Biomedical subjects

Ming D Li

Publications and source records attributed to Ming D Li.

At least 19 recordsLinked to original sources

PubMed2007

Association analysis of the protein phosphatase 1 regulatory subunit 1B (PPP1R1B) gene with nicotine dependence in European- and African-American smokers.

The protein phosphatase 1 regulatory subunit 1B gene (PPP1R1B; also known as dopamine and cAMP-regulated phosphoprotein; DARPP32) is a target for the actions of dopamine. Because the mesolimbic dopaminergic system is implicated in the reinforcing effects of many drugs, including nicotine, PPP1R1B is considered a plausible candidate for involvement in the development of vulnerability to nicotine dependence (ND). Further, this gene is located within a region on chromosome 17 that demonstrated "suggestive linkage" to ND in our previous genome-wide scan. In the present study, we analyzed six single nucleotide polymorphisms (SNPs) within PPP1R1B for association with three ND measures: smoking quantity (SQ), the heaviness of smoking index (HSI), and the Fagerström Test for ND (FTND) score. Our sample consisted of 602 nuclear families of African-American (AA) or European-American (EA) origin. No significant associations were found for single SNPs after correction for multiple testing. However, haplotype analysis indicated that in the EA sample, the C-T-G-C haplotype formed by rs2271309-rs907094-rs3764352-rs3817160 with a frequency of 32.0% was significantly associated with SQ (Z = 2.50; P = 0.01), even after Bonferroni correction. No significant associations with haplotypes were found in the AA sample. In summary, our findings provide the first evidence for the potential involvement of PPP1R1B in the etiology of ND and further investigation is thus warranted.

Adult↗

PubMed2006

Fine mapping of a linkage region on chromosome 17p13 reveals that GABARAP and DLG4 are associated with vulnerability to nicotine dependence in European-Americans.

A two-stage association study was conducted targeting a genomic region on chromosome 17p13 that we reported likely to harbor susceptibility gene(s) for nicotine dependence (ND). Participants were 2037 subjects from 602 nuclear families of either African-American (AA) or European-American (EA) origin from our Mid-South Tobacco Family (MSTF) cohort. We first examined 10 single nucleotide polymorphisms (SNPs) in six genes within the targeted region of about 90 kb to determine which SNP/gene was associated with ND, assessed by smoking quantity (SQ), the heaviness of smoking index (HSI) and the Fagerström Test for ND (FTND). Individual SNP analysis revealed that SNPs rs17710 and rs222843 in GABA(A) receptor-associated protein (GABARAP) exhibited a significant association with at least one age- and gender-adjusted ND measure in the EA sample and rs222843 remained significant with the FTND after correction for multiple testing (P = 0.009). Although no SNP in DLG4 was significantly associated with ND, we found a G-G haplotype with a frequency of 14.2% formed by SNPs rs2242449 and rs507506 within the gene that showed significant inverse associations with all three ND measures [P = 0.003, 0.015 and 0.024, for SQ (defined as the number of cigarettes smoked per day), HSI and FTND, respectively]. We also found an A-A haplotype with a frequency of 8.8% formed by SNPs rs17710 and rs222843 in GABARAP, which revealed significant associations with all three ND measures (P = 0.006, 0.019 and 0.024, for SQ, HSI and FTND, respectively). To confirm these findings with a better coverage of GABARAP and DLG4, we conducted a second-stage association analysis by genotyping four more SNPs for GABARAP and nine more for DLG4 on the same set of samples. Our results from the second stage of individual SNP- and/or haplotype-based association analysis supported our finding of significant association of the DLG4 gene with ND. No significant association of GABARAP or DLG4 with ND was detected in the AA sample. Further, by comparing the linkage signal before and after adjustment for the SNPs of GABARAP and DLG4, we found that inclusion of the SNPs of the two genes as covariates largely reduced the linkage signal in the EA sample, but kept nearly unchanged in the AA sample. Taken together, our two-stage association analysis and linkage analysis results indicate that the GABARAP and DLG4 genes are involved in the etiology of ND in EA smokers. Further investigation of neurobiological mechanisms of the two genes in the etiology of ND is thus warranted.

Adaptor Proteins, Signal Transducing↗

PubMed2006

A genomewide search finds major susceptibility loci for nicotine dependence on chromosome 10 in African Americans.

Epidemiological studies have demonstrated that genetic factors account for at least 50% of the liability for nicotine dependence (ND). Although several linkage studies have been conducted, all samples to date were primarily of European origin. In this study, we conducted a genomewide scan of 1,261 individuals, representing 402 nuclear families, of African American (AA) origin. We examined 385 autosomal microsatellite markers for ND, which was assessed by smoking quantity (SQ), the Heaviness of Smoking Index (HSI), and the Fagerstrom Test for ND (FTND). After performing linkage analyses using various methods implemented in the GENEHUNTER and S.A.G.E. programs, we found a region near marker D10S1432 on chromosome 10q22 that showed a significant linkage to indexed SQ, with a maximum LOD score of 4.17 at 92 cM and suggestive linkage to HSI, SQ, and log-transformed SQ. Additionally, we identified three regions that met the criteria for suggestive linkage to at least one ND measure: on chromosomes 9q31 at marker D9S1825, 11p11 between markers D11S1993 and D11S1344, and 13q13 between markers D13S325 and D13S788. Other locations on chromosomes 15p11, 17q25, and 18q12 exhibited some evidence of linkage for ND (LOD >1.44). The four regions with significant or suggestive linkage were positive for multiple ND measures by multiple statistical methods. Some of these regions have been linked to smoking behavior at nominally significant levels in other studies, which provides independent replication of the regions for ND in different cohorts. In summary, we found significant linkage on chromosome 10q22 and suggestive linkage on chromosomes 9, 11, and 13 for major genetic determinants of ND in an AA sample. Further analysis of these positive regions by fine mapping and/or association analysis is thus warranted. To our knowledge, this study represents the first genomewide linkage scan of ND in an AA sample.

Adolescent↗

PubMed2006

Gene-based analysis suggests association of the nicotinic acetylcholine receptor beta1 subunit (CHRNB1) and M1 muscarinic acetylcholine receptor (CHRM1) with vulnerability for nicotine dependence.

Based on our previously identified linkage regions for nicotine dependence (ND), we selected six and five single nucleotide polymorphisms (SNPs) in the muscarinic cholinergic receptor subtype M1 (CHRM1) and nicotinic cholinergic receptor beta1 (CHRNB1), respectively, to determine the association of the two genes with ND in a total of 2,037 subjects from 602 nuclear families of either African-American (AA) or European-American (EA) origin. Individual SNP- and/or haplotype-based analyses indicated that the CHRNB1 was significantly associated with ND, which was assessed by smoking quantity (SQ), the Heaviness of Smoking Index (HSI), and the Fagerström Test for ND (FTND), in both ethnic samples. The association of rs2302763 in the CHRNB1 was significant with adjusted SQ in the EA sample after correction for multiple testing (P=0.013). Haplotype A-T-A formed by SNPs rs2302765, rs2302762, and rs9217 in the CHRNB1 was significantly associated with the high risk allele for all the three ND measures (minimum P=0.009, 0.006, and 0.008 for SQ, HSI and FTND, respectively) in the AA sample while haplotype A-T-A formed by rs2302765, rs2302763, and rs9217 was significantly positively associated with ND (minimum P=0.005, 0.016, and 0.016 for SQ, HSI and FTND, respectively) in the EA sample. The CHRM1 exhibited significant protective associations of haplotype C-C-A-T-G-G formed by all six SNPs of this gene with at least one ND measure in the AA sample after Bonferroni correction (minimum P=0.008, 0.013, and 0.009 for SQ, HSI and FTND, respectively), but no significant association was found in the EA sample. The significant associations, together with their location of linked region to ND, suggest that the CHRNB1 and CHRM1 are likely candidates for further investigation.

Adult↗

PubMed2006

Regulation by nicotine of Gpr51 and Ntrk2 expression in various rat brain regions.

Our previous genetic studies demonstrated that variants of the gamma-Aminobutyric acid B receptor subunit 2 (GPR51) and neurotrophic tyrosine kinase receptor type 2 (NTRK2) genes are significantly associated with nicotine dependence (ND) in smokers. However, whether such genetic associations lead to changes in the expression of the two genes in response to nicotine remains undetermined. In this study, we investigated the regulatory effect of nicotine on the expression of Gpr51 and Ntrk2 in seven rat brain regions during the administration of nicotine in a daily dose of 3.15 mg/kg for 7 days. With quantitative real-time RT-PCR, we found that nicotine increased the mRNA of Gpr51 by 70, 78, and 32% in the amygdala, striatum, and prefrontal cortex (PFC), respectively, but decreased by 54% in the nucleus accumbens (NA). The Gpr51 protein was upregulated by nicotine in the amygdala (26%), striatum (73%), PFC (28%), and medial basal hypothalamus (MBH; 19%) but downregulated in the NA (-72%). Similarly, the mRNA level of Ntrk2 was enhanced by nicotine in the striatum (86%) and PFC (38%), but decreased in the NA (-46%) and ventral tegmental area (VTA; -49%). A significant change in protein expression was also obtained for Ntrk2 in the PFC (24%), MBH (33%), NA (-33%), and VTA (-70%). Interestingly, these two genes showed a closely coordinated expression pattern in response to nicotine in most of the brain regions examined. In summary, our results demonstrate that the expression of Gpr51 and Ntrk2 is significantly regulated by nicotine at both the mRNA and protein levels in various brain regions, which provides further evidence that these two genes are involved in the etiology of ND, as reported in our previous genetic association studies in humans.

Animals↗

PubMed2006

Association of specific haplotypes of neurotrophic tyrosine kinase receptor 2 gene (NTRK2) with vulnerability to nicotine dependence in African-Americans and European-Americans.

BACKGROUND: The gene encoding neurotrophic tyrosine kinase receptor 2 (NTRK2) has been localized to a region on chromosome 9q22-q23 that showed a "suggestive" linkage to nicotine dependence (ND) in our previous linkage analyses. However, no association of NTRK2 with ND has been identified. METHODS: Family-based association analyses of 2037 participants (1366 African Americans [AA], 671 European Americans [EA]) representing 602 nuclear families were performed to evaluate association of nine single nucleotide polymorphisms (SNPs) within NTRK2 with ND. RESULTS: Individual SNP-based association analysis indicated that in the EA sample, SNPs rs1659400 and rs1187272 were significantly associated with at least one adjusted ND measure. Haplotype analysis revealed that even after Bonferroni correction, the haplotype T-T-A of rs1659400-rs1187272-rs1122530 had a highly significant positive association, with adjusted ND measures in the EA sample (max Z = 3.78; p = .0001, frequency 59.9%). We further identified a major haplotype, T-G-C-A-A (26%), formed by rs993315-rs736744-rs920776-rs4075274-rs729560, which showed a significant positive association (max Z = 2.97, p = .003) with adjusted ND measures in the AA sample. CONCLUSIONS: These results strongly suggest that NTRK2 is a susceptibility gene for ND. These findings imply that NTRK2 plays a role in the etiology of ND and represents an important biological candidate for further investigation.

Adult↗

PubMed2006

Nicotine modulates expression of amyloid precursor protein and amyloid precursor-like protein 2 in mouse brain and in SH-SY5Y neuroblastoma cells.

Epidemiological studies indicate that tobacco smoking can be protective against neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). The objective of the present study was to examine the changes in gene expression induced by chronic oral nicotine administration (100 mug/ml in 2% saccharin for 14 days), with special emphasis on amyloid precursor protein (APP) and its homologue, amyloid precursor-like protein 2 (APLP2), in different brain regions of C57BL/6 mice using a pathway-focused microarray. Our results revealed that nicotine stimulated mRNA expression of APP in the amygdala (64%; P = 0.003) and hippocampus (32%; P = 0.034) and of APLP2 in the amygdala (39%; P = 0.002). These results were verified by quantitative real-time RT-PCR except that expression of APLP2 was also significantly upregulated by nicotine in the hippocampus. In addition, in vitro nicotine treatment of SH-SY5Y neuroblastoma cells resulted in a significant increase in expression of APP protein, soluble APP, and APLP2, whereas co-treatment with mecamylamine (an antagonist of nicotinic acetylcholine receptors) attenuated the stimulating effect of nicotine on APP and APLP2 expression. These findings suggest that nicotine treatment facilitates the increase in the expression of mRNA and protein of the APP and APLP2 genes in rat brain and SH-SY5Y neuroblastoma cells.

Amyloid beta-Protein Precursor↗

PubMed2006

Proteins differentially expressed in response to nicotine in five rat brain regions: identification using a 2-DE/MS-based proteomics approach.

To determine protein expression patterns within the central nervous system (CNS) in response to nicotine, 2-DE/MS was performed on samples from five brain regions of rats that had received nicotine bitartrate by osmotic minipump infusion at a dose of 3.15 mg/kg/day for 7 days. After spot matching and statistical analysis, 41 spots in the amygdala, 49 in the nucleus accumbens (NA), 46 in the prefrontal cortex (PFC), 36 in the striatum, and 28 in the ventral tegmental area (VTA) showed significant differences in the nicotine-treated compared with control samples. Using MALDI-TOF MS peptide fingerprinting, 14 proteins in the amygdala, 11 in the NA, 19 in the PFC, 13 in the striatum, and 19 in the VTA were identified. Several proteins (e.g. dynamin 1, laminin receptors, aldolase A, enolase 1 alpha, Hsc70-ps1, and N-ethylmaleimide-sensitive fusion protein) were differentially expressed in multiple brain regions. By gene ontology analysis, these differentially expressed proteins were grouped into biological process categories, such as energy metabolism, synaptic function, and oxidative stress metabolism. These data, in combination with microarray analysis of mRNA transcripts, have the potential to identify the CNS gene products that show coordinated changes in expression at both the RNA and protein levels in response to nicotine.

Animals↗

PubMed2006

The genetics of nicotine dependence.

Despite almost two decades of intensive tobacco-control efforts, approximately 23% of American adults continue to smoke, and 13% are nicotine-dependent. Cigarette smoking is the greatest preventable cause of cancer, accounting for at least 30% of all cancer deaths and 87% of lung cancer deaths. Smoking behavior is influenced by both genetic and environmental factors. Many years of twin and adoption studies have demonstrated that the heritability of liability for nicotine dependence (ND) is at least 50%. During the past several years, significant efforts have been made to identify susceptibility genes for ND using both genome-wide linkage and association analysis approaches. It is expected that identification of susceptibility genes for ND will allow the development and tailoring of both prevention strategies for individuals at risk and effective treatment programs and medicines for individuals who use tobacco products. This review summarizes the recent progress in genetic studies of ND. As genotyping technology is being improved and well-characterized clinical samples on smoking behavior become available, more and more genes and genetic variants responsible for ND will be identified in the near future.

Brain-Derived Neurotrophic Factor↗

PubMed2006

Significant association of catechol-O-methyltransferase (COMT) haplotypes with nicotine dependence in male and female smokers of two ethnic populations.

The catechol-O-methyltransferase (COMT) gene plays a prominent role in dopaminergic circuits central to drug reward. Allelic variants within the COMT gene are therefore potential candidates for examining interindividual differences in vulnerability to nicotine dependence (ND). We analyzed five single nucleotide polymorphisms (SNPs), including the Val/Met variant (rs4680), which results in a three- to four-fold difference in enzyme activity within COMT, for association with the three ND measures, SQ, HSI, and FTND, in 602 nuclear families of African-American (AA) or European-American (EA) origin. The Val/Met variant showed a significant association with the three ND measures in the pooled and EA samples and with FTND in the AA sample. Haplotype analysis revealed a major protective A-G-T haplotype (frequency 23.6%) for rs740603-rs4680-rs174699 in the AA sample (minimum Z=-3.35; P=0.0005 for FTND), a major protective T-G-T haplotype (frequency 15.2%; minimum Z=-2.92; P=0.003 for FTND) in the EA sample, and a high-risk C-A-T haplotype (frequency 16.9%; minimum Z=3.16; P=0.002 for SQ) in the AA sample for rs933271-rs4680-rs174699. Furthermore, we found that the significant haplotypes within COMT were gender-specific and the significantly associated A-G-T is protective in AA females only, whereas T-G-T is protective in EA males only. Moreover, we found a major high-risk T-A-T haplotype (frequency 56.7%) that showed significant association with the three ND measures in EA males. Further examination of two protective haplotypes, A-G-T in AAs and T-G-T in EAs, indicated that the low COMT enzyme activity Met allele is protective to become nicotine dependent. In summary, our results provide evidence for a role of COMT in the susceptibility to ND and further confirm that its effect is ethnic and gender specific.

Adult↗

PubMed2006

DOPA decarboxylase gene is associated with nicotine dependence.

INTRODUCTION: Cigarette smoking is a prevalent and harmful behavior. Although the heritability of nicotine dependence (ND) is well documented and many candidate genetic regions have been identified, few of them were confirmed. This may be, in part, due to analytic methods that sacrifice power. METHODS: Using a recently developed, more powerful method for testing association between a genetic marker and an ordinal trait, we analyzed data from 1879 smokers and nonsmokers from 600 nuclear families of African- or European-American (AA or EA) ancestry. This method increases power principally by accounting for differences in severity between affected subjects. RESULTS: To demonstrate the more powerful method, we re-analyzed an existing dataset, which confirmed the association of the DOPA decarboxylase (DDC) gene on chromosome 7p11 with measures of nicotine dependence. Although none of the eight single nucleotide polymorphisms (SNPs) studied were found to be significantly associated with nicotine dependence (unadjusted p-value > 0.01), we identified haplotypes from those SNPs that were significantly associated with nicotine dependence in both AA and EA samples. CONCLUSION: The associated haplotypes differed in the AA and EA samples. The strongest association (p-value = 0.003) was identified between the 'heaviness of smoking index' and haplotype C-A-T-G in SNPs rs921451-rs3735273-rs1451371-rs2060762. However, this association was not found significant in a previous report (p-value = 0.19) that used the same sample, underscoring the importance of using the statistical methods that use more of the available phenotypic information, and thereby better reflect the distribution of the phenotypes.

Black or African American↗

PubMed2005

Significant association of BDNF haplotypes in European-American male smokers but not in European-American female or African-American smokers.

Brain-derived neurotrophic factor (BDNF) influences dopamine and serotonin neurotransmission in the brain, both of which are involved in the reward system of addiction. The BDNF gene is located in a genomic region on chromosome 11p where we and others have found 'significant' linkage to nicotine dependence (ND). We tested the potential role of variants within BDNF in vulnerability to ND, which was assessed by Smoking Quantity (SQ), the Heaviness of Smoking Index (HSI), and the Fagerström Test for ND (FTND). Six single nucleotide polymorphisms (SNPs) in BDNF were analyzed in an extensively phenotyped cohort of 602 nuclear families with smokers and non-smokers of African-American (AA) or European-American (EA) ancestry. Individual SNP analysis revealed that two SNPs in the pooled male and three SNPs in the EA male samples were significantly associated with at least one adjusted ND measure. However, none of these associations remained significant after correction for multiple testing. Haplotype analysis of rs6484320-rs988748-rs2030324-rs7934165 revealed that a major T-C-T-G haplotype was significantly associated, even after Bonferroni correction, with the three ND measures in the pooled and EA male samples (maximum Z = 3.00, P = 0.002 and maximum Z = 3.13, P = 0.0009 for SQ, respectively). No significant association of a major haplotype with ND was found in the AA or EA female smokers. The significant association of BDNF variants with ND implies that this gene plays a role in the etiology of ND in EAs and that its involvement is gender specific. BDNF may warrant further investigation in ND.

Adult↗

PubMed2005

Improvement of mapping accuracy by unifying linkage and association analysis.

It is well known that pedigree/family data record information on the coexistence in founder haplotypes of alleles at nearby loci and the cotransmission from parent to offspring that reveal different, but complementary, profiles of the genetic architecture. Either conventional linkage analysis that assumes linkage equilibrium or family-based association tests (FBATs) capture only partial information, leading to inefficiency. For example, FBATs will fail to detect even very tight linkage in the case where no allelic association exists, while a violation of the assumption of linkage equilibrium will result in biased estimation and reduced efficiency in linkage mapping. In this article, by using a data augmentation technique and the EM algorithm, we propose a likelihood-based approach that embeds both linkage and association analyses into a unified framework for general pedigree data. Relative to either linkage or association analysis, the proposed approach is expected to have greater estimation accuracy and power. Monte Carlo simulations support our theoretical expectations and demonstrate that our new methodology: (1) is more powerful than either FBATs or classic linkage analysis; (2) can unbiasedly estimate genetic parameters regardless of whether association exists, thus remedying the bias and less precision of traditional linkage analysis in the presence of association; and (3) is capable of identifying tight linkage alone. The new approach also holds the theoretical advantage that it can extract statistical information to the maximum extent and thereby improve mapping accuracy and power because it integrates multilocus population-based association study and pedigree-based linkage analysis into a coherent framework. Furthermore, our method is numerically stable and computationally efficient, as compared to existing parametric methods that use the simplex algorithm or Newton-type methods to maximize high-order multidimensional likelihood functions, and also offers the computation of Fisher's information matrix. Finally, we apply our methodology to a genetic study on bone mineral density (BMD) for the vitamin D receptor (VDR) gene and find that VDR is significantly linked to BMD at the one-third region of the wrist.

Algorithms↗

PubMed2005

Haplotype analysis indicates an association between the DOPA decarboxylase (DDC) gene and nicotine dependence.

DOPA decarboxylase (DDC; also known as L-amino acid decarboxylase; AADC) is involved in the synthesis of dopamine, norepinephrine and serotonin. Because the mesolimbic dopaminergic system is implicated in the reinforcing effects of many drugs, including nicotine, the DDC gene is considered a plausible candidate for involvement in the development of vulnerability to nicotine dependence (ND). Further, this gene is located within the 7p11 region that showed a 'suggestive linkage' to ND in our previous genome-wide scan in the Framingham Heart Study population. In the present study, we tested eight single nucleotide polymorphisms (SNPs) within DDC for association with ND, which was assessed by smoking quantity (SQ), the heaviness of smoking index (HSI) and the Fagerstrom test for ND (FTND) score, in a total of 2037 smokers and non-smokers from 602 nuclear families of African- or European-American (AA or EA, respectively) ancestry. Association analysis for individual SNPs using the PBAT-GEE program indicated that SNP rs921451 was significantly associated with two of the three adjusted ND measures in the EA sample (P=0.01-0.04). Haplotype-based association analysis revealed a protective T-G-T-G haplotype for rs921451-rs3735273-rs1451371-rs2060762 in the AA sample, which was significantly associated with all three adjusted ND measures after correction for multiple testing (min Z=-2.78, P=0.006 for HSI). In contrast, we found a high-risk T-G-T-G haplotype for a different SNP combination in the EA sample, rs921451-rs3735273-rs1451371-rs3757472, which showed a significant association after Bonferroni correction with the SQ and FTND score (max Z=2.73, P=0.005 for FTND). In summary, our findings provide the first evidence for the involvement of DDC in the susceptibility to ND and, further, reveal the racial specificity of its impact.

Adult↗

PubMed2005

Ethnic- and gender-specific association of the nicotinic acetylcholine receptor alpha4 subunit gene (CHRNA4) with nicotine dependence.

We tested six single nucleotide polymorphisms (SNPs) in the alpha4 subunit gene (CHRNA4) and four SNPs in the beta2 subunit gene (CHRNB2) of nicotinic acetylcholine receptors (nAChRs) for association with nicotine dependence (ND), which was assessed by smoking quantity (SQ), the heaviness of smoking index (HSI) and the Fagerstrom test for ND (FTND) in 2037 subjects from 602 nuclear families of either European-American (EA) or African-American (AA) ancestry. Analysis of the six SNPs within CHRNA4 demonstrated that in the EA sample SNPs rs2273504 and rs1044396 are significantly associated with the adjusted SQ and FTND score, respectively. In the AA samples, SNPs rs3787137 and rs2236196 are each significantly associated with at least two adjusted ND measures. Association of rs2236196 with the adjusted HSI and FTND scores in the AA samples remained significant after correction for multiple testing. Furthermore, analysis revealed gender- and ethnic-specific associations for several SNPs with ND measures in both ethnic samples; however, only the association of SNP rs2236196 with the three adjusted ND measures remained significant after correcting for multiple testing in the AA female samples. Haplotype analysis of rs2273505-rs2273504-rs2236196 showed significant association after Bonferroni correction of a C-G-G haplotype (53.4%) with three adjusted ND measures in samples from the AA females. A similar analysis for the four SNPs within CHRNB2 did not reveal significant association with the three ND measures. In summary, our findings provide convincing evidence for the involvement of the nAChR alpha4 subunit, but not of the nAChR beta2 subunit, in nicotine addiction.

Black People↗

PubMed2005

Single- and multilocus allelic variants within the GABA(B) receptor subunit 2 (GABAB2) gene are significantly associated with nicotine dependence.

Twelve single-nucleotide polymorphisms (SNPs) in the human gamma-aminobutyric acid type B (GABA(B)) receptor subunit 2 gene (GABAB2) were tested for association with nicotine dependence (ND) in an extensively phenotyped cohort of 1,276 smokers and nonsmokers, representing approximately 404 nuclear families of African American (AA) or European American (EA) origin. The GABAB2 gene encodes a subunit of the GABA(B) receptor for GABA, an inhibitory neurotransmitter involved in the regulation of many physiological and psychological processes in the brain. The gene is located within a region of chromosome 9q22 that showed a "suggestive" linkage to ND. Individual SNP analysis performed using the PBAT-GEE program indicated that two SNPs in the AAs and four SNPs in the EAs were significantly associated with ND. Haplotype analysis using the Family-Based Association Test revealed that, even after Bonferroni correction, the haplotype C-C-G of rs2491397-rs2184026-rs3750344 had a significant positive association with ND in both the pooled and the AA samples. In the EAs, we identified two haplotypes, C-A-C-A and T-A-T-A, formed by SNPs rs1435252-rs378042-rs2779562-rs3750344, that showed a highly significant negative and positive association with ND, respectively. In summary, our findings provide evidence of a significant association of GABAB2 variants with ND, implying that this gene plays an important role in the etiology of this drug addiction.

Adult↗

PubMed2005

Fine mapping functional sites or regions from case-control data using haplotypes of multiple linked SNPs.

Previously, we reported an algorithm for scanning a large number of tightly linked single nucleotide polymorphisms (SNPs) for LD mapping of functional sites or regions from a family-based association design. In the present study, we extend our method to a case-control design. We first use the expectation maximization (EM) algorithm to estimate haplotype frequencies of multiple linked SNPs, and follow this by constructing a contingency table statistic S for LD analysis, based on the estimated haplotype frequencies. An empirical p-value is obtained based on the null distribution of the maximum of S (S*) from a large number (e.g., 1,000 or more) of randomized permutations. The proposed algorithm has been implemented in a computer program in which window searching for functional SNP sites can cover any number of loci without limitation, except that of computer storage. Unlike other programs for a case-control design that always conduct tests at a fix window width, in our program after setting a maximum size of haplotype window width, for a given maximum window width all possible widths of haplotypes are utilized to find the maximum statistic S * for each locus under investigation. The sensitivity of the proposed algorithm has been examined with simulated and real genotyping datasets. Association analyses indicate that our program is powerful enough to detect most, if not all, functional SNPs simulated in the original model or identified in the original report. Moreover, the program is very flexible and can be used in either regional or genome-wide scanning for association analysis with SNP markers.

Algorithms↗

PubMed2005

Comorbid alcohol and nicotine dependence: from the biomolecular basis to clinical consequences.

This article represents the proceedings of a symposium presented at the 12th Congress of the International Society for Biomedical Research on Alcoholism held in Heidelberg/Mannheim, Germany, on October 1, 2004. The organizers and cochairs were Nassima Ait-Daoud, MD, and Gerhard A. Wiesbeck, MD. The presentations included the following:L (1) The Role of Nicotinic Acetylcholine Receptors in Alcohol-Seeking Behavior, by Przemyslaw Bienkowski, MD, PhD; (2) Utilization of Linkage Analysis Combined with Microarray Technology to Identify Genes and Mechanisms Underlying Nicotine and Alcohol Use and Abuse in Humans and Rodents, by Ming D. Li, PhD; (3) Smoking and Alcoholic Chronic Pancreatitis: The Underestimated Risk?, by Roland H. Pfützer, MD; (4) Anticraving Medication in Alcohol and Nicotine Dependence, by Otto M. Lesch, MD, PhD; and (5) Pharmacotherapy for Promotion of Abstinence from Nicotine Among Alcohol-Dependent Individuals, by Bankole A. Johnson, DSc, MD, PhD.

Alcohol Deterrents↗