Association and linkage of anxiety-related traits with a functional polymorphism of the serotonin transporter gene regulatory region in Israeli sibling pairs

Osher, Yamima; Hamer, Dean H.; Benjamin, Jonathan

doi:10.1038/sj.mp.4000660

Cited by 118 publications

(69 citation statements)

References 20 publications

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“…190,196 An early, much studied and highly debated finding is the association of novelty seeking, with a functional variant in the DA D4 receptor gene. 197,198 Similar findings have implicated genetic variants in personality traits such as harm avoidance 199 and neuroticism. 200 Thus, although genetic variants may influence ND directly, they may also do so through their influence on personality traits that are related to cigarette smoking and use of other substances.…”

Section: General Overviewsupporting

confidence: 52%

Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions

Greenbaum¹,

Lerer²

2009

Mol Psychiatry

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Nicotine dependence (ND), a major public health challenge, is a complex, multifactorial behavior, in which both genetic and environmental factors have a role. Brain nicotinic acetylcholine receptor (nAChR)-encoding genes are among the most prominent candidate genes studied in the context of ND, because of their biological relevance as binding sites for nicotine. Until recently, most research on the role of nAChRs in ND has focused on two of these genes (encoding the a4-and b2-subunits) and not much attention has been paid to the possible contribution of the other nine brain nAChR subunit genes (a2-a3, a5-a7, a9-a10, b3-b4) to the pathophysiology and genetics of ND. This situation has changed dramatically in the last 2 years during which intensive research had addressed the issue, mainly from the genetics perspective, and has shown the importance of the CHRNA5-CHRNA3-CHRNB4 and CHRNA6-CHRNB3 loci in ND-related phenotypes. In this review, we highlight recent findings regarding the contribution of non-a4/b2-subunit containing nAChRs to ND, based on several lines of evidence: (1) human genetics studies (including linkage analysis, candidate-gene association studies and whole-genome association studies) of several ND-related phenotypes; (2) differential pharmacological and biochemical properties of receptors containing these subunits; (3) evidence from genetically manipulated mice; and (4) the contribution of nAChR genes to ND-related personality traits and neurocognitive profiles. Combining neurobiological genetic and behavioral perspectives, we suggest that genetic susceptibility to ND is not linked to one or two specific nAChR subtype genes but to several. In particular, the a3, a5-6 and b3-4 nAChR subunit-encoding genes may play a much more pivotal role in the neurobiology and genetics of ND than was appreciated earlier. At the functional level, variants in these subunit genes (most likely regulatory) may have independent as well as interactive contributions to the ND phenotype spectrum. We address methodological challenges in the field, highlight open questions and suggest possible pathways for future research.

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Section: General Overviewsupporting

confidence: 52%

Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions

Greenbaum¹,

Lerer²

2009

Mol Psychiatry

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“…Although Pearson correlations are not often used to analyze such data, in which one of the variables is dichotomous, they are equally valid to and in fact more useful than conventional t-tests or ANOVA for the following reasons: 36 (i) the significance (P value) of the Pearson correlation is exactly the same as the significance of a t-test or ANOVA; (ii) the Pearson correlation is standardized, thereby providing a direct estimate of the magnitude of the linear relationship between two variables, whereas t-test and ANOVA statistics do not provide this information; and (iii) the use of Pearson correlations allows direct comparison to the results of Lerman et al's parallel study. 32 The significances of the differences between genotype-stratified R values were determined by Fisher's Z test: 36…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, individuals and siblings with s/l and s/s genotypes scored on average 0.29 standard deviations higher on a standardized scale of neuroticism than did individuals with l/l genotypes. 26 Recently, this observation has been replicated in independent samples in the United States, 28,29 Japan, 30,31 and Israel, 32 although not in other populations. 33,34 The present work investigated the interrelationships between the serotonin transporter gene, neuroticism, and cigarette smoking behavior in a series of sib-pairs that included never, current and former smokers.…”

Section: Introductionmentioning

confidence: 94%

Interaction between the serotonin transporter gene and neuroticism in cigarette smoking behavior

et al. 2000

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Cigarette smoking behavior is influenced by both personality traits and inherited factors. Previous research showed that neuroticism-a broad personality domain that includes anxiety, depression, impulsiveness and vulnerability-increases the risk of being a smoker, primarily because of difficulty in quitting. Neuroticism has also been associated with the 5-HTTLPR, a functional polymorphism in the promoter for the serotonin transporter gene. We used population and family-based methods to analyze the joint effects of the 5-HTTLPR and neuroticism on smoking behavior in a population of 759 never, current, and former smokers, all members of sib-pairs. Our main finding is that smoking behavior is influenced by an interaction between neuroticism and 5-HTTLPR genotype. Specifically, neuroticism was positively correlated with current smoking and negatively associated with smoking cessation in individuals and siblings with poorly transcribed 5-HTTLPR-S genotypes, but not in those with the more highly expressed 5-HTTLPR-L genotype. Individuals with both a 5-HTTLPR-S genotype and a high level of neuroticism had the greatest difficulty in quitting smoking. These data, if replicated, suggest that smoking behavior is more strongly influenced by the combination of the serotonin transporter gene and neuroticism than by either factor alone, and that personality scores and 5-HTTLPR genotype may predict the clinical efficacy of certain smoking cessation drugs. Molecular Psychiatry (2000) 5, 181-188.

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“…An association between 5-HTT promoter variation and anxiety-related personality traits first reported by Lesch 1 has subsequently been replicated by some, but not all investigations (reviewed in Veenstra-VanderWeele et al 2 ). Thus, the original finding of higher neuroticism and harm avoidance in adult individuals with the short variant of the 5HTTLPR has been replicated and extended to younger individuals 3 and to other anxietyrelated dimensions of personality, [4][5][6] but has also failed replication. [7][8][9][10][11][12][13] Similarly, studies examining possible association between allelic variation in the promoter region of the serotonin transporter gene and risk for unipolar and bipolar depression have produced inconsistent findings (reviewed in Furlong et al 14 ).…”

mentioning

confidence: 95%

Early experience and serotonin transporter gene variation interact to influence primate CNS function

et al. 2002

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Nonhuman primates offer unique opportunities to study the effects of genes, environments, and their interaction, on physiology and complex behavior. We examined genotype and early environment contributions to CNS function in a large sample of rhesus monkeys. In humans, length variation of the serotonin (5-HT) transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) that results in allelic variation in 5-HTT expression is associated with decreased serotonergic function and 5-HT-mediated psychopathology. We report that an analogous variation of the gene's regulatory region in monkeys interacts with early experience to affect central 5-HT functioning. Monkeys with deleterious early rearing experiences were differentiated by genotype in cerebrospinal fluid concentrations of the 5-HT metabolite, 5-hydroxyindoleacetic acid, while monkeys reared normally were not. These findings demonstrate an environment-dependent effect of the rh5-HTTLPR genotype on CNS 5-HT function and suggest nonhuman primates may provide an important avenue for investigating gene/environment interactions using candidate genes for physiological and behavioral traits.

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Association and linkage of anxiety-related traits with a functional polymorphism of the serotonin transporter gene regulatory region in Israeli sibling pairs

Cited by 118 publications

References 20 publications

Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions

Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions

Interaction between the serotonin transporter gene and neuroticism in cigarette smoking behavior

Early experience and serotonin transporter gene variation interact to influence primate CNS function

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