolactin secretion related to pharmacogenetics in healthy volunteers

    No full text
    File 1. Demographic characteristics of the volunteers from the aripiprazole study. File 2. Prolactin pharmacokinetic parameters after aripiprazole and ibuprofen administration. This xls file shows the modifications in the prolactin concentrations after the administration of aripiprazole or ibuprofen A It is been shown the prolactin concentrations versus time in women and men treated with aripiprazole compared to ibuprofen File 3 Genotype Matrix. The xls file show the detected genetic polymorphism associated with the effects of aripiprazole File 4 Aripiprazole and dehydro-aripiprazole pharmacokinetic parameters. File 5 The influence of polymorphisms on prolactin concentrations.Aripiprazole treatment in schizophrenic patients was previously associated with lower or normalized prolactin levels. Genetic variants in cytochrome P450 (CYP) (CYP2D6), dopamine receptor (DRD2, DRD3) and serotonin receptor (HTR2A, HTR2C) genes were previously associated with antipsychotic-induced hyperprolactinaemia. Our aim was to evaluate whether aripiprazole affects prolactin secretion and its relationship with pharmacogenetics. Thirty-one healthy volunteers receiving a 10-mg single oral dose of aripiprazole were genotyped for 12 polymorphisms in CYP2D6, DRD2, DRD3, HTR2A and HTR2C genes by qPCR. Aripiprazole and dehydro-aripiprazole plasma concentrations were measured by HPLC-MS/MS. Prolactin concentrations of the 31 volunteers taking aripiprazole and 12 volunteers receiving ibuprofen were determined by ELISA. Prolactin concentrations after ibuprofen intake were considered as control, since it is known to cause no effect. Prolactin concentrations were slightly higher in the aripiprazole group compared to the ibuprofen group. All prolactin pharmacokinetic parameters were higher in females than in males. CYP2D6 poor and intermediate metabolizers had notably higher prolactin Cmax and AUC0-12 than normal and ultrarapid metabolizers. The DRD3 rs6280 polymorphism affected prolactin levels: volunteers carrying Ser/Ser genotype had significantly lower prolactin levels than volunteers carrying the Gly allele. Furthermore, HTR2C rs3813929 C/C homozygotes had significantly lower prolactin levels than T allele carriers. Nevertheless, aripiprazole did increase prolactin levels compared to ibuprofen.European Comission ITN Treatment H2020-MSCA-ITN-721236Peer reviewe
    • ‚Ķ
    corecore