Association Study of Alcoholism Subtypes with a Functional Promoter Polymorphism in the Serotonin Transporter Protein Gene

Kranzler, Henry R.; Lappalainen, Jaakko; Nellissery, Maggie; Gelernter, Joel

doi:10.1111/j.1530-0277.2002.tb02675.x

Cited by 61 publications

(35 citation statements)

References 54 publications

(59 reference statements)

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“…We were struck by the multiple associations between the GK haplotype and ethanol-related behaviors, where the GK low-uptake activity is associated with lower ethanol consumption and acceptance. In humans, individuals with the lowfunctioning S allele of the 5HTTLPR, and presumably increased synaptic 5-HT availability, demonstrate lower voluntary ethanol consumption (30,31). These findings also point to further utility of gene ϫ environment designs in analysis of the functional impact of the ER/GK haplotype.…”

Section: Discussionmentioning

confidence: 83%

Functional coding variation in recombinant inbred mouse lines reveals multiple serotonin transporter-associated phenotypes

Carneiro¹,

Airey²,

Thompson³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The human serotonin (5-hydroxytryptamine, 5-HT) transporter (hSERT, SLC6A4) figures prominently in the etiology and treatment of many prevalent neurobehavioral disorders including anxiety, alcoholism, depression, autism, and obsessive-compulsive disorder (OCD). Here, we use naturally occurring polymorphisms in recombinant inbred (RI) lines to identify multiple phenotypes associated with altered SERT function. The widely used mouse strain C57BL/ 6J, harbors a SERT haplotype defined by 2 nonsynonymous coding variants [Gly-39 and Lys-152 (GK)]. At these positions, many other mouse lines, including DBA/2J, encode, respectively, Glu-39 and Arg-152 (ER haplotype), amino acids found also in hSERT. Ex vivo synaptosomal 5-HT transport studies revealed reduced uptake associated with the GK variant, a finding confirmed by in vitro heterologous expression studies. Experimental and in silico approaches using RI lines (C57BL/6J ؋ DBA/2J ‫؍‬ BXD) identify multiple anatomical, biochemical, and behavioral phenotypes specifically impacted by GK/ER variation. Among our findings are several traits associated with alcohol consumption and multiple traits associated with dopamine signaling. Further bioinformatic analysis of BXD phenotypes, combined with biochemical evaluation of SERT knockout mice, nominates SERT-dependent 5-HT signaling as a major determinant of midbrain iron homeostasis that, in turn, dictates iron-regulated DA phenotypes. Our studies provide an example of the power of coordinated in vitro, in vivo, and in silico approaches using mouse RI lines to elucidate and quantify the system-level impact of gene variation.A complex set of phylogentically conserved traits relies upon the production, secretion, and inactivation of the biogenic amine 5-HT (1). A critical and conserved mechanism to regulate 5-HT signaling involves the action of the presynaptic 5-HT transporter, SERT (2). SERTs are not only responsible for the clearance of 5-HT after release, but also recycle synaptic 5-HT to sustain adequate stores for 5-HT release (3).The recognition of the central role played by SERT in 5-HT inactivation has been reinforced by studies where mouse SERT (mSERT) has been eliminated (4), suppressed (5, 6), or enhanced (7). Although investigations with these models provide critical support for a role of SERT in presynaptic 5-HT clearance and homeostasis, inferences linking SERT to neural signaling and behavior are complicated by significant compensatory changes in other genes (8). Conversely, a lack of recognition for background genetic diversity in mouse strains likely limits the full elaboration of phenotypes associated with SERT genetic variation (9). Indeed, SERT knockout mice display different phenotypes depending on their genetic background (10).An alternative approach is the identification of traits that are sensitive to naturally occurring polymorphisms using genetic reference populations, such as BXD recombinant inbred (RI) lines (11). BXD RI lines are isogenic, homozygous mosaics of C57BL/6J and DBA/2J inbred strains, previ...

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Section: Discussionmentioning

confidence: 83%

Functional coding variation in recombinant inbred mouse lines reveals multiple serotonin transporter-associated phenotypes

Carneiro¹,

Airey²,

Thompson³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Further supporting a functional relationship between ethanol and the 5-HTT, there is growing evidence of abnormal 5-HTT function in alcoholism and in animal models of the disease. For example, significant reductions in 5-HTT binding have been found in the living and the postmortem brains of alcoholics (Heinz et al, 2000;Kranzler et al, 2002). In addition, a polymorphism in the promoter region of the human and nonhuman primate 5-HTT gene, which confers low-expression of 5-HTT, has been associated with alcoholism and certain neuropsychiatric disorders that are frequently comorbid with the disease, such as anxiety and depression (Thompson et al, 2000;Kranzler et al, 2002;Barr et al, 2004a,b).…”

Section: Introductionmentioning

confidence: 99%

“…For example, significant reductions in 5-HTT binding have been found in the living and the postmortem brains of alcoholics (Heinz et al, 2000;Kranzler et al, 2002). In addition, a polymorphism in the promoter region of the human and nonhuman primate 5-HTT gene, which confers low-expression of 5-HTT, has been associated with alcoholism and certain neuropsychiatric disorders that are frequently comorbid with the disease, such as anxiety and depression (Thompson et al, 2000;Kranzler et al, 2002;Barr et al, 2004a,b). Together, these findings support a possible role for the 5-HTT in modulating the effects of ethanol on brain 5-HT and, further, suggest that the level of 5-HTT function or expression may impact the behavioral effects of ethanol (Roach et al, 1973;Daoust et al, 1985Daoust et al, , 1991aLe Marquand et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Ethanol Inhibits Clearance of Brain Serotonin by a Serotonin Transporter-Independent Mechanism

Daws

Montañez

Munn

et al. 2006

Journal of Neuroscience

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“…Although twin and adoption studies suggest a substantial genetic component in alcoholism, efforts to identify specific genes that contribute to the risk of the disorder have had limited success (Kranzler et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…For example, alterations in synaptic serotonin (5-HT) concentration have been suggested as the underlying cause for certain behavioral changes (Grove et al, 1997;Meltzer et al, 1994;Owens and Nemeroff, 1994). 5-HT concentration in the synapse is controlled by the presynaptic 5-HT transporter (5-HTT), and, therefore, the gene encoding the 5-HTT protein (genetic locus SLC6A4 on chromosome 17q11.1-q12) is viewed as a candidate gene for alcohol dependence (Kranzler et al, 2002). The 5′-regulatory promoter region of SLC6A4 contains the only known functional polymorphism in the serotonergic system (5-HTT-linked polymorphic region (5′-HTTLPR)) (Heils et al, , 1997.…”

Section: Introductionmentioning

confidence: 99%

Platelet serotonin uptake and paroxetine binding among allelic genotypes of the serotonin transporter in alcoholics

Javors

Seneviratne

Roache

et al. 2005

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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Expression rates of long (L) and short (S) alleles of the serotonin (5-HT) transporter (5-HTT) gene have been shown to differ under various circumstances. We compared 5-HTT uptake (function) level and paroxetine binding (density) in platelets of alcoholics as indices of 5-HTT expression rate among LL, LS, and SS genotypes. Concentration curves of [ 3 H]5-HT and [ 3 H]paroxetine were used to quantify the equilibrium constant (Km) and maximum 5-HT uptake rate (Vmax) for 5-HTT uptake into intact platelets and the dissociation constant (Kd) and maximum specific binding density (Bmax) for paroxetine binding to platelet membranes, respectively. Genotypes were determined using electrophoresis with fluorescent markers. Vmax for 5-HTT uptake did not correlate with Bmax for paroxetine binding (r=−0.095, P=0.415). Means of Vmax and Bmax did not differ in a statistically significant manner among LL, LS, and SS genotypes in these alcoholic subjects. However, Vmax for LL and SS appeared to have a bimodal distribution, so the percentage of subjects with Vmax <200 fmol/min-10 7 platelets was statistically significantly higher in LL than in SS (51.5% vs. 22.7%, respectively), with an odds ratio of 3.6 (P<0.05). The percentage of Vmax <200 fmol/min-10 7 platelets for LS was 39.3% (not significant vs. LL or SS). Previous studies of healthy human controls have shown that 5-HTT density in raphe nuclei and 5-HTT uptake in platelets are higher in the LL genotype than in S carriers. Our findings in currently drinking alcoholics support the hypothesis that those with the LL genotype of the 5′-HTTLPR region of the 5-HTT gene have reduced 5-HTT function.

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Association Study of Alcoholism Subtypes with a Functional Promoter Polymorphism in the Serotonin Transporter Protein Gene

Cited by 61 publications

References 54 publications

Functional coding variation in recombinant inbred mouse lines reveals multiple serotonin transporter-associated phenotypes

Functional coding variation in recombinant inbred mouse lines reveals multiple serotonin transporter-associated phenotypes

Ethanol Inhibits Clearance of Brain Serotonin by a Serotonin Transporter-Independent Mechanism

Platelet serotonin uptake and paroxetine binding among allelic genotypes of the serotonin transporter in alcoholics

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