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Science 29 November 1996:
Vol. 274. no. 5292, pp. 1527 - 1531
DOI: 10.1126/science.274.5292.1527
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Reports

Association of Anxiety-Related Traits with a Polymorphism in the Serotonin Transporter Gene Regulatory Region

Klaus-Peter Lesch, * Dietmar Bengel, Armin Heils, Sue Z. Sabol, Benjamin D. Greenberg, Susanne Petri, Jonathan Benjamin, Clemens R. Müller, Dean H. Hamer, Dennis L. Murphy

Transporter-facilitated uptake of serotonin (5-hydroxytryptamine or 5-HT) has been implicated in anxiety in humans and animal models and is the site of action of widely used uptake-inhibiting antidepressant and antianxiety drugs. Human 5-HT transporter (5-HTT) gene transcription is modulated by a common polymorphism in its upstream regulatory region. The short variant of the polymorphism reduces the transcriptional efficiency of the 5-HTT gene promoter, resulting in decreased 5-HTT expression and 5-HT uptake in lymphoblasts. Association studies in two independent samples totaling 505 individuals revealed that the 5-HTT polymorphism accounts for 3 to 4 percent of total variation and 7 to 9 percent of inherited variance in anxiety-related personality traits in individuals as well as sibships.

K.-P. Lesch, A. Heils, S. Petri, Department of Psychiatry, University of Würzburg, Füchsleinstrasse 15, 97080 Würzburg, Germany.
D. Bengel, B. D. Greenberg, J. Benjamin, D. L. Murphy, Laboratory of Clinical Science, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
S. Z. Sabol and D. H. Hamer, Laboratory of Biochemistry, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
C. R. Müller, Institute of Human Genetics, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
*   To whom correspondence should be addressed. E-mail: kplesch{at}rzbox.uni-wuerzburg.de

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Am. J. Respir. Crit. Care Med. 173, 693-694
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Serotonin Transporter Polymorphisms in Familial and Idiopathic Pulmonary Arterial Hypertension.
E. D. Willers, J. H. Newman, J. E. Loyd, I. M. Robbins, L. A. Wheeler, M. A. Prince, K. C. Stanton, J. A. Cogan, J. R. Runo, D. Byrne, et al. (2006)
Am. J. Respir. Crit. Care Med. 173, 798-802
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Neuroimaging findings with MDMA/ecstasy: technical aspects, conceptual issues and future prospects.
L. Reneman, M. M. L. de Win, W. van den Brink, J. Booij, and G. J. den Heeten (2006)
J Psychopharmacol 20, 164-175
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Common genetic vulnerability to depressive symptoms and coronary artery disease: a review and development of candidate genes related to inflammation and serotonin..
J. M. McCaffery, N. Frasure-Smith, M.-P. Dube, P. Theroux, G. A. Rouleau, Q. Duan, and F. Lesperance (2006)
Psychosom Med 68, 187-200
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Life events, first depression onset and the serotonin transporter gene.
K. WILHELM, P. B. MITCHELL, H. NIVEN, A. FINCH, L. WEDGWOOD, A. SCIMONE, I. P. BLAIR, G. PARKER, and P. R. SCHOFIELD (2006)
The British Journal of Psychiatry 188, 210-215
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Late Developmental Stage-Specific Role of Tryptophan Hydroxylase 1 in Brain Serotonin Levels.
K. Nakamura, Y. Sugawara, K. Sawabe, A. Ohashi, H. Tsurui, Y. Xiu, M. Ohtsuji, Q. S. Lin, H. Nishimura, H. Hasegawa, et al. (2006)
J. Neurosci. 26, 530-534
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SERT-ainly Involved in Depression, But When?.
E. Sibille and D. A. Lewis (2006)
Am J Psychiatry 163, 8-11
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Investigation of the Serotonin Transporter Regulatory Region Polymorphism in Bulimia Nervosa: Relationships to Harm Avoidance, Nutritional Parameters, and Psychiatric Comorbidity.
P. Monteleone, P. Santonastaso, M. Mauri, L. Bellodi, S. Erzegovesi, A. Fuschino, A. Favaro, A. Rotondo, E. Castaldo, and M. Maj (2006)
Psychosom Med 68, 99-103
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Structure and Variation of Three Canine Genes Involved in Serotonin Binding and Transport: The Serotonin Receptor 1A Gene (htr1A), Serotonin Receptor 2A Gene (htr2A), and Serotonin Transporter Gene (slc6A4).
L. van den Berg, L. Kwant, M. S. Hestand, B. A. van Oost, and P. A. J. Leegwater (2005)
J. Hered. 96, 786-796
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Pharmacogenetics/genomics and personalized medicine.
W. Sadee and Z. Dai (2005)
Hum. Mol. Genet. 14, R207-R214
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The genetics of attention deficit hyperactivity disorder.
A. Thapar, M. O'Donovan, and M. J Owen (2005)
Hum. Mol. Genet. 14, R275-R282
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Cysteine-scanning Mutagenesis of Serotonin Transporter Intracellular Loop 2 Suggests an {alpha}-Helical Conformation.
Y.-W. Zhang and G. Rudnick (2005)
J. Biol. Chem. 280, 30807-30813
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