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Reliable chiral discrimination of enantiomers with simple devices is of great importance for chiral analysis. Here, a chiral sensing platform is developed for chiral discrimination through two different modes: electrochemistry and temperature. Au nanoparticles (AuNPs) are grown in situ on the nanosheets of MXene by utilizing the strong metal reduction ability of MXene, which can be further used for the anchoring of N-acetyl-l-cysteine (NALC), a commonly used chiral source, through Au-S bonds. Owing to the excellent electrical conductivity and photothermal conversion efficiency of MXene, the resultant MXene-AuNPs-NALC is applied in the construction of a chiral sensing platform for the discrimination of tryptophan (Trp) enantiomers through two different modes: electrochemistry and temperature. Compared with conventional single-mode chiral sensors, the proposed chiral sensing platform can integrate two different indicators (currents and temperature) into one chiral sensor, greatly improving the reliability of chiral discrimination.
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An electrochemical chiral sensing platform based on a multi-substituted ferrocene-cuprous ion (Cu+) complex is constructed for the discrimination of electroactive amino acid (AA) isomers. Due to the opposite configurations of the AA isomers, the developed multi-substituted ferrocene-Cu+ can preferably combine with a right-handed AA (D-AA) isomer to form the ternary complex of multi-substituted ferrocene-Cu+-D-AA through π-π interactions, resulting in higher peak currents of D-AA. Therefore, the isomers of electroactive AA can be successfully discriminated. Among the tested electroactive AA isomers, the chiral sensing platform exhibits higher discrimination capability toward the isomers of tryptophan (Trp) than that of tyrosine (Tyr) and cysteine (Cys), which might be ascribed to the stronger π-π interactions between the benzene ring of the multi-substituted ferrocene and the indole ring of the Trp isomers.
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Aminoácidos , Triptofano , Metalocenos , Triptofano/químicaRESUMO
A novel electrochemical chiral sensor has been designed based on the principle of competitive host-guest interaction and utilized for the discrimination of electroinactive proline (Pro) isomers. Electroactive methylene blue (MB) was used as the signal probe, which was combined with multi-walled carbon nanotubes (MWCNTs)-decorated ß-cyclodextrin (ß-CD), via host-guest interaction, where the oxidation peak currents of MB decreased after isomers of Pro were combined with the MWCNTs-ß-CD via a competitive host-guest interaction. Due to the steric configuration of L-Pro matching the cavity of ß-CD, more L-Pro than D-Pro was combined with MWCNTs-ß-CD, resulting in a more pronounced decrease of MB peak currents. Therefore, the isomers of Pro could be discriminated. Besides Pro, the isomers of electroinactive histidine (His) could also be discriminated with the chiral sensor. In addition, the contents of L-Pro in non-racemic mixtures could be detected with the developed chiral sensor.
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Técnicas Eletroquímicas , Nanotubos de Carbono , Técnicas Eletroquímicas/métodos , Nanotubos de Carbono/química , Aminoácidos , Azul de Metileno/químicaRESUMO
Well-dispersed chiral Ag2S quantum dots (Ag2S QDs) were facilely synthesized by using N-acetyl-L-cysteine (NALC) as the chiral ligand and loaded onto nanosheets of two-dimensional (2D) few-layer carbon nitride (C3N4). The resultant nanocomposite (Ag2S QDs/few-layer C3N4) shows enhanced electrochemiluminescence (ECL) while maintaining the chirality of Ag2S QDs, which can be used for the chiral discrimination of the enantiomers of tyrosine (Tyr). Due to the higher affinity of chiral Ag2S QDs toward L-Tyr than toward its enantiomer, the ECL intensity of Ag2S QDs/few-layer C3N4 is significantly decreased after its incubation with L-Tyr, and thus the Tyr enantiomers can be discriminated. The developed ECL chiral sensor exhibits high stability and reproducibility. The universality of the ECL chiral sensor for the discrimination of other chiral amino acids is also studied, and the results indicate that it can work only in the case of chiral aromatic amino acids.
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Nanocompostos , Pontos Quânticos , Nitrilas , Reprodutibilidade dos TestesRESUMO
Methamphetamine (MA) is a potent stimulant and notoriously addictive. Individuals respond to MA effects differently and thus have a varying susceptible risk of developing MA use disorder. Cumulative evidence has indicated that gut dysbiosis contributes to behavioral response to drug effects. However, the role of gut microbiota in the susceptible risk of developing MA use disorder has remained elusive. Using an MA-induced conditioned place preference (CPP) rat model, we administrated the same dose of MA to rats, which then showed distinct preferences in drug-related place, indicating their different responses to MA. From all of the MA-exposed rats, the eight with the highest CPP scores were labeled as group high CPP (H-CPP), and the eight with the lowest were labeled as group low CPP (L-CPP). By 16S ribosomal RNA (rRNA) sequencing, we found that the gut microbiota compositions differed between H-CPP and L-CPP. Specifically, Akkermansia was significantly higher in H-CPP and positively correlated with the CPP scores. Notably, H-CPP and L-CPP differed in the gut microbiota composition prior to the CPP training; Ruminococcus was the dominant phylotype in H-CPP at baseline. More importantly, rats pretreated by antibiotics showed a significantly stronger MA-induced CPP than did the controls. Our study demonstrates that the gut dysbiosis was associated with the MA-induced CPP, indicating that the gut microbiota might be important modulators for MA-induced behavior and vulnerability to MA use disorder.
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Comportamento Animal/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Condicionamento Clássico/efeitos dos fármacos , Disbiose/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Metanfetamina/farmacologia , Animais , Modelos Animais de Doenças , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
The United States is experiencing the worst opioid overdose (OpOD) crisis in its history. We carried out a genome-wide association study on OpOD severity among 3 477 opioid-exposed individuals, 1 019 of whom experienced OpODs, including 2 032 European Americans (EAs) (653 overdose cases), and 1 445 African Americans (AAs) (366 overdose cases). Participants were scored 1 to 4 based on their reported overdose status and the number of times that medical treatment was required. Genome-wide association study (GWAS) of EAs and AAs separately resulted in two genome-wide significant (GWS) signals in AAs but none in EAs. The first signal was represented by three closely mapped variants (rs115208233, rs116181528, and rs114077267) located near mucolipin 1 (MCOLN1) and patatin-like phospholipase domain containing 6 (PNPLA6), and the other signal was represented by rs369098800 near dead-box helicase 18 (DDX18). There were no additional GWS signals in the trans-population meta-analysis, so that post-GWAS analysis focused on these loci. In network analysis, MCOLN1 was coexpressed with PNPLA6, but only MCOLN1-associated genes were enriched in functional categories relevant to OpOD, including calcium and cation channel activities; no enrichment was observed for PNPLA6-associated genes. Drug repositioning analysis was carried out in the connectivity map (CMap) database for MCOLN1 (PNPLA6 was not available in CMap) and showed that the opioid agonist drug-induced expression profile is similar to that of MCOLN1 overexpression and yielded the highest-ranked expression profile of 83 drug classes. Thus, MCOLN1 may be a risk gene for OpOD, but replication is needed. This knowledge could be helpful in the identification of drug targets for preventing OpOD.
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Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Overdose de Opiáceos/genética , Canais de Potencial de Receptor Transitório/genética , Negro ou Afro-Americano/estatística & dados numéricos , Analgésicos Opioides/farmacologia , Humanos , Medição de Risco , Índice de Gravidade de Doença , Estados Unidos , População Branca/estatística & dados numéricosRESUMO
Stereospecific molecular recognition with simple and easily available proteins is of significant importance in life science and biomaterial science. Herein, we report on a chiral sensing platform, graphene quantum dots (GQDs)-functionalized bovine serum albumin (BSA), for chiral recognition of tryptophan (Trp) isomers. Amidation reaction between BSA and GQDs was directly responsible for the introduction of GQDs to BSA, resulting in significant changes in the spatial configuration of BSA and the exposure of more chiral sites at the protein surface. The BSA-GQDs-based chiral sensor exhibited good biomolecular homochirality in the recognition of Trp isomers, and the higher affinity of BSA-GQDs toward l-Trp than its isomer, d-Trp, was also revealed by density functional theory (DFT) considering the possible hydrogen bonds between the Trp isomers and the solvent-accessible residues of BSA.
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Grafite/química , Pontos Quânticos/química , Soroalbumina Bovina/química , Triptofano/análise , Triptofano/química , Teoria da Densidade Funcional , Técnicas Eletroquímicas , Isomerismo , Solventes/química , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
Alcohol dependence (AD) and nicotine dependence (ND) co-occur frequently (AD+ND). We integrated SNP-based, gene-based, and protein-protein interaction network analyses to identify shared risk genes or gene subnetworks for AD+ND in African Americans (AAs, N = 2,094) and European Americans (EAs, N = 1,207). The DSM-IV criterion counts for AD and ND were modeled as two dependent variables in a multivariate linear mixed model, and analyzed separately for the two populations. The most significant SNP was rs6579845 in EAs (p < 1.29 × 10-8 ) in GM2A, which encodes GM2 ganglioside activator, and is a cis-expression quantitative locus that affects GM2A expression in blood and brain tissues. However, this SNP was not replicated in our another small sample (N = 678). We identified a subnetwork of 24 genes that contributed to the AD+ND criterion counts. In the gene-set analysis for the subnetwork in an independent sample, the Study of Addiction: Genetics and Environment project (predominately EAs), these 24 genes as a set differed in AD+ND versus control subjects in EAs (p = .041). Functional enrichment analysis for this subnetwork revealed that the gene enrichment involved primarily nerve growth factor pathways, and cocaine and amphetamine addiction. In conclusion, we identified a genome-wide significant variant at GM2A and a gene subnetwork underlying the genetic trait of shared AD+ND. These results increase our understanding of the shared (pleiotropic) genetic risk that underlies AD+ND.
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Alcoolismo/genética , Redes Reguladoras de Genes/genética , Tabagismo/genética , Adulto , Negro ou Afro-Americano/genética , Alcoolismo/epidemiologia , Alelos , Comorbidade , Etanol/metabolismo , Feminino , Proteína Ativadora de G(M2)/genética , Proteína Ativadora de G(M2)/metabolismo , Frequência do Gene/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Nicotina/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Mapas de Interação de Proteínas/genética , Fatores de Risco , Tabagismo/epidemiologia , População Branca/genéticaRESUMO
Molecular self-assemblies offer a promising strategy for the synthesis of advanced materials for the construction of novel chiral sensing systems, and latest innovations on such self-assemblies are focused on simple building blocks in biology such as nucleic acids, lipids, and peptides. Herein, the self-assemblies of diphenylalanine (FF) and oxalic acid (OA) were prepared as the chiral sensing device for the recognition of tryptophan (Trp) isomers. Interestingly, the self-assemblies composed of OA and FF with different charging states (neutral, positively charged, and negatively charged) exhibited quite different morphologies, resulting in significantly different chiral recognition ability toward the Trp isomers. Also, in this work, the temperature sensitivity and chiral selectivity of the proposed FF-OA self-assemblies were also studied. From a practical point of view, the FF-OA self-assemblies were finally applied for the determination of precise levels of d-Trp in the racemic mixture of Trp isomers.
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OBJECTIVE: To determine if measures of adverse childhood experiences and DNA methylation relate to indices of obesity in youth. STUDY DESIGN: Participants were derived from a cohort of 321 8 to 15-year-old children recruited for an investigation examining risk and resilience and psychiatric outcomes in maltreated children. Assessments of obesity were collected as an add-on for a subset of 234 participants (56% female; 52% maltreated). Illumina arrays were used to examine whole genome epigenetic predictors of obesity in saliva DNA. For analytic purposes, the cohort analyzed in the first batch comprised the discovery sample (n = 160), and the cohort analyzed in the second batch the replication sample (n = 74). RESULTS: After controlling for race, sex, age, cell heterogeneity, 3 principal components, and whole genome testing, 10 methylation sites were found to interact with adverse childhood experiences to predict cross-sectional measures of body mass index, and an additional 6 sites were found to exert a main effect in predicting body mass index (P < 5.0 × 10-7, all comparisons). Eight of the methylation sites were in genes previously associated with obesity risk (eg, PCK2, CxCl10, BCAT1, HID1, PRDM16, MADD, PXDN, GALE), with several of the findings from the discovery data set replicated in the second cohort. CONCLUSIONS: This study lays the groundwork for future longitudinal studies to elucidate these mechanisms further and identify novel interventions to alleviate the health burdens associated with early adversity.
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Experiências Adversas da Infância/estatística & dados numéricos , Proteção da Criança , Metilação de DNA/genética , Epigênese Genética , Obesidade Infantil/epidemiologia , Obesidade Infantil/genética , Adolescente , Distribuição por Idade , Criança , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Incidência , Masculino , Obesidade Infantil/fisiopatologia , Valores de Referência , Medição de Risco , Distribuição por Sexo , Estados UnidosRESUMO
A quinine (QN)-based chiral sensing platform with alterable enantioselectivity is constructed for electrochemical chiral recognition of tryptophan (Trp) isomers. The electrochemical signals of l- and d-Trp on the QN modified electrode depend closely on temperature, and more particularly are reversed at certain temperatures, which could be attributed to the temperature-sensitive H-bonds and π-π interactions between QN and the Trp isomers. The mechanisms of the reverse chiral recognition are investigated by density functional theory (DFT), variable-temperature UV spectra, and variable-temperature 1H NMR spectra. In addition, the chiral recognition is highly specific to the isomers of Trp compared with other chiral amino acids. This study is the first example showing how temperature influences the reverse recognition of electrochemical chiral interfaces.
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Construction of convenient systems for isomer discrimination is of great importance for medical and life sciences. Here, we report a simple and effective chiral sensing device based on a highly ordered self-assembly framework. Cu2+-modified ß-cyclodextrin (Cu-ß-CD) was self-assembled to the ammonia-ethanol cotreated chitosan (ae-CS), and the highly ordered framework was gradually formed during the "re-growth" process of the shrinked ae-CS films. Tryptophan (Trp) isomers were well discriminated with the highly ordered framework by electrochemical approach. This study is the first example showing how an ordered structure influences chiral recognition.
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BACKGROUND: The heritable risk for alcohol use disorder (AUD) is expressed partly through alterations in subjective alcohol response. In this study, we investigated the effects of 2 AUD-risk-associated single nucleotide polymorphisms, GABRA2 rs279858 and GRIK1 rs2832407, on the subjective response to alcohol administered intravenously to healthy social drinkers in a laboratory setting. METHODS: In total, 93 self-identified European American social drinkers underwent 3 blinded laboratory sessions in which they received intravenous infusions of ethanol at 3 target blood alcohol levels (0.00 mg%, 40 mg%, and 100 mg%) using a "clamp" procedure. The self-reported Biphasic Alcohol Effects Scale (BAES) stimulation and sedation subscales were the primary outcome measures. We examined the effects of these 2 genetic variants on subjective response to alcohol. RESULTS: For the BAES stimulation subscale scores, adjusting for age, baseline scores, and time effects, individuals with 2 copies of the GABRA2 rs279858 C "risk" allele for AUD exhibited the greatest stimulant responses to high-dose alcohol compared to the other risk allele counts (dose-by-allele count interaction effect, p = 0.001, post hoc contrast for C-allele, p = 0.012). For the BAES sedation subscale scores, adjusting for the same covariates, we detected a dose-by-allele count interaction effect (p = 0.0044) such that subjects with 2 copies of the GRIK1 C "risk" allele reported the greatest sedative response to the higher alcohol dose. CONCLUSIONS: This study suggests that gene variants contributing to the risk for AUD may alter features of the alcohol dose-response relationship in specific ways. GABRA2 rs279858*C enhances stimulant responses to higher levels of alcohol, while the GRIK1 rs2832407*C-allele increases sedative responses. In summary, GRIK1 and GABRA2 variants have distinct effects on the dose-related subjective response to intravenous alcohol in humans.
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Consumo de Bebidas Alcoólicas/genética , Etanol/administração & dosagem , Etanol/farmacologia , Voluntários Saudáveis/psicologia , Receptores de GABA-A/genética , Receptores de Ácido Caínico/genética , Administração Intravenosa , Adulto , Estimulantes do Sistema Nervoso Central/farmacologia , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Hipnóticos e Sedativos/farmacologia , Masculino , Polimorfismo de Nucleotídeo Único/genética , Adulto JovemRESUMO
A series of cyclometalated platinum(ii) complexes have been investigated with the TDDFT method. These complexes have similar structures but distinct phosphorescence quantum yields. Theoretical calculations were carried out to explain the differences in quantum yields from the conjugation effect of the cyclometalated ligand, molecular rigidity and ligand-field strength of the monodentate ligand. The radiative decay rate constants (kr) have been discussed with the oscillator strength (fn), the strength of the spin-orbit coupling (SOC) interaction between the lowest energy triplet excited state (T1) and singlet excited states (Sn), and the energy gaps between E(T1) and E(Sn). To illustrate the nonradiative decay processes, the transition states (TS) between the triplet metal-centered state (3MC) and T1 states have been optimized. In addition, the minimum energy crossing points (MECPs) between 3MC and the ground states (S0) were optimized. Finally, the potential energy curves along the nonradiative decay pathways are simulated. To obtain a phosphorescent complex with a high quantum yield, the complex should retain molecular rigidity well in the S1 and T1 states, while showing significant structural distortion at the MECP structure.
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A first optical resolution of 6,12-diphenyldibenzo[b,f][1,5]diazocine with stable boat conformation was achieved by chiral supercritical fluid chromatography (SFC). The absolute configurations of enantiomers were first assigned and determined by X-ray crystal structure based on CIP-rules. The high optical rotation and circular dichroism spectrum were well explained by electronic helix theory. Owing to the high stabilization of boat conformation, the chiral configuration could be maintained at very high temperature, more than 200 °C, which was proved by Density Functional Theory calculations.
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Serotonin signaling pathways play a key role in brain development, stress reactivity, and mental health. Epigenetic alterations in the serotonin system may underlie the effect of early life stress on psychopathology. The current study examined methylation of the serotonin receptor 2A (HTR2A) gene in a sample of 228 children including 119 with child welfare documentation of moderate to severe maltreatment within the last 6 months. Child protection records, semistructured interviews in the home, and parent reports were used to assess child stress exposure, psychiatric symptoms, and behavior. The HTR2A genotype and methylation of HTR2A were measured at two CpG sites (-1420 and -1224) from saliva DNA. HTR2A genotype was associated with HTR2A methylation at both CpG sites. HTR2A genotype also moderated associations of contextual stress exposure and HTR2A methylation at site -1420. Contextual stress was positively associated with -1420 methylation among A homozygotes, but negatively associated with -1420 methylation among G homozygotes. Posttraumatic stress disorder and major depressive disorder symptoms were negatively associated with methylation at -1420, but positively associated with methylation at -1224. Results support the view that the serotonin system is sensitive to stress exposure and psychopathology, and HTR2A methylation may be a mechanism by which early adversity is biologically encoded.
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Maus-Tratos Infantis/psicologia , Metilação de DNA , Transtorno Depressivo Maior/genética , Receptor 5-HT2A de Serotonina/genética , Transtornos de Estresse Pós-Traumáticos/genética , Pré-Escolar , Transtorno Depressivo Maior/psicologia , Feminino , Interação Gene-Ambiente , Genótipo , Humanos , Masculino , Regiões Promotoras Genéticas , Transdução de Sinais/genética , Transtornos de Estresse Pós-Traumáticos/psicologia , Estresse Psicológico/genética , Estresse Psicológico/psicologiaRESUMO
Epigenetics processes may play a vital role in the biological embedding of early environmental adversity and the development of psychopathology. Accumulating evidence suggests that maltreatment is linked to methylation of the glucocorticoid receptor gene, nuclear receptor subfamily 3, group C, member 1 (NR3C1), which is a key regulator of the hypothalamus-pituitary-adrenal axis. However, prior work has been exclusively cross-sectional, greatly constraining our understanding of stress-related epigenetic processes over time. In the current study, we examined the effect of maltreatment and other adversity on change in NR3C1 methylation among at-risk preschoolers to begin to characterize within-child epigenetic changes during this sensitive developmental period. Participants were 260 preschoolers (3-5 years old, 53.8% female), including 51.5% with moderate to severe maltreatment in the past 6 months. Child protection records, semistructured interviews, and parent reports were used to assess child stress exposure. Methylation of exons 1D and 1F of NR3C1 via saliva DNA were measured at two time points approximately 6 months apart. Results indicate that maltreated children evidence higher baseline levels of NR3C1 methylation, significant decreases in methylation over time, and then at follow-up, lower levels of methylation, relative to nonmaltreated preschoolers. Findings from the current study highlight the complex nature of stress-related epigenetic processes during early development.
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Maus-Tratos Infantis , Desenvolvimento Infantil/fisiologia , Metilação de DNA , Receptores de Glucocorticoides/genética , Pré-Escolar , Éxons , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Sistema Hipófise-Suprarrenal/metabolismo , Receptores de Glucocorticoides/metabolismoRESUMO
FK506 binding protein 5 (FKBP5) alters stress response system functioning, and childhood maltreatment is associated with methylation of the FKBP5 gene. Yet it is unknown if maltreatment contributes to change in FKBP5 methylation over time. The current study draws upon a sample of 231 preschoolers, including 123 with child welfare documentation of moderate to severe maltreatment in the past 6 months, to understand if maltreatment contributes to change in FKBP5 methylation over a 6-month period. Review of child protection records and semistructured interviews in the home were used to assess maltreatment and exposure to other contextual stressors, as well as service utilization. Methylation of FKBP5 at two CpG sites in intron 7 was measured from saliva DNA at the time of initial study enrollment, and 6 months following enrollment. Child maltreatment was associated with change in FKBP5 methylation over time, but only when children were exposed to high levels of other contextual stressors. Service utilization was associated with increases in methylation over time, but only among children with the FKPB5 rs1360780 protective CC genotype. Methylation of FKBP5 is sensitive to stress exposure and may be a mechanism linking early adversity to long-term health and developmental outcomes.
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Maus-Tratos Infantis , Metilação de DNA , Proteínas de Ligação a Tacrolimo/genética , Pré-Escolar , Feminino , Genótipo , Humanos , Íntrons , MasculinoRESUMO
Sex influences risk for opioid dependence (OD). We hypothesized that sex might interact with genetic loci that influence the risk for OD. Therefore we performed an analysis to identify sex-specific genomic susceptibility regions for OD using linkage. Over 6,000 single nucleotide polymorphism (SNP) markers were genotyped for 1,758 African- and European-American (AA and EA) individuals from 739 families, ascertained via affected sib-pairs with OD and/or cocaine dependence. Autosomewide non-parametric linkage scans, stratified by sex and population, were performed. We identified one significant linkage region, segregating with OD in EA men, at 71.1 cM on chromosome 4 (LOD = 3.29; point-wise P = 0.00005; empirical autosome-wide P = 0.042), which significantly differed from the linkage signal at the same location in EA women (empirical P = 0.002). Three suggestive linkage signals were identified at 181.3 cM on chromosome 7 (LOD = 2.18), 104 cM on chromosome 11 (LOD = 1.85), and 60.9 cM on chromosome 16 (LOD = 1.93) in EA women. In AA men, four suggestive linkage signals were detected at 201.1 cM on chromosome 3 (LOD = 2.32), 152.9 cM on chromosome 6 (LOD = 1.86), 16.8 cM on chromosome 7 (LOD = 1.95), and 36.1 cM on chromosome 17 (LOD = 1.99). The significant region, mapping to 4q12-4q13.1, harbors several OD candidate genes with interconnected functionality, including VEGFR, CLOCK, PDCL2, NMU, NRSF, and IGFBP7. In conclusion, these results provide an evidence for the existence of sex-specific and population-specific differences in OD. Furthermore, these results provide positional information that will facilitate the use of targeted next-generation sequencing to search for genes that contribute to sex-specific differences in OD. © 2016 Wiley Periodicals, Inc.
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Transtornos Relacionados ao Uso de Cocaína/genética , Transtornos Relacionados ao Uso de Opioides/genética , Adulto , Negro ou Afro-Americano/genética , População Negra/genética , Mapeamento Cromossômico/métodos , Feminino , Ligação Genética/genética , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Escore Lod , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Fatores Sexuais , População Branca/genéticaRESUMO
Despite a significant genetic contribution to alcohol dependence (AD), few AD-risk genes have been identified to date. In the current study, we aimed to integrate genome-wide association studies (GWASs) and human protein interaction networks to investigate whether a subnetwork of genes whose protein products interact with one another might collectively contribute to AD. By using two discovery GWAS data sets of the Study of Addiction: Genetics and Environment (SAGE) and the Collaborative Study on the Genetics of Alcoholism (COGA), we identified a subnetwork of 39 genes that not only was enriched for genes associated with AD, but also collectively associated with AD in both European Americans (p < 0.0001) and African Americans (p = 0.0008). We replicated the association of the gene subnetwork with AD in three independent samples, including two samples of European descent (p = 0.001 and p = 0.006) and one sample of African descent (p = 0.0069). To evaluate whether the significant associations are likely to be false-positive findings and to ascertain their specificity, we examined the same gene subnetwork in three other human complex disorders (bipolar disorder, major depressive disorder, and type 2 diabetes) and found no significant associations. Functional enrichment analysis revealed that the gene subnetwork was enriched for genes involved in cation transport, synaptic transmission, and transmission of nerve impulses, all of which are biologically meaningful processes that may underlie the risk for AD. In conclusion, we identified a gene subnetwork underlying AD that is biologically meaningful and highly reproducible, providing important clues for future research into AD etiology and treatment.