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• W1569003132 abstract "In his paper, Gunter Schumann provides an excellent review of the progress and perspectives of an approach that tries to link genetic variance with heritable biological phenotypes (‘endophenotypes’) rather than complex disease categories [1]. In complex disorders such as alcohol dependence, it may be extremely complicated to identify the multitude of genetic interactions that dispose a certain individual to develop addictive behaviour, while Schumann and collaborators successfully discovered a gene that interacts with circumscribed phenotypes such as glutamate transporter expression, excessive alcohol intake and acamprosate response [2]. This discovery may help to elucidate individual differences in medication response and thus help to establish individually tailored treatment algorithms in alcohol-dependent patients. However, while such studies have helped substantially to shed light on previously unknown genotype–phenotype interactions, studies with other genes have yielded controversial results. One example also discussed by Schumann [1] is the role of a functional polymorphism that is composed either of 14 (‘short’) or 16 (‘long’) repeat elements containing 22–23 base-pairs imperfect repeat polymorphisms in the regulatory region of the serotonin transporter gene (5-HTTLPR). In accordance with the concept of intermediate phenotypes, it can be shown that the effects of genetic variation in the 5-HTTLPR are strongest when gene-related protein expression is measured, while effects are substantially weaker when functional brain activation or clinical behavior is assessed: compared with carriers with one or two 5-HTTLPR short alleles (S-carriers), homozygote carriers of two long alleles (LL) displayed a 50% increase in serotonin transporter (5-HTT) density and function [3] if they do not carry an A→G substitution in the 5-HTTLPR that results in functional similarity of LG and S[4, 5]. While the 5-HTTLPR thus profoundly modulates serotonin transporter expression, it shows only a minor effect on trait anxiety, explaining not more than 4% of the interindividual variance [3]. Trait anxiety seems to be modulated by serotonin effects on amygdala activation during confrontation with aversive stimuli, which was increased in human S-carriers with low serotonin transporter availability [6-9]. Because high trait anxiety may predispose humans and non-human primates towards excessive alcohol intake, the 5-HTTLPR has been associated with alcohol dependence, albeit with inconsistent results (e.g. [10]). One possible explanation for the inconsistent data is the existence of gene–environmental interactions that mimic 5-HTTLPR effects on serotonin transporter availability. For example, it has been shown that serotonin turnover rates are reduced substantially in non-human primates, but only if they carry the 5-HTTLPR S-allele and have experienced early social isolation stress [11]. Endogenous serotonin competes with brain imaging radioligands such as β-CIT for 5-HTT binding [12]. As a consequence, low extracellular serotonin concentrations are associated with an elevation of serotonin transporters in the raphe (brainstem) area [13]. Elevated brainstem 5-HTT availability was correlated with low effects of acute alcohol intake [13], an endophenotype that predicts the risk to develop alcoholism [14], and with excessive alcohol consumption in non-human primates [15]. In these non-human primates that carried a 5-HTTLPR S-allele, elevated serotonin transporter availability and a low response to alcohol effects resulted from low serotonin turnover rates following social isolation stress. However, elevated serotonin transporters and a low response to alcohol cannot occur only in 5-HTTLPR S-carriers following social isolation stress [13, 15, 16]; it is also found in LL-homozygotes, as this genotype normally increases the expression and function of serotonin transporters [3, 5, 17]. Indeed, in human studies and animal experiments, LL-homozygotes displayed a low response to alcohol and excessive alcohol consumption [14, 17, 18]. This observation shows that in certain genotypes (e.g. S-carriers of the 5-HTTLPR), gene–environment interactions (e.g. developmentally early social isolation stress) may result in a phenotype (in this case: increased 5-HTT availability and a low response to alcohol) that is also present in individuals who carry another genotype (here: 5-HTTLPR LL-homozygotes). Given a certain environmental background, both 5-HTT genetic variants may thus result in high availability of 5-HTT brainstem transporters and predispose to excessive alcohol intake, which may explain why no straightforward association has been found between 5-HTT genotype and alcohol dependence [10]. While such phenocopies may render the search for the genetic causes of addictive behaviour substantially more difficult, they shed light on gene–environmental interactions and on the neurobiological underpinnings of behavior traits associated with excessive alcohol intake. Ultimately, the research of Gunter Schumann and other geneticists will improve our understanding of both genetic and social factors in the development of alcoholism [1]. This study was supported by the Deutsche Forschungsgemeinschaft (He 2597/7-3 and 4-3)." @default.
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• W1569003132 date "2007-11-01" @default.
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• W1569003132 title "GENETIC RESEARCH WITH INTERMEDIATE PHENOTYPES: PHENOCOPIES, PERSPECTIVES AND PITFALLS" @default.
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• W1569003132 doi "https://doi.org/10.1111/j.1360-0443.2007.01994.x" @default.
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