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Weihong Tang - One of the best experts on this subject based on the ideXlab platform.
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gene centric approach identifies new and known loci for fviii activity and vwf antigen levels in European Americans and african Americans
American Journal of Hematology, 2015Co-Authors: Weihong Tang, Stephen S Rich, Mary Cushman, Saonli Basu, David Green, Leslie A Lange, Qiong Yang, Russell P Tracy, Geoffrey H Tofler, James G WilsonAbstract:Coagulation factor VIII and von Willebrand factor (VWF) are key proteins in procoagulant activation. Higher FVIII coagulant activity (FVIII:C) and VWF antigen (VWF:Ag) are risk factors for cardiovascular disease and venous thromboembolism. Beyond associations with ABO blood group, genetic determinants of FVIII and VWF are not well understood, especially in non European-American populations. We performed a genetic association study of FVIII:C and VWF:Ag that assessed 50,000 gene-centric single nucleotide polymorphisms (SNPs) in 18,556 European Americans (EAs) and 5,047 African Americans (AAs) from five population-based cohorts. Previously unreported associations for FVIII:C were identified in both AAs and EAs with KNG1 (most significantly associated SNP rs710446, Ile581Thr, P = 5.10 × 10−7 in EAs and P = 3.88 × 10−3 in AAs) and VWF rs7962217 (Gly2705Arg, P = 6.30 × 10−9 in EAs and P = 2.98 × 10−2 in AAs). Significant associations for FVIII:C were also observed with F8/TMLHE region SNP rs12557310 in EAs (P = 8.02 × 10−10), with VWF rs1800380 in AAs (P = 5.62 × 10−11), and with MAT1A rs2236568 in AAs (P = 1.69 × 10−6). We replicated previously reported associations of FVIII:C and VWF:Ag with the ABO blood group, VWF rs1063856 (Thr789Ala), rs216321 (Ala852Gln), and VWF rs2229446 (Arg2185Gln). Findings from this study expand our understanding of genetic influences for FVIII:C and VWF:Ag in both EAs and AAs. Am. J. Hematol. 90:534–540, 2015. © 2015 Wiley Periodicals, Inc.
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gene centric approach identifies new and known loci for fviii activity and vwf antigen levels in European Americans and african Americans
American Journal of Hematology, 2015Co-Authors: Weihong Tang, Stephen S Rich, Mary Cushman, Saonli Basu, David Green, Leslie A Lange, Qiong Yang, Russell P Tracy, Geoffrey H Tofler, James G WilsonAbstract:Coagulation factor VIII and von Willebrand factor (VWF) are key proteins in procoagulant activation. Higher FVIII coagulant activity (FVIII :C) and VWF antigen (VWF :Ag) are risk factors for cardiovascular disease and venous thromboembolism. Beyond associations with ABO blood group, genetic determinants of FVIII and VWF are not well understood, especially in non European-American populations. We performed a genetic association study of FVIII :C and VWF:Ag that assessed 50,000 gene-centric single nucleotide polymorphisms (SNPs) in 18,556 European Americans (EAs) and 5,047 African Americans (AAs) from five population-based cohorts. Previously unreported associations for FVIII :C were identified in both AAs and EAs with KNG1 (most significantly associated SNP rs710446, Ile581Thr, Ile581Thr, P = 5.10 × 10(-7) in EAs and P = 3.88 × 10(-3) in AAs) and VWF rs7962217 (Gly2705Arg,P = 6.30 × 10(-9) in EAs and P = 2.98 × 10(-2) in AAs. Significant associations for FVIII :C were also observed with F8/TMLHE region SNP rs12557310 in EAs (P = 8.02 × 10(-10) ), with VWF rs1800380 in AAs (P = 5.62 × 10(-11) ), and with MAT1A rs2236568 in AAs (P51.69 × 10(-6) ). We replicated previously reported associations of FVIII :C and VWF :Ag with the ABO blood group, VWF rs1063856(Thr789Ala), rs216321 (Ala852Gln), and VWF rs2229446 (Arg2185Gln). Findings from this study expand our understanding of genetic influences for FVIII :C and VWF :Ag in both EAs and AAs.
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a genetic association study of activated partial thromboplastin time in European Americans and african Americans the aric study
Human Molecular Genetics, 2015Co-Authors: Luchen Weng, Eric Boerwinkle, Mary Cushman, James S Pankow, Saonli Basu, Aaron R Folsom, Weihong TangAbstract:Reduced activated partial thromboplastin time (aPTT) is a risk marker for incident and recurrent venous thromboembolism (VTE). Genetic factors influencing aPTT are not well understood, especially in populations of non-European ancestry. The present study aimed to identify aPTT-related gene variants in both European Americans (EAs) and African Americans (AAs). We conducted a genetic association study for aPTT in 9719 EAs and 2799 AAs from the Atherosclerosis Risk in Communities (ARIC) study. Using the Candidate Gene Association Resource (CARe) consortium candidate gene array, the analyses were based on ∼50 000 SNPs in ∼2000 candidate genes. In EAs, the analyses identified a new independent association for aPTT in F5 (rs2239852, P-value = 1.9 × 10(-8)), which clusters with a coding variant rs6030 (P-value = 7.8 × 10(-7)). The remaining significant signals were located on F5, HRG, KNG1, F11, F12 and ABO and have been previously reported in EA populations. In AAs, significant signals were identified in KNG1, HRG, F12, ABO and VWF, with the leading variants in KNG1, HRG and F12 being the same as in the EAs; the significant variant in VWF (rs2229446, P-value = 1.2 × 10(-6)) was specific to the AA sample (minor allele frequency = 19% in AAs and 0.2% in EAs) and has not been previously reported. This is the first study to report aPTT-related genetic variants in AAs. Our findings in AAs demonstrate transferability of previously reported associations with KNG1, HRG and F12 in EAs. We also identified new associations at F5 in EAs and VWF in AAs that have not been previously reported for aPTT.
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association of genome wide variation with highly sensitive cardiac troponin t levels in European Americans and blacks a meta analysis from atherosclerosis risk in communities and cardiovascular health studies
Circulation-cardiovascular Genetics, 2013Co-Authors: Maja Barbalic, Thomas H Mosley, Ariel Brautbar, Vijay Nambi, Ron C Hoogeveen, Weihong Tang, Jerome I Rotter, Christopher Defilippi, Christopher J Odonnell, Sekar KathiresanAbstract:Background— High levels of cardiac troponin T, measured by a highly sensitive assay (hs-cTnT), are strongly associated with incident coronary heart disease and heart failure. To date, no large-scale genome-wide association study of hs-cTnT has been reported. We sought to identify novel genetic variants that are associated with hs-cTnT levels. Methods and Results— We performed a genome-wide association in 9491 European Americans and 2053 blacks free of coronary heart disease and heart failure from 2 prospective cohorts: the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study. Genome-wide association studies were conducted in each study and race stratum. Fixed-effect meta-analyses combined the results of linear regression from 2 cohorts within each race stratum and then across race strata to produce overall estimates and probability values. The meta-analysis identified a significant association at chromosome 8q13 (rs10091374; P =9.06×10−9) near the nuclear receptor coactivator 2 ( NCOA2 ) gene. Overexpression of NCOA2 can be detected in myoblasts. An additional analysis using logistic regression and the clinically motivated 99th percentile cut point detected a significant association at 1q32 (rs12564445; P =4.73×10−8) in the gene TNNT2 , which encodes the cardiac troponin T protein itself. The hs-cTnT-associated single-nucleotide polymorphisms were not associated with coronary heart disease in a large case-control study, but rs12564445 was significantly associated with incident heart failure in Atherosclerosis Risk in Communities Study European Americans (hazard ratio=1.16; P =0.004). Conclusions— We identified 2 loci, near NCOA2 and in the TNNT2 gene, at which variation was significantly associated with hs-cTnT levels. Further use of the new assay should enable replication of these results.
Robert Culverhouse - One of the best experts on this subject based on the ideXlab platform.
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multiple distinct chrnb3 chrna6 variants are genetic risk factors for nicotine dependence in african Americans and European Americans
Addiction, 2014Co-Authors: Robert Culverhouse, Naomi Breslau, Eric O. Johnson, Dorothy K Hatsukami, Brooke Sadler, Andrew Brooks, Victor Hesselbrock, Marc A Schuckit, Jay A TischfieldAbstract:Aims Studies have shown association between common variants in the α6-β3 nicotinic receptor subunit gene cluster and nicotine dependence in European ancestry populations. We investigate whether this generalizes to African Americans, whether the association is specific to nicotine dependence and whether this region contains additional genetic contributors to nicotine dependence. Design We examined consistency of association across studies and race between the α6β3 nicotinic receptor subunit locus and nicotine, alcohol, marijuana and cocaine dependence in three independent studies. Setting United States of America. Participants European Americans and African Americans from three case-control studies of substance dependence. Measurements Subjects were evaluated using the Semi- Structured Assessment for the Genetics of Alcoholism. Nicotine dependence was determined using the Fagerstrom Test for Nicotine Dependence. Findings The single nucleotide polymorphism rs13273442 was associated significantly with nicotine dependence across all three studies in both ancestry groups (odds ratio (OR) = 0.75, P = 5.8 × 10 −4 European Americans; OR = 0.80, P = 0.05 African Americans). No other substance dependence was associated con- sistently with this variant in either group. Another SNP in the region, rs4952, remains modestly associated with nicotine dependence in the combined data after conditioning on rs13273442. Conclusions The common variant rs13273442 in the CHRNB3-CHNRA6 region is associated significantly with nicotine dependence in European Americans and African Americans across studies recruited for nicotine, alcohol and cocaine dependence. Although these data are modestly powered for other substances, our results provide no evidence that correlates of rs13273442 represent a general substance dependence liability. Additional variants probably account for some of the association of this region to nicotine dependence.
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the chrna5 chrna3 chrnb4 nicotinic receptor subunit gene cluster affects risk for nicotine dependence in african Americans and in European Americans
Cancer Research, 2009Co-Authors: Nancy L Saccone, Weimin Duan, Jen C Wang, Scott F Saccone, John P Budde, Richard A Grucza, Naomi Breslau, Eric O. Johnson, Robert CulverhouseAbstract:Genetic association studies have shown the importance of variants in the CHRNA5-CHRNA3-CHRNB4 cholinergic nicotinic receptor subunit gene cluster on chromosome 15q24-25.1 for the risk of nicotine dependence, smoking, and lung cancer in populations of European descent. We have carried out a detailed study of this region using dense genotyping in both European-Americans and African-Americans. We genotyped 75 known single nucleotide polymorphisms (SNPs) and one sequencing-discovered SNP in an African-American sample ( N = 710) and in a European-American sample ( N = 2,062). Cases were nicotine-dependent and controls were nondependent smokers. The nonsynonymous CHRNA5 SNP rs16969968 is the most significant SNP associated with nicotine dependence in the full sample of 2,772 subjects [ P = 4.49 × 10 −8 ; odds ratio (OR), 1.42; 95% confidence interval (CI), 1.25–1.61] as well as in African-Americans only ( P = 0.015; OR, 2.04; 1.15–3.62) and in European-Americans only ( P = 4.14 × 10 −7 ; OR, 1.40; 1.23–1.59). Other SNPs that have been shown to affect the mRNA levels of CHRNA5 in European-Americans are associated with nicotine dependence in African-Americans but not in European-Americans. The CHRNA3 SNP rs578776, which has a low correlation with rs16969968, is associated with nicotine dependence in European-Americans but not in African-Americans. Less common SNPs (frequency ≤ 5%) are also associated with nicotine dependence. In summary, multiple variants in this gene cluster contribute to nicotine dependence risk, and some are also associated with functional effects on CHRNA5 . The nonsynonymous SNP rs16969968, a known risk variant in populations of European-descent, is also significantly associated with risk in African-Americans. Additional SNPs contribute to risk in distinct ways in these two populations. [Cancer Res 2009;69(17):6848–56]
Joel Gelernter - One of the best experts on this subject based on the ideXlab platform.
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genome wide association study identifies a regulatory variant of rgma associated with opioid dependence in European Americans
Biological Psychiatry, 2018Co-Authors: Zhongshan Cheng, Lindsay A Farrer, Henry R Kranzler, Richard Sherva, Hang Zhou, Joel GelernterAbstract:Abstract Background Opioid dependence (OD) is at epidemic levels in the United States. Genetic studies can provide insight into its biology. Methods We completed an OD genome-wide association study in 3058 opioid-exposed European Americans, 1290 of whom met criteria for a DSM-IV diagnosis of OD. Analysis used DSM-IV criterion count. Results By meta-analysis of four cohorts, Yale-Penn 1 (n = 1388), Yale-Penn 2 (n = 996), Yale-Penn 3 (n = 98), and SAGE (Study of Addiction: Genetics and Environment) (n = 576), we identified a variant on chromosome 15, rs12442183, near RGMA, associated with OD (p = 1.3 × 10−8). The association was also genome-wide significant in Yale-Penn 1 taken individually and nominally significant in two of the other three samples. The finding was further supported in a meta-analysis of all available opioid-exposed African Americans (n = 2014 [1106 meeting DSM-IV OD criteria]; p = 3.0 × 10−3) from three cohorts; there was nominal significance in two of these samples. Thus, of seven subsamples examined in two populations, one was genome-wide significant, and four of six were nominally (or nearly) significant. RGMA encodes repulsive guidance molecule A, which is a central nervous system axon guidance protein. Risk allele rs12442183*T was correlated with higher expression of a specific RGMA transcript variant in frontal cortex (p = 2 × 10−3). After chronic morphine injection, the homologous mouse gene (Rgma) was upregulated in C57BL/6J striatum. Coexpression analysis of 1301 brain samples revealed that RGMA messenger RNA expression was associated with that of four genes implicated in other psychiatric disorders, including GRIN1. Conclusions This is the first study to demonstrate an association of RGMA with OD. It provides a new lead into our understanding of OD pathophysiology.
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genomewide association study for maximum number of alcoholic drinks in European Americans and african Americans
Alcoholism: Clinical and Experimental Research, 2015Co-Authors: Henry R Kranzler, Lindsay A Farrer, Richard Sherva, Carolyn E Sartor, Laura Almasy, Ryan Koesterer, Hongyu Zhao, Joel GelernterAbstract:Background We conducted a genomewide association study (GWAS) for maximum number of alcoholic drinks consumed in a 24-hour period (“MaxDrinks”), in 2 independent samples comprised of over 9,500 subjects, following up on our GWAS for alcohol dependence (AD) in European Americans (EAs) and African Americans (AAs). Methods The samples included our GWAS samples (Yale-UPenn) recruited for studies of the genetics of drug or AD, and a publicly available sample: the Study of Addiction: Genetics and Environment (SAGE). Genomewide association analysis was performed for ~890,000 single nucleotide polymorphisms (SNPs) using linear association random effects models. EAs and AAs were separately analyzed. Results The results confirmed significant associations of the well-known functional loci at ADH1B with MaxDrinks in EAs (rs1229984 Arg48His p = 5.96 × 10−15) and AAs (rs2066702 Arg370Cys, p = 2.50 × 10−10). The region of significant association on chromosome 4 was extended to LOC100507053 in AAs but not EAs. We also identified potentially novel significant common SNPs for MaxDrinks in EAs in the Yale-UPenn sample: rs1799876 at SERPINC1 on chromosome 1 (4.00 × 10−8) and rs2309169 close to ANKRD36 on chromosome 2 (p = 5.58 × 10−9). After adjusting for the peak SNP rs1229984 on ADH1B, rs1799876 was nearly significant (p = 1.99 × 10−7) and rs2309169 remained highly significant (2.12 × 10−9). Conclusions The results provide further support that ADH1B modulates alcohol consumption. Future replications of potential novel loci are warranted. This is the largest MaxDrinks GWAS to date, the first in AAs.
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Eye color: A potential indicator of alcohol dependence risk in European Americans
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 2015Co-Authors: Arvis Sulovari, Lindsay A Farrer, Joel GelernterAbstract:In archival samples of European-ancestry subjects, light-eyed individuals have been found to consume more alcohol than dark-eyed individuals. No published population-based studies have directly tested the association between alcohol dependence (AD) and eye color. We hypothesized that light-eyed individuals have a higher prevalence of AD than dark-eyed individuals. A mixture model was used to select a homogeneous sample of 1,263 European-Americans and control for population stratification. After quality control, we conducted an association study using logistic regression, adjusting for confounders (age, sex, and genetic ancestry). We found evidence of association between AD and blue eye color (P = 0.0005 and odds ratio = 1.83 (1.31-2.57)), supporting light eye color as a risk factor relative to brown eye color. Network-based analyses revealed a statistically significant (P = 0.02) number of genetic interactions between eye color genes and AD-associated genes. We found evidence of linkage disequilibrium between an AD-associated GABA receptor gene cluster, GABRB3/GABRG3, and eye color genes, OCA2/HERC2, as well as between AD-associated GRM5 and pigmentation-associated TYR. Our population-phenotype, network, and linkage disequilibrium analyses support association between blue eye color and AD. Although we controlled for stratification we cannot exclude underlying occult stratification as a contributor to this observation. Although replication is needed, our findings suggest that eye pigmentation information may be useful in research on AD. Further characterization of this association may unravel new AD etiological factors. © 2015 Wiley Periodicals, Inc. Language: en
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hypermethylation of oprm1 promoter region in European Americans with alcohol dependence
Journal of Human Genetics, 2012Co-Authors: Huiping Zhang, Aryeh I Herman, Henry R Kranzler, Raymond F Anton, Arthur A Simen, Joel GelernterAbstract:The μ-opioid receptor mediates rewarding effects of alcohol and illicit drugs. We hypothesized that altered DNA methylation in the μ-opioid receptor gene (OPRM1) might influence the vulnerability to alcohol dependence (AD). Genomic DNA was extracted from the peripheral blood of 125 European Americans with AD and 69 screened European American controls. Methylation levels of 16 CpGs in the OPRM1 promoter region were examined by bisulfite sequencing analysis. A multivariate analysis of covariance was conducted to analyze AD-associated methylation changes in the OPRM1 promoter region, using days of intoxication in the past 30 days, sex, age, ancestry proportion and childhood adversity (CA) as covariates. Three CpGs (80, 71, and 10 bp upstream of the OPRM1 translation start site) were more highly methylated in AD cases than in controls (CpG-80: P=0.033; CpG-71: P=0.004; CpG-10: P=0.008). Although these sites were not significant after correction for multiple comparisons, the overall methylation level of the 16 CpGs was significantly higher in AD cases (13.6%) than in controls (10.6%) (P=0.049). Sex and CA did not significantly influence OPRM1 promoter methylation levels. Our findings suggest that OPRM1 promoter hypermethylation may increase the risk for AD and other substance dependence disorders.
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adh4 gene variation is associated with alcohol dependence and drug dependence in European Americans results from hwd tests and case control association studies
Neuropsychopharmacology, 2006Co-Authors: Xingguang Luo, Henry R Kranzler, Lingjun Zuo, Jaakko Lappalainen, Baozhu Yang, Joel GelernterAbstract:The alcohol dehydrogenase (ADH) family constitutes one of the key sets of enzymes responsible for the oxidation of alcohol. The ADH4 gene, an important member of this family, is a functional and positional candidate for alcohol dependence. The present study aimed to investigate the relationship between ADH4 gene variation and alcohol dependence and drug dependence in European-Americans (EAs) and African-Americans (AAs). Seven single nucleotide polymorphisms (SNPs) spanning the ADH4 gene were genotyped in 365 healthy controls (317 EAs and 48 AAs) and 561 subjects (400 EAs and 161 AAs) affected with alcohol dependence and/or drug dependence (436 with alcohol dependence; 356 with drug dependence). Hardy–Weinberg equilibrium (HWE) for the genotype frequency distributions of these markers was tested in all phenotype groups to evaluate association between ADH4 gene variation and phenotypes and to fine-map the disease risk locus. The allele, genotype, and haplotype frequency distributions of these markers were compared between cases and controls to confirm the associations. The genotype frequency distributions of ADH4 markers were in HWE in EA controls, but were in Hardy–Weinberg disequilibrium (HWD) (ie, deviation from HWE) in EA cases. Among all markers, SNP2 (rs1042363) at exon 9 or SNP6 (rs1800759) at the promoter showed the greatest degree of HWD, among patients with either alcohol dependence or drug dependence. Significant differences between EA cases and controls were seen for genotype (10−6
risk loci for both alcohol dependence and drug dependence.
Eric O. Johnson - One of the best experts on this subject based on the ideXlab platform.
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multiple distinct chrnb3 chrna6 variants are genetic risk factors for nicotine dependence in african Americans and European Americans
Addiction, 2014Co-Authors: Robert Culverhouse, Naomi Breslau, Eric O. Johnson, Dorothy K Hatsukami, Brooke Sadler, Andrew Brooks, Victor Hesselbrock, Marc A Schuckit, Jay A TischfieldAbstract:Aims Studies have shown association between common variants in the α6-β3 nicotinic receptor subunit gene cluster and nicotine dependence in European ancestry populations. We investigate whether this generalizes to African Americans, whether the association is specific to nicotine dependence and whether this region contains additional genetic contributors to nicotine dependence. Design We examined consistency of association across studies and race between the α6β3 nicotinic receptor subunit locus and nicotine, alcohol, marijuana and cocaine dependence in three independent studies. Setting United States of America. Participants European Americans and African Americans from three case-control studies of substance dependence. Measurements Subjects were evaluated using the Semi- Structured Assessment for the Genetics of Alcoholism. Nicotine dependence was determined using the Fagerstrom Test for Nicotine Dependence. Findings The single nucleotide polymorphism rs13273442 was associated significantly with nicotine dependence across all three studies in both ancestry groups (odds ratio (OR) = 0.75, P = 5.8 × 10 −4 European Americans; OR = 0.80, P = 0.05 African Americans). No other substance dependence was associated con- sistently with this variant in either group. Another SNP in the region, rs4952, remains modestly associated with nicotine dependence in the combined data after conditioning on rs13273442. Conclusions The common variant rs13273442 in the CHRNB3-CHNRA6 region is associated significantly with nicotine dependence in European Americans and African Americans across studies recruited for nicotine, alcohol and cocaine dependence. Although these data are modestly powered for other substances, our results provide no evidence that correlates of rs13273442 represent a general substance dependence liability. Additional variants probably account for some of the association of this region to nicotine dependence.
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the chrna5 chrna3 chrnb4 nicotinic receptor subunit gene cluster affects risk for nicotine dependence in african Americans and in European Americans
Cancer Research, 2009Co-Authors: Nancy L Saccone, Weimin Duan, Jen C Wang, Scott F Saccone, John P Budde, Richard A Grucza, Naomi Breslau, Eric O. Johnson, Robert CulverhouseAbstract:Genetic association studies have shown the importance of variants in the CHRNA5-CHRNA3-CHRNB4 cholinergic nicotinic receptor subunit gene cluster on chromosome 15q24-25.1 for the risk of nicotine dependence, smoking, and lung cancer in populations of European descent. We have carried out a detailed study of this region using dense genotyping in both European-Americans and African-Americans. We genotyped 75 known single nucleotide polymorphisms (SNPs) and one sequencing-discovered SNP in an African-American sample ( N = 710) and in a European-American sample ( N = 2,062). Cases were nicotine-dependent and controls were nondependent smokers. The nonsynonymous CHRNA5 SNP rs16969968 is the most significant SNP associated with nicotine dependence in the full sample of 2,772 subjects [ P = 4.49 × 10 −8 ; odds ratio (OR), 1.42; 95% confidence interval (CI), 1.25–1.61] as well as in African-Americans only ( P = 0.015; OR, 2.04; 1.15–3.62) and in European-Americans only ( P = 4.14 × 10 −7 ; OR, 1.40; 1.23–1.59). Other SNPs that have been shown to affect the mRNA levels of CHRNA5 in European-Americans are associated with nicotine dependence in African-Americans but not in European-Americans. The CHRNA3 SNP rs578776, which has a low correlation with rs16969968, is associated with nicotine dependence in European-Americans but not in African-Americans. Less common SNPs (frequency ≤ 5%) are also associated with nicotine dependence. In summary, multiple variants in this gene cluster contribute to nicotine dependence risk, and some are also associated with functional effects on CHRNA5 . The nonsynonymous SNP rs16969968, a known risk variant in populations of European-descent, is also significantly associated with risk in African-Americans. Additional SNPs contribute to risk in distinct ways in these two populations. [Cancer Res 2009;69(17):6848–56]
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the chrna5 chrna3 chrnb4 nicotinic receptor subunit gene cluster affects risk for nicotine dependence in african Americans and in European Americans
Cancer Research, 2009Co-Authors: Nancy L Saccone, Weimin Duan, Jen C Wang, Scott F Saccone, Richard A Grucza, Naomi Breslau, Eric O. Johnson, Dorothy K Hatsukami, Lingwei Sun, John P BuddeAbstract:Genetic association studies have shown the importance of variants in the CHRNA5-CHRNA3-CHRNB4 cholinergic nicotinic receptor subunit gene cluster on chromosome 15q24-25.1 for the risk of nicotine dependence, smoking, and lung cancer in populations of European descent. We have carried out a detailed study of this region using dense genotyping in both European-Americans and African-Americans. We genotyped 75 known single nucleotide polymorphisms (SNPs) and one sequencing-discovered SNP in an African-American sample (N = 710) and in a European-American sample (N = 2,062). Cases were nicotine-dependent and controls were nondependent smokers. The nonsynonymous CHRNA5 SNP rs16969968 is the most significant SNP associated with nicotine dependence in the full sample of 2,772 subjects [P = 4.49 x 10(-8); odds ratio (OR), 1.42; 95% confidence interval (CI), 1.25-1.61] as well as in African-Americans only (P = 0.015; OR, 2.04; 1.15-3.62) and in European-Americans only (P = 4.14 x 10(-7); OR, 1.40; 1.23-1.59). Other SNPs that have been shown to affect the mRNA levels of CHRNA5 in European-Americans are associated with nicotine dependence in African-Americans but not in European-Americans. The CHRNA3 SNP rs578776, which has a low correlation with rs16969968, is associated with nicotine dependence in European-Americans but not in African-Americans. Less common SNPs (frequency
Naomi Breslau - One of the best experts on this subject based on the ideXlab platform.
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multiple distinct chrnb3 chrna6 variants are genetic risk factors for nicotine dependence in african Americans and European Americans
Addiction, 2014Co-Authors: Robert Culverhouse, Naomi Breslau, Eric O. Johnson, Dorothy K Hatsukami, Brooke Sadler, Andrew Brooks, Victor Hesselbrock, Marc A Schuckit, Jay A TischfieldAbstract:Aims Studies have shown association between common variants in the α6-β3 nicotinic receptor subunit gene cluster and nicotine dependence in European ancestry populations. We investigate whether this generalizes to African Americans, whether the association is specific to nicotine dependence and whether this region contains additional genetic contributors to nicotine dependence. Design We examined consistency of association across studies and race between the α6β3 nicotinic receptor subunit locus and nicotine, alcohol, marijuana and cocaine dependence in three independent studies. Setting United States of America. Participants European Americans and African Americans from three case-control studies of substance dependence. Measurements Subjects were evaluated using the Semi- Structured Assessment for the Genetics of Alcoholism. Nicotine dependence was determined using the Fagerstrom Test for Nicotine Dependence. Findings The single nucleotide polymorphism rs13273442 was associated significantly with nicotine dependence across all three studies in both ancestry groups (odds ratio (OR) = 0.75, P = 5.8 × 10 −4 European Americans; OR = 0.80, P = 0.05 African Americans). No other substance dependence was associated con- sistently with this variant in either group. Another SNP in the region, rs4952, remains modestly associated with nicotine dependence in the combined data after conditioning on rs13273442. Conclusions The common variant rs13273442 in the CHRNB3-CHNRA6 region is associated significantly with nicotine dependence in European Americans and African Americans across studies recruited for nicotine, alcohol and cocaine dependence. Although these data are modestly powered for other substances, our results provide no evidence that correlates of rs13273442 represent a general substance dependence liability. Additional variants probably account for some of the association of this region to nicotine dependence.
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the chrna5 chrna3 chrnb4 nicotinic receptor subunit gene cluster affects risk for nicotine dependence in african Americans and in European Americans
Cancer Research, 2009Co-Authors: Nancy L Saccone, Weimin Duan, Jen C Wang, Scott F Saccone, John P Budde, Richard A Grucza, Naomi Breslau, Eric O. Johnson, Robert CulverhouseAbstract:Genetic association studies have shown the importance of variants in the CHRNA5-CHRNA3-CHRNB4 cholinergic nicotinic receptor subunit gene cluster on chromosome 15q24-25.1 for the risk of nicotine dependence, smoking, and lung cancer in populations of European descent. We have carried out a detailed study of this region using dense genotyping in both European-Americans and African-Americans. We genotyped 75 known single nucleotide polymorphisms (SNPs) and one sequencing-discovered SNP in an African-American sample ( N = 710) and in a European-American sample ( N = 2,062). Cases were nicotine-dependent and controls were nondependent smokers. The nonsynonymous CHRNA5 SNP rs16969968 is the most significant SNP associated with nicotine dependence in the full sample of 2,772 subjects [ P = 4.49 × 10 −8 ; odds ratio (OR), 1.42; 95% confidence interval (CI), 1.25–1.61] as well as in African-Americans only ( P = 0.015; OR, 2.04; 1.15–3.62) and in European-Americans only ( P = 4.14 × 10 −7 ; OR, 1.40; 1.23–1.59). Other SNPs that have been shown to affect the mRNA levels of CHRNA5 in European-Americans are associated with nicotine dependence in African-Americans but not in European-Americans. The CHRNA3 SNP rs578776, which has a low correlation with rs16969968, is associated with nicotine dependence in European-Americans but not in African-Americans. Less common SNPs (frequency ≤ 5%) are also associated with nicotine dependence. In summary, multiple variants in this gene cluster contribute to nicotine dependence risk, and some are also associated with functional effects on CHRNA5 . The nonsynonymous SNP rs16969968, a known risk variant in populations of European-descent, is also significantly associated with risk in African-Americans. Additional SNPs contribute to risk in distinct ways in these two populations. [Cancer Res 2009;69(17):6848–56]
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the chrna5 chrna3 chrnb4 nicotinic receptor subunit gene cluster affects risk for nicotine dependence in african Americans and in European Americans
Cancer Research, 2009Co-Authors: Nancy L Saccone, Weimin Duan, Jen C Wang, Scott F Saccone, Richard A Grucza, Naomi Breslau, Eric O. Johnson, Dorothy K Hatsukami, Lingwei Sun, John P BuddeAbstract:Genetic association studies have shown the importance of variants in the CHRNA5-CHRNA3-CHRNB4 cholinergic nicotinic receptor subunit gene cluster on chromosome 15q24-25.1 for the risk of nicotine dependence, smoking, and lung cancer in populations of European descent. We have carried out a detailed study of this region using dense genotyping in both European-Americans and African-Americans. We genotyped 75 known single nucleotide polymorphisms (SNPs) and one sequencing-discovered SNP in an African-American sample (N = 710) and in a European-American sample (N = 2,062). Cases were nicotine-dependent and controls were nondependent smokers. The nonsynonymous CHRNA5 SNP rs16969968 is the most significant SNP associated with nicotine dependence in the full sample of 2,772 subjects [P = 4.49 x 10(-8); odds ratio (OR), 1.42; 95% confidence interval (CI), 1.25-1.61] as well as in African-Americans only (P = 0.015; OR, 2.04; 1.15-3.62) and in European-Americans only (P = 4.14 x 10(-7); OR, 1.40; 1.23-1.59). Other SNPs that have been shown to affect the mRNA levels of CHRNA5 in European-Americans are associated with nicotine dependence in African-Americans but not in European-Americans. The CHRNA3 SNP rs578776, which has a low correlation with rs16969968, is associated with nicotine dependence in European-Americans but not in African-Americans. Less common SNPs (frequency
