RESUMO
BACKGROUND: A comprehensive understanding of the etiology and neurobiology of nicotine dependence is not available. We sought to identify genomic regions that might contain etiologically-relevant loci using genomewide univariate and bivariate linkage analyses. METHODS: We conducted secondary data analyses of 626 all possible sibling pairs ascertained in Ireland and Northern Ireland on the basis of alcohol dependence. A set of 1020 short tandem repeat genetic markers were genotyped in all subjects. The phenotypes analyzed were the Fagerström Test for Nicotine Dependence (FTND), a history of nicotine dependence, the number of symptoms of alcohol dependence (AlcSx), and a history of alcohol dependence. Genomewide linkage analyses were conducted with non-parametric and variance components methods. FINDINGS: For the bivariate variance component analysis of the continuous FTND and AlcSx scores, multipoint LOD scores were >4 in two genomic regions--an 11cM region on chr7 (D7S2252-D7S691, empirical p=0.0006) and an 8cM region on chr18 flanking D18S63 (empirical p=0.0007). These findings did not exceed a conservative estimate of study-wide significance. The remaining sets of findings had considerably smaller or less consistent peak signals. Notably, strong linkage signal at D4S1611 for AlcSx from a prior report (PMID 16534506) was not found when jointly analyzed with FTND. INTERPRETATION: Replication is required. However, chromosomes 7 and 18 may contain genetic loci relevant to the etiology of nicotine-related phenotypes.
Assuntos
Tabagismo/genética , Tabagismo/psicologia , Adulto , Idoso , Alcoolismo/complicações , Alcoolismo/epidemiologia , Cromossomos Humanos Par 18/genética , Cromossomos Humanos Par 7/genética , Coleta de Dados , Feminino , Ligação Genética/genética , Humanos , Irlanda/epidemiologia , Desequilíbrio de Ligação , Escore Lod , Masculino , Pessoa de Meia-Idade , Irlanda do Norte/epidemiologia , Fenótipo , Sequências de Repetição em Tandem , Tabagismo/complicaçõesRESUMO
CONTEXT: Prior evidence from twin studies suggested genetic moderation of the depressogenic effects of stressful life events (SLEs). Can the specific genes involved in this effect be identified? OBJECTIVE: To replicate and extend a recent study that a functional variant in the serotonin transporter (5-HTT) might in part explain these findings. DESIGN: Characterizing risk for major depression and generalized anxiety syndrome in the last year as a function of 5-HTT genotype, sex, and the occurrence of SLEs and ratings of the SLE-associated level of threat. SETTING: A population-based sample of adult twins. PARTICIPANTS: Five hundred forty-nine male and female twins with a mean age at participation of 34.9 years (SD 9.1). MAIN OUTCOME MEASURE: Episodes of major depression and generalized anxiety syndrome in the last year with onset measured to the nearest month. RESULTS: Individuals with 2 short (S) alleles at the 5-HTT locus were more sensitive to the depressogenic effects of all SLEs than were those with 1 or 2 long (L) alleles. When level of SLE-associated threat was examined, the interaction between genotype and SLE resulted from an increased sensitivity of SS individuals to the depressogenic effects of common low-threat events. These events had little impact on risk for those possessing the SL and LL genotypes. The 5-HTT genotype did not modify the effects of SLEs on risk for generalized anxiety syndrome. CONCLUSION: Variation at the 5-HTT moderates the sensitivity of individuals to the depressogenic effects of SLEs largely by producing, in SS individuals, an increased sensitivity to the impact of mild stressors. Replication of these intriguing results is needed.
Assuntos
Transtorno Depressivo Maior/etiologia , Doenças em Gêmeos/etiologia , Genótipo , Acontecimentos que Mudam a Vida , Glicoproteínas de Membrana/genética , Proteínas de Membrana Transportadoras/genética , Proteínas do Tecido Nervoso/genética , Polimorfismo Genético , Adulto , Transtornos de Ansiedade/epidemiologia , Transtornos de Ansiedade/etiologia , Transtornos de Ansiedade/genética , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/genética , Doenças em Gêmeos/epidemiologia , Doenças em Gêmeos/genética , Feminino , Predisposição Genética para Doença/genética , Predisposição Genética para Doença/psicologia , Variação Genética , Humanos , Masculino , Reprodutibilidade dos Testes , Fatores de Risco , Proteínas da Membrana Plasmática de Transporte de Serotonina , Gêmeos Dizigóticos/genética , Gêmeos Dizigóticos/psicologia , Gêmeos Monozigóticos/genética , Gêmeos Monozigóticos/psicologiaRESUMO
BACKGROUND: Alcoholism is a phenotypically and probably genetically heterogeneous condition. Thus, one strategy for finding genes influencing liability to alcoholism is to study the components of alcoholism, which may be more directly related to the underlying pathophysiology than is clinical diagnosis. The goal of this study was to identify genomic regions containing susceptibility loci for alcohol-related traits. METHODS: A 4-cM dense whole-genome linkage study was conducted in the Irish Affected Sib Pair Study of Alcohol Dependence. Probands, affected siblings, and parents were evaluated by structured interview. Variance component linkage analysis was applied to data from 485 families for 5 measures: initial sensitivity and tolerance (based on scales from the self-report of the effects of ethanol; maximum drinks within 24 hours, an empirically derived factor score based on withdrawal symptoms, and age at onset of alcohol dependence. RESULTS: Evidence for linkage (p<0.005) was found on 9 chromosomes. For age at onset, 2 regions were found on chromosome 9 (highest Lod=2.3, p=0.0005). For initial level of response to alcohol, suggestive regions were on chromosomes 1 and 11 (highest Lod=2.9, p=0.0001 on chromosome 11), while those for tolerance signals were on chromosomes 1, 6, and 22. Maximum drinking was associated with regions on chromosomes 12 and 18. For withdrawal symptoms, the highest peak was on chromosome 2 (Lod=2.2, p=0.0007). CONCLUSIONS: Using quantitative measures of components of alcohol dependence, we identified several regions of the genome that may contain susceptibility loci for specific alcohol-related traits and merit additional study.