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1.
Nicotine Tob Res ; 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31294817

RESUMO

INTRODUCTION: FTND (FagerstrÓ§m test for nicotine dependence) and TTFC (time to smoke first cigarette in the morning) are common measures of nicotine dependence (ND). However, genome-wide meta-analysis for these phenotypes has not been reported. METHODS: Genome-wide meta-analyses for FTND (N = 19,431) and TTFC (N = 18,567) phenotypes were conducted for adult smokers of European ancestry from 14 independent cohorts. RESULTS: We found that SORBS2 on 4q35 (p = 4.05 × 10-8), BG182718 on 11q22 (p = 1.02 × 10-8), and AA333164 on 14q21 (p = 4.11 × 10-9) were associated with TTFC phenotype. We attempted replication of leading candidates with independent samples (FTND, N = 7010 and TTFC, N = 10 061), however, due to limited power of the replication samples, the replication of these new loci did not reach significance. In gene-based analyses, COPB2 was found associated with FTND phenotype, and TFCP2L1, RELN, and INO80C were associated with TTFC phenotype. In pathway and network analyses, we found that the interconnected interactions among the endocytosis, regulation of actin cytoskeleton, axon guidance, MAPK signaling, and chemokine signaling pathways were involved in ND. CONCLUSIONS: Our analyses identified several promising candidates for both FTND and TTFC phenotypes, and further verification of these candidates was necessary. Candidates supported by both FTND and TTFC (CHRNA4, THSD7B, RBFOX1, and ZNF804A) were associated with addiction to alcohol, cocaine, and heroin, and were associated with autism and schizophrenia. We also identified novel pathways involved in cigarette smoking. The pathway interactions highlighted the importance of receptor recycling and internalization in ND. IMPLICATIONS: Understanding the genetic architecture of cigarette smoking and ND is critical to develop effective prevention and treatment. Our study identified novel candidates and biological pathways involved in FTND and TTFC phenotypes, and this will facilitate further investigation of these candidates and pathways.

2.
Br J Nutr ; 120(10): 1159-1170, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30205856

RESUMO

The role that vitamin D plays in pulmonary function remains uncertain. Epidemiological studies reported mixed findings for serum 25-hydroxyvitamin D (25(OH)D)-pulmonary function association. We conducted the largest cross-sectional meta-analysis of the 25(OH)D-pulmonary function association to date, based on nine European ancestry (EA) cohorts (n 22 838) and five African ancestry (AA) cohorts (n 4290) in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Data were analysed using linear models by cohort and ancestry. Effect modification by smoking status (current/former/never) was tested. Results were combined using fixed-effects meta-analysis. Mean serum 25(OH)D was 68 (sd 29) nmol/l for EA and 49 (sd 21) nmol/l for AA. For each 1 nmol/l higher 25(OH)D, forced expiratory volume in the 1st second (FEV1) was higher by 1·1 ml in EA (95 % CI 0·9, 1·3; P<0·0001) and 1·8 ml (95 % CI 1·1, 2·5; P<0·0001) in AA (P race difference=0·06), and forced vital capacity (FVC) was higher by 1·3 ml in EA (95 % CI 1·0, 1·6; P<0·0001) and 1·5 ml (95 % CI 0·8, 2·3; P=0·0001) in AA (P race difference=0·56). Among EA, the 25(OH)D-FVC association was stronger in smokers: per 1 nmol/l higher 25(OH)D, FVC was higher by 1·7 ml (95 % CI 1·1, 2·3) for current smokers and 1·7 ml (95 % CI 1·2, 2·1) for former smokers, compared with 0·8 ml (95 % CI 0·4, 1·2) for never smokers. In summary, the 25(OH)D associations with FEV1 and FVC were positive in both ancestries. In EA, a stronger association was observed for smokers compared with never smokers, which supports the importance of vitamin D in vulnerable populations.

3.
Artigo em Inglês | MEDLINE | ID: mdl-30199657

RESUMO

RATIONALE: Omega-3 poly-unsaturated fatty acids (n-3 PUFAs) have anti-inflammatory properties that could benefit adults with comprised pulmonary health. OBJECTIVE: To investigate n-3 PUFA associations with spirometric measures of pulmonary function tests (PFTs) and determine underlying genetic susceptibility. METHODS: Associations of n-3 PUFA biomarkers (alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid [DPA], and docosahexaenoic acid [DHA]) were evaluated with PFTs (forced expiratory volume in the first second [FEV1], forced vital capacity [FVC], and [FEV1/FVC]) in meta-analyses across seven cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (N=16,134 of European or African ancestry). PFT-associated n-3 PUFAs were carried forward to genome-wide interaction analyses in the four largest cohorts (N=11,962) and replicated in one cohort (N=1,687). Cohort-specific results were combined using joint 2 degree-of-freedom (2df) meta-analyses of single nucleotide polymorphism (SNP) associations and their interactions with n-3 PUFAs. RESULTS: DPA and DHA were positively associated with FEV1 and FVC (P<0.025), with evidence for effect modification by smoking and by sex. Genome-wide analyses identified a novel association of rs11693320-an intronic DPP10 SNP-with FVC when incorporating an interaction with DHA, and the finding was replicated (P2df=9.4×10-9 across discovery and replication cohorts). The rs11693320-A allele (frequency~80%) was associated with lower FVC (PSNP=2.1×10-9; ßSNP= -161.0mL), and the association was attenuated by higher DHA levels (PSNP×DHA interaction=2.1×10-7; ßSNP×DHA interaction=36.2mL). CONCLUSIONS: We corroborated beneficial effects of n-3 PUFAs on pulmonary function. By modeling genome-wide n-3 PUFA interactions, we identified a novel DPP10 SNP association with FVC that was not detectable in much larger studies ignoring this interaction.

4.
Mol Psychiatry ; 2018 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-30131587

RESUMO

Cigarette smoking during pregnancy is a major public health concern. While there are well-described consequences in early child development, there is very little known about the effects of maternal smoking on human cortical biology during prenatal life. We therefore performed a genome-wide differential gene expression analysis using RNA sequencing (RNA-seq) on prenatal (N = 33; 16 smoking-exposed) as well as adult (N = 207; 57 active smokers) human postmortem prefrontal cortices. Smoking exposure during the prenatal period was directly associated with differential expression of 14 genes; in contrast, during adulthood, despite a much larger sample size, only two genes showed significant differential expression (FDR < 10%). Moreover, 1,315 genes showed significantly different exposure effects between maternal smoking during pregnancy and direct exposure in adulthood (FDR < 10%)-these differences were largely driven by prenatal differences that were enriched for pathways previously implicated in addiction and synaptic function. Furthermore, prenatal and age-dependent differentially expressed genes were enriched for genes implicated in non-syndromic autism spectrum disorder (ASD) and were differentially expressed as a set between patients with ASD and controls in postmortem cortical regions. These results underscore the enhanced sensitivity to the biological effect of smoking exposure in the developing brain and offer insight into how maternal smoking during pregnancy affects gene expression in the prenatal human cortex. They also begin to address the relationship between in utero exposure to smoking and the heightened risks for the subsequent development of neuropsychiatric disorders.

5.
Curr Psychiatry Rep ; 20(2): 8, 2018 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-29504045

RESUMO

PURPOSE OF REVIEW: With the advent of the genome-wide association study (GWAS), our understanding of the genetics of addiction has made significant strides forward. Here, we summarize genetic loci containing variants identified at genome-wide statistical significance (P < 5 × 10-8) and independently replicated, review evidence of functional or regulatory effects for GWAS-identified variants, and outline multi-omics approaches to enhance discovery and characterize addiction loci. RECENT FINDINGS: Replicable GWAS findings span 11 genetic loci for smoking, eight loci for alcohol, and two loci for illicit drugs combined and include missense functional variants and noncoding variants with regulatory effects in human brain tissues traditionally viewed as addiction-relevant (e.g., prefrontal cortex [PFC]) and, more recently, tissues often overlooked (e.g., cerebellum). GWAS analyses have discovered several novel, replicable variants contributing to addiction. Using larger sample sizes from harmonized datasets and new approaches to integrate GWAS with multiple 'omics data across human brain tissues holds great promise to significantly advance our understanding of the biology underlying addiction.

6.
Drug Alcohol Depend ; 185: 127-132, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29438887

RESUMO

BACKGROUND: The Fagerström Test for Nicotine Dependence (FTND), a derivation of the Fagerström Tolerance Questionnaire, was first published in 1991. The FTND remains one of the most widely used measures of nicotine dependence for studying genetic and epidemiological risk factors and the likelihood of smoking cessation. However, it is unclear whether secular trends in patterns of smoking alter the psychometric properties of the FTND and its interpretation. METHODS: We examined measurement invariance in the lifetime and current FTND scores across birth cohorts using participants drawn from six study samples (N = 13,775). RESULTS: We found significant (p < 0.05) measurement non-invariance in means and factor loadings of most FTND items by birth cohort, but effect sizes, ranging from r2 = 0.0001 to r2 = 0.0035, indicated that less than 0.5% of the model variance was explained by the measurement non-invariance for each factor loading. To assess its impact, we regressed the lifetime FTND latent variable on well-established factors associated with nicotine dependence (quitting smoking and the nicotinic acetylcholine receptor gene [CHRNA5] variant rs16969968, separately), and we observed that the regression coefficients were unchanged between models with and without adjustment for measurement non-invariance. CONCLUSIONS: These findings suggest that possible FTND non-invariance that occurs across study samples of various birth years has a negligible impact on study results.


Assuntos
Receptores Nicotínicos/genética , Abandono do Hábito de Fumar , Fumar/genética , Tabagismo/diagnóstico , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Polimorfismo de Nucleotídeo Único , Psicometria , Fatores de Risco , Tabagismo/genética , Adulto Jovem
7.
Schizophr Res ; 194: 86-90, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28285025

RESUMO

Nicotine dependence is highly comorbid with schizophrenia, and the etiology of the comorbidity is unknown. To determine whether there is a genetic correlation of smoking behavior with schizophrenia, genome-wide association study (GWAS) meta-analysis results from five smoking phenotypes (ever/never smoker (N=74,035), age of onset of smoking (N=28,647), cigarettes smoked per day (CPD, N=38,860), nicotine dependence (N=10,666), and current/former smoker (N=40,562)) were compared to GWAS meta-analysis results from schizophrenia (N=79,845) using linkage disequilibrium (LD) score regression. First, the SNP heritability (h2g) of each of the smoking phenotypes was computed using LD score regression (ever/never smoker h2g=0.08, age of onset of smoking h2g=0.06, CPD h2g=0.06, nicotine dependence h2g=0.15, current/former smoker h2g=0.07, p<0.001 for all phenotypes). The SNP heritability for nicotine dependence was statistically higher than the SNP heritability for the other smoking phenotypes (p<0.0005 for all two-way comparisons). Next, a statistically significant (p<0.05) genetic correlation was observed between schizophrenia and three of the five smoking phenotypes (nicotine dependence rg=0.14, CPD rg=0.12, and ever/never smoking rg=0.10). These results suggest that there is a component of common genetic variation that is shared between smoking behaviors and schizophrenia.


Assuntos
Esquizofrenia/complicações , Esquizofrenia/genética , Fumar/genética , Comorbidade , Predisposição Genética para Doença , Humanos
8.
Nicotine Tob Res ; 20(4): 448-457, 2018 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-28520984

RESUMO

Introduction: Genetic variants associated with nicotine dependence have previously been identified, primarily in European-ancestry populations. No genome-wide association studies (GWAS) have been reported for smoking behaviors in Hispanics/Latinos in the United States and Latin America, who are of mixed ancestry with European, African, and American Indigenous components. Methods: We examined genetic associations with smoking behaviors in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) (N = 12 741 with smoking data, 5119 ever-smokers), using ~2.3 million genotyped variants imputed to the 1000 Genomes Project phase 3. Mixed logistic regression models accounted for population structure, sampling, relatedness, sex, and age. Results: The known region of CHRNA5, which encodes the α5 cholinergic nicotinic receptor subunit, was associated with heavy smoking at genome-wide significance (p ≤ 5 × 10-8) in a comparison of 1929 ever-smokers reporting cigarettes per day (CPD) > 10 versus 3156 reporting CPD ≤ 10. The functional variant rs16969968 in CHRNA5 had a p value of 2.20 × 10-7 and odds ratio (OR) of 1.32 for the minor allele (A); its minor allele frequency was 0.22 overall and similar across Hispanic/Latino background groups (Central American = 0.17; South American = 0.19; Mexican = 0.18; Puerto Rican = 0.22; Cuban = 0.29; Dominican = 0.19). CHRNA4 on chromosome 20 attained p < 10-4, supporting prior findings in non-Hispanics. For nondaily smoking, which is prevalent in Hispanic/Latino smokers, compared to daily smoking, loci on chromosomes 2 and 4 achieved genome-wide significance; replication attempts were limited by small Hispanic/Latino sample sizes. Conclusions: Associations of nicotinic receptor gene variants with smoking, first reported in non-Hispanic European-ancestry populations, generalized to Hispanics/Latinos despite different patterns of smoking behavior. Implications: We conducted the first large-scale genome-wide association study (GWAS) of smoking behavior in a US Hispanic/Latino cohort, and the first GWAS of daily/nondaily smoking in any population. Results show that the region of the nicotinic receptor subunit gene CHRNA5, which in non-Hispanic European-ancestry smokers has been associated with heavy smoking as well as cessation and treatment efficacy, is also significantly associated with heavy smoking in this Hispanic/Latino cohort. The results are an important addition to understanding the impact of genetic variants in understudied Hispanic/Latino smokers.

9.
Biol Psychiatry ; 82(10): 709-715, 2017 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-28739213

RESUMO

BACKGROUND: There are high levels of comorbidity between schizophrenia and substance use disorder, but little is known about the genetic etiology of this comorbidity. METHODS: We tested the hypothesis that shared genetic liability contributes to the high rates of comorbidity between schizophrenia and substance use disorder. To do this, polygenic risk scores for schizophrenia derived from a large meta-analysis by the Psychiatric Genomics Consortium were computed in three substance use disorder datasets: the Collaborative Genetic Study of Nicotine Dependence (ascertained for tobacco use disorder; n = 918 cases; 988 control subjects), the Collaborative Study on the Genetics of Alcoholism (ascertained for alcohol use disorder; n = 643 cases; 384 control subjects), and the Family Study of Cocaine Dependence (ascertained for cocaine use disorder; n = 210 cases; 317 control subjects). Phenotypes were harmonized across the three datasets and standardized analyses were performed. Genome-wide genotypes were imputed to the 1000 Genomes reference panel. RESULTS: In each individual dataset and in the mega-analysis, strong associations were observed between any substance use disorder diagnosis and the polygenic risk score for schizophrenia (mega-analysis pseudo-R2 range 0.8-3.7%; minimum p = 4 × 10-23). CONCLUSIONS: These results suggest that comorbidity between schizophrenia and substance use disorder is partially attributable to shared polygenic liability. This shared liability is most consistent with a general risk for substance use disorder rather than specific risks for individual substance use disorders and adds to increasing evidence of a blurred boundary between schizophrenia and substance use disorder.


Assuntos
Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Herança Multifatorial/genética , Esquizofrenia/genética , Transtornos Relacionados ao Uso de Substâncias/genética , Adulto , Estudos de Casos e Controles , Comorbidade , Feminino , Genótipo , Humanos , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Adulto Jovem
10.
Hum Genet ; 136(7): 911-919, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28567521

RESUMO

Genome-wide association study (GWAS)-identified variants are enriched for functional elements. However, we have limited knowledge of how functional enrichment may differ by disease/trait and tissue type. We tested a broad set of eight functional elements for enrichment among GWAS-identified SNPs (p < 5×10-8) from the NHGRI-EBI Catalog across seven disease/trait categories: cancer, cardiovascular disease, diabetes, autoimmune disease, psychiatric disease, neurological disease, and anthropometric traits. SNPs were annotated using HaploReg for the eight functional elements across any tissue: DNase sites, expression quantitative trait loci (eQTL), sequence conservation, enhancers, promoters, missense variants, sequence motifs, and protein binding sites. In addition, tissue-specific annotations were considered for brain vs. blood. Disease/trait SNPs were compared to a control set of 4809 SNPs matched to the GWAS SNPs (N = 1639) on allele frequency, gene density, distance to nearest gene, and linkage disequilibrium at ~3:1 ratio. Enrichment analyses were conducted using logistic regression, with Bonferroni correction. Overall, a significant enrichment was observed for all functional elements, except sequence motifs. Missense SNPs showed the strongest magnitude of enrichment. eQTLs were the only functional element significantly enriched across all diseases/traits. Magnitudes of enrichment were generally similar across diseases/traits, where enrichment was statistically significant. Blood vs. brain tissue effects on enrichment were dependent on disease/trait and functional element (e.g., cardiovascular disease: eQTLs P TissueDifference = 1.28 × 10-6 vs. enhancers P TissueDifference = 0.94). Identifying disease/trait-relevant functional elements and tissue types could provide new insight into the underlying biology, by guiding a priori GWAS analyses (e.g., brain enhancer elements for psychiatric disease) or facilitating post hoc interpretation.


Assuntos
Estudo de Associação Genômica Ampla , Fenótipo , Polimorfismo de Nucleotídeo Único , Antropometria , Doenças Autoimunes/genética , Doenças Cardiovasculares/genética , Diabetes Mellitus/genética , Frequência do Gene , Humanos , Desequilíbrio de Ligação , Transtornos Mentais/genética , Mutação de Sentido Incorreto , Neoplasias/genética , Doenças do Sistema Nervoso/genética , Regiões Promotoras Genéticas , Locos de Características Quantitativas
11.
Int J Epidemiol ; 46(3): 894-904, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28082375

RESUMO

Background: Smoking is the strongest environmental risk factor for reduced pulmonary function. The genetic component of various pulmonary traits has also been demonstrated, and at least 26 loci have been reproducibly associated with either FEV 1 (forced expiratory volume in 1 second) or FEV 1 /FVC (FEV 1 /forced vital capacity). Although the main effects of smoking and genetic loci are well established, the question of potential gene-by-smoking interaction effect remains unanswered. The aim of the present study was to assess, using a genetic risk score approach, whether the effect of these 26 loci on pulmonary function is influenced by smoking. Methods: We evaluated the interaction between smoking exposure, considered as either ever vs never or pack-years, and a 26-single nucleotide polymorphisms (SNPs) genetic risk score in relation to FEV 1 or FEV 1 /FVC in 50 047 participants of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) and SpiroMeta consortia. Results: We identified an interaction ( ßint = -0.036, 95% confidence interval, -0.040 to -0.032, P = 0.00057) between an unweighted 26 SNP genetic risk score and smoking status (ever/never) on the FEV 1 /FVC ratio. In interpreting this interaction, we showed that the genetic risk of falling below the FEV /FVC threshold used to diagnose chronic obstructive pulmonary disease is higher among ever smokers than among never smokers. A replication analysis in two independent datasets, although not statistically significant, showed a similar trend in the interaction effect. Conclusions: This study highlights the benefit of using genetic risk scores for identifying interactions missed when studying individual SNPs and shows, for the first time, that persons with the highest genetic risk for low FEV 1 /FVC may be more susceptible to the deleterious effects of smoking.


Assuntos
Volume Expiratório Forçado/genética , Interação Gene-Ambiente , Fumar/epidemiologia , Fumar/genética , Capacidade Vital/genética , Europa (Continente) , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Polimorfismo de Nucleotídeo Único , Medição de Risco , Espirometria
12.
Addict Biol ; 21(6): 1217-1232, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-26202629

RESUMO

Drug abuse is a common and heritable set of disorders, but the underlying genetic factors are largely unknown. We conducted genome-wide association studies of drug abuse using 7 million imputed single nucleotide polymorphisms (SNPs) and insertions/deletions in African Americans (AAs; n = 3742) and European Americans (EAs; n = 6845). Cases were drawn from the Urban Health Study of street-recruited people, who injected drugs and reported abusing opioids, cocaine, marijuana, stimulants and/or other drugs 10 or more times in the past 30 days, and were compared with population controls. Independent replication testing was conducted in 755 AAs and 1131 EAs from the Genetic Association Information Network. An intronic SNP (rs9829896) in the K(lysine) acetyltransferase 2B (KAT2B) gene was significantly associated with drug abuse in AAs (P = 4.63 × 10-8 ) and independently replicated in AAs (P = 0.0019). The rs9829896-C allele (frequency = 12%) had odds ratios of 0.68 and 0.53 across the AA cohorts: meta-analysis P = 3.93 × 10-10 . Rs9829896-C was not associated with drug abuse across the EA cohorts: frequency = 36% and meta-analysis P = 0.12. Using dorsolateral prefrontal cortex data from the BrainCloud cohort, we found that rs9829896-C was associated with reduced KAT2B expression in AAs (n = 113, P = 0.050) but not EAs (n = 110, P = 0.39). KAT2B encodes a transcriptional regulator in the cyclic adenosine monophosphate and dopamine signaling pathways, and rs9829896-C was associated with expression of genes in these pathways: reduced CREBBP expression (P = 0.011) and increased OPRM1 expression (P = 0.016), both in AAs only. Our study identified the KAT2B SNP rs9829896 as having novel and biologically plausible associations with drug abuse and gene expression in AAs but not EAs, suggesting ancestry-specific effects.


Assuntos
Afro-Americanos/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Córtex Pré-Frontal/efeitos dos fármacos , Transtornos Relacionados ao Uso de Substâncias/genética , Fatores de Transcrição de p300-CBP/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Masculino , População Urbana
13.
BMC Genet ; 16: 141, 2015 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-26635092

RESUMO

BACKGROUND: Asthma is a chronic disease of the airways and, despite the advances in the knowledge of associated genetic regions in recent years, their mechanisms have yet to be explored. Several genome-wide association studies have been carried out in recent years, but none of these have involved Latin American populations with a high level of miscegenation, as is seen in the Brazilian population. METHODS: 1246 children were recruited from a longitudinal cohort study in Salvador, Brazil. Asthma symptoms were identified in accordance with an International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. Following quality control, 1,877,526 autosomal SNPs were tested for association with childhood asthma symptoms by logistic regression using an additive genetic model. We complemented the analysis with an estimate of the phenotypic variance explained by common genetic variants. Replications were investigated in independent Mexican and US Latino samples. RESULTS: Two chromosomal regions reached genome-wide significance level for childhood asthma symptoms: the 14q11 region flanking the DAD1 and OXA1L genes (rs1999071, MAF 0.32, OR 1.78, 95% CI 1.45-2.18, p-value 2.83 × 10(-8)) and 15q22 region flanking the FOXB1 gene (rs10519031, MAF 0.04, OR 3.0, 95% CI 2.02-4.49, p-value 6.68 × 10(-8) and rs8029377, MAF 0.03, OR 2.49, 95% CI 1.76-3.53, p-value 2.45 × 10(-7)). eQTL analysis suggests that rs1999071 regulates the expression of OXA1L gene. However, the original findings were not replicated in the Mexican or US Latino samples. CONCLUSIONS: We conclude that the 14q11 and 15q22 regions may be associated with asthma symptoms in childhood.


Assuntos
Asma/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Criança , Pré-Escolar , Cromossomos Humanos Par 14/genética , Feminino , Humanos , América Latina , Masculino , Redes e Vias Metabólicas/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Análise de Componente Principal
14.
PLoS One ; 10(10): e0137601, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26458263

RESUMO

Imputation, the process of inferring genotypes for untyped variants, is used to identify and refine genetic association findings. Inaccuracies in imputed data can distort the observed association between variants and a disease. Many statistics are used to assess accuracy; some compare imputed to genotyped data and others are calculated without reference to true genotypes. Prior work has shown that the Imputation Quality Score (IQS), which is based on Cohen's kappa statistic and compares imputed genotype probabilities to true genotypes, appropriately adjusts for chance agreement; however, it is not commonly used. To identify differences in accuracy assessment, we compared IQS with concordance rate, squared correlation, and accuracy measures built into imputation programs. Genotypes from the 1000 Genomes reference populations (AFR N = 246 and EUR N = 379) were masked to match the typed single nucleotide polymorphism (SNP) coverage of several SNP arrays and were imputed with BEAGLE 3.3.2 and IMPUTE2 in regions associated with smoking behaviors. Additional masking and imputation was conducted for sequenced subjects from the Collaborative Genetic Study of Nicotine Dependence and the Genetic Study of Nicotine Dependence in African Americans (N = 1,481 African Americans and N = 1,480 European Americans). Our results offer further evidence that concordance rate inflates accuracy estimates, particularly for rare and low frequency variants. For common variants, squared correlation, BEAGLE R2, IMPUTE2 INFO, and IQS produce similar assessments of imputation accuracy. However, for rare and low frequency variants, compared to IQS, the other statistics tend to be more liberal in their assessment of accuracy. IQS is important to consider when evaluating imputation accuracy, particularly for rare and low frequency variants.


Assuntos
Genômica/métodos , Genótipo , Adulto , Comportamento de Escolha , Frequência do Gene , Humanos , Desequilíbrio de Ligação , Probabilidade , Controle de Qualidade , Tabagismo/genética
15.
Hum Mol Genet ; 24(23): 6836-48, 2015 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-26395457

RESUMO

Chronic respiratory disorders are important contributors to the global burden of disease. Genome-wide association studies (GWASs) of lung function measures have identified several trait-associated loci, but explain only a modest portion of the phenotypic variability. We postulated that integrating pathway-based methods with GWASs of pulmonary function and airflow obstruction would identify a broader repertoire of genes and processes influencing these traits. We performed two independent GWASs of lung function and applied gene set enrichment analysis to one of the studies and validated the results using the second GWAS. We identified 131 significantly enriched gene sets associated with lung function and clustered them into larger biological modules involved in diverse processes including development, immunity, cell signaling, proliferation and arachidonic acid. We found that enrichment of gene sets was not driven by GWAS-significant variants or loci, but instead by those with less stringent association P-values. Next, we applied pathway enrichment analysis to a meta-analyzed GWAS of airflow obstruction. We identified several biologic modules that functionally overlapped with those associated with pulmonary function. However, differences were also noted, including enrichment of extracellular matrix (ECM) processes specifically in the airflow obstruction study. Network analysis of the ECM module implicated a candidate gene, matrix metalloproteinase 10 (MMP10), as a putative disease target. We used a knockout mouse model to functionally validate MMP10's role in influencing lung's susceptibility to cigarette smoke-induced emphysema. By integrating pathway analysis with population-based genomics, we unraveled biologic processes underlying pulmonary function traits and identified a candidate gene for obstructive lung disease.


Assuntos
Obstrução das Vias Respiratórias/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Pulmão/fisiopatologia , Polimorfismo de Nucleotídeo Único , Obstrução das Vias Respiratórias/fisiopatologia , Animais , Proliferação de Células , Grupo com Ancestrais do Continente Europeu/genética , Genômica , Humanos , Sistema Imunitário , Masculino , Redes e Vias Metabólicas , Camundongos , Fenótipo , Transdução de Sinais
16.
Hum Mol Genet ; 24(20): 5940-54, 2015 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-26220977

RESUMO

Nicotine dependence is influenced by chromosome 15q25.1 single nucleotide polymorphisms (SNPs), including the missense SNP rs16969968 that alters function of the α5 nicotinic acetylcholine receptor (CHRNA5) and noncoding SNPs that regulate CHRNA5 mRNA expression. We tested for cis-methylation quantitative trait loci (cis-meQTLs) using SNP genotypes and DNA methylation levels measured across the IREB2-HYKK-PSMA4-CHRNA5-CHRNA3-CHRNB4 genes on chromosome 15q25.1 in the BrainCloud and Brain QTL cohorts [total N = 175 European-Americans and 65 African-Americans (AAs)]. We identified eight SNPs that were significantly associated with CHRNA5 methylation in prefrontal cortex: P ranging from 6.0 × 10(-10) to 5.6 × 10(-5). These SNP-methylation associations were also significant in frontal cortex, temporal cortex and pons: P ranging from 4.8 × 10(-12) to 3.4 × 10(-3). Of the eight cis-meQTL SNPs, only the intronic CHRNB4 SNP rs11636753 was associated with CHRNA5 methylation independently of the known SNP effects in prefrontal cortex, and it was the most significantly associated SNP with nicotine dependence across five independent cohorts (total N = 7858 European ancestry and 3238 AA participants): P = 6.7 × 10(-4), odds ratio (OR) [95% confidence interval (CI)] = 1.11 (1.05-1.18). The rs11636753 major allele (G) was associated with lower CHRNA5 DNA methylation, lower CHRNA5 mRNA expression and increased nicotine dependence risk. Haplotype analyses showed that rs11636753-G and the functional rs16969968-A alleles together increased risk of nicotine dependence more than each variant alone: P = 3.1 × 10(-12), OR (95% CI) = 1.32 (1.22-1.43). Our findings identify a novel regulatory SNP association with nicotine dependence and connect, for the first time, previously observed differences in CHRNA5 mRNA expression and nicotine dependence risk to underlying DNA methylation differences.


Assuntos
Encéfalo/metabolismo , Metilação de DNA , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único , Receptores Nicotínicos/genética , Tabagismo/genética , Adolescente , Adulto , Afro-Americanos/genética , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Cromossomos Humanos Par 15 , Regulação para Baixo , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudos de Associação Genética , Haplótipos , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/metabolismo , Locos de Características Quantitativas , RNA Mensageiro , Receptores Nicotínicos/metabolismo , Risco , Tabagismo/metabolismo , Adulto Jovem
18.
AIDS ; 29(7): 767-77, 2015 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-25985399

RESUMO

OBJECTIVE: The bone marrow stromal cell antigen 2 (BST2) gene encodes a host restriction factor that acts as an innate immune sensor of HIV-1 exposure and suppresses release of HIV-1 particles. We aimed to identify associations of variants in the BST2 gene region with HIV-1 acquisition and disease progression. DESIGN/METHODS: Using HIV+ cases and HIV- controls from the Urban Health Study (n=3136 African Americans and European Americans who inject drugs), we tested 470 variants in BST2 and its flanking regions for association with HIV-1 acquisition and log-transformed viral load. RESULTS: We found that the single nucleotide polymorphism (SNP) rs113189798 surpassed the P value threshold corrected for multiple testing. The rs113189798-G allele (frequency=16% in African Americans, 4% in European Americans) was associated with increased HIV-1 acquisition risk (meta-analysis P=1.43 × 10): odds ratio (95% confidence interval) of 1.22 (1.01-1.49) in African Americans and 2.17 (1.43-3.33) in European Americans. We also found that the previously reported rs12609479-A allele (frequency=35% in African Americans, 81% in European Americans) was nominally associated with decreased risk of acquiring HIV-1 in our study (meta-analysis P=0.036). Rs12609479-A is predicted to increase BST2 expression and thereby decrease risk of acquiring HIV-1. Rs113189798 and rs12609479 were only weakly correlated [square of the correlation coefficient (r)=0.2-0.4] and represented distinct association signals. None of our tested variants were significantly associated with log-transformed viral load among the HIV-infected cases. CONCLUSION: Our findings support BST2 as a genetic susceptibility factor for HIV-1 acquisition: identifying a novel SNP association for rs13189798 and linking the previously reported regulatory SNP rs12609479 to HIV-1 acquisition.


Assuntos
Antígenos CD/genética , Predisposição Genética para Doença , Infecções por HIV/epidemiologia , Infecções por HIV/genética , Abuso de Substâncias por Via Intravenosa/complicações , Adolescente , Adulto , Afro-Americanos , Grupo com Ancestrais do Continente Europeu , Proteínas Ligadas por GPI/genética , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Carga Viral , Adulto Jovem
19.
Biol Psychiatry ; 78(7): 474-84, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-25744370

RESUMO

BACKGROUND: No opioid receptor, mu 1 (OPRM1) gene polymorphisms, including the functional single nucleotide polymorphism (SNP) rs1799971, have been conclusively associated with heroin/other opioid addiction, despite their biological plausibility. We used evidence of polymorphisms altering OPRM1 expression in normal human brain tissue to nominate and then test associations with heroin addiction. METHODS: We tested 103 OPRM1 SNPs for association with OPRM1 messenger RNA expression in prefrontal cortex from 224 European Americans and African Americans of the BrainCloud cohort. We then tested the 16 putative cis-expression quantitative trait loci (cis-eQTL) SNPs for association with heroin addiction in the Urban Health Study and two replication cohorts, totaling 16,729 European Americans, African Americans, and Australians of European ancestry. RESULTS: Four putative cis-eQTL SNPs were significantly associated with heroin addiction in the Urban Health Study (smallest p = 8.9 × 10(-5)): rs9478495, rs3778150, rs9384169, and rs562859. Rs3778150, located in OPRM1 intron 1, was significantly replicated (p = 6.3 × 10(-5)). Meta-analysis across all case-control cohorts resulted in p = 4.3 × 10(-8): the rs3778150-C allele (frequency = 16%-19%) being associated with increased heroin addiction risk. Importantly, the functional SNP allele rs1799971-A was associated with heroin addiction only in the presence of rs3778150-C (p = 1.48 × 10(-6) for rs1799971-A/rs3778150-C and p = .79 for rs1799971-A/rs3778150-T haplotypes). Lastly, replication was observed for six other intron 1 SNPs that had prior suggestive associations with heroin addiction (smallest p = 2.7 × 10(-8) for rs3823010). CONCLUSIONS: Our findings show that common OPRM1 intron 1 SNPs have replicable associations with heroin addiction. The haplotype structure of rs3778150 and nearby SNPs may underlie the inconsistent associations between rs1799971 and heroin addiction.


Assuntos
Dependência de Heroína/genética , Dependência de Heroína/metabolismo , Polimorfismo de Nucleotídeo Único , Córtex Pré-Frontal/metabolismo , Receptores Opioides mu/genética , Receptores Opioides mu/metabolismo , Adolescente , Adulto , Afro-Americanos/genética , Idoso , Austrália/epidemiologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Dependência de Heroína/epidemiologia , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Estados Unidos/epidemiologia , Adulto Jovem
20.
PLoS One ; 10(3): e0118149, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25786224

RESUMO

Fifty percent of variability in HIV-1 susceptibility is attributable to host genetics. Thus identifying genetic associations is essential to understanding pathogenesis of HIV-1 and important for targeting drug development. To date, however, CCR5 remains the only gene conclusively associated with HIV acquisition. To identify novel host genetic determinants of HIV-1 acquisition, we conducted a genome-wide association study among a high-risk sample of 3,136 injection drug users (IDUs) from the Urban Health Study (UHS). In addition to being IDUs, HIV-controls were frequency-matched to cases on environmental exposures to enhance detection of genetic effects. We tested independent replication in the Women's Interagency HIV Study (N=2,533). We also examined publicly available gene expression data to link SNPs associated with HIV acquisition to known mechanisms affecting HIV replication/infectivity. Analysis of the UHS nominated eight genetic regions for replication testing. SNP rs4878712 in FRMPD1 met multiple testing correction for independent replication (P=1.38x10(-4)), although the UHS-WIHS meta-analysis p-value did not reach genome-wide significance (P=4.47x10(-7) vs. P<5.0x10(-8)) Gene expression analyses provided promising biological support for the protective G allele at rs4878712 lowering risk of HIV: (1) the G allele was associated with reduced expression of FBXO10 (r=-0.49, P=6.9x10(-5)); (2) FBXO10 is a component of the Skp1-Cul1-F-box protein E3 ubiquitin ligase complex that targets Bcl-2 protein for degradation; (3) lower FBXO10 expression was associated with higher BCL2 expression (r=-0.49, P=8x10(-5)); (4) higher basal levels of Bcl-2 are known to reduce HIV replication and infectivity in human and animal in vitro studies. These results suggest new potential biological pathways by which host genetics affect susceptibility to HIV upon exposure for follow-up in subsequent studies.


Assuntos
Proteínas de Transporte/genética , Loci Gênicos , Predisposição Genética para Doença , Infecções por HIV/genética , HIV-1/fisiologia , Replicação Viral , Estudos Transversais , Proteínas F-Box/genética , Feminino , Expressão Gênica , Estudo de Associação Genômica Ampla , Infecções por HIV/fisiopatologia , HIV-1/patogenicidade , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas c-bcl-2/genética , Ubiquitina-Proteína Ligases/genética
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