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Identification of genetic modifiers of behavioral phenotypes in serotonin transporter knockout rats

BACKGROUND: Genetic variation in the regulatory region of the human serotonin transporter gene (SLC6A4) has been shown to affect brain functionality and personality. However, large heterogeneity in its biological effects is observed, which is at least partially due to genetic modifiers. To gain insi...

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Detalles Bibliográficos
Autores principales: Homberg, Judith, Nijman, Isaäc J, Kuijpers, Sylvia, Cuppen, Edwin
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874760/
https://www.ncbi.nlm.nih.gov/pubmed/20459657
http://dx.doi.org/10.1186/1471-2156-11-37
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author Homberg, Judith
Nijman, Isaäc J
Kuijpers, Sylvia
Cuppen, Edwin
author_facet Homberg, Judith
Nijman, Isaäc J
Kuijpers, Sylvia
Cuppen, Edwin
author_sort Homberg, Judith
collection PubMed
description BACKGROUND: Genetic variation in the regulatory region of the human serotonin transporter gene (SLC6A4) has been shown to affect brain functionality and personality. However, large heterogeneity in its biological effects is observed, which is at least partially due to genetic modifiers. To gain insight into serotonin transporter (SERT)-specific genetic modifiers, we studied an intercross between the Wistar SERT(-/- )rat and the behaviorally and genetically divergent Brown Norway rat, and performed a QTL analysis. RESULTS: In a cohort of >150 intercross SERT(-/- )and control (SERT(+/+)) rats we characterized 12 traits that were previously associated with SERT deficiency, including activity, exploratory pattern, cocaine-induced locomotor activity, and abdominal and subcutaneous fat. Using 325 genetic markers, 10 SERT(-/-)-specific quantitative trait loci (QTLs) for parameters related to activity and exploratory pattern (Chr.1,9,11,14), and cocaine-induced anxiety and locomotor activity (Chr.5,8) were identified. No significant QTLs were found for fat parameters. Using in silico approaches we explored potential causal genes within modifier QTL regions and found interesting candidates, amongst others, the 5-HT1D receptor (Chr. 5), dopamine D2 receptor (Chr. 8), cannabinoid receptor 2 (Chr. 5), and genes involved in fetal development and plasticity (across chromosomes). CONCLUSIONS: We anticipate that the SERT(-/-)-specific QTLs may lead to the identification of new modulators of serotonergic signaling, which may be targets for pharmacogenetic and therapeutic approaches.
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spelling pubmed-28747602010-05-24 Identification of genetic modifiers of behavioral phenotypes in serotonin transporter knockout rats Homberg, Judith Nijman, Isaäc J Kuijpers, Sylvia Cuppen, Edwin BMC Genet Research article BACKGROUND: Genetic variation in the regulatory region of the human serotonin transporter gene (SLC6A4) has been shown to affect brain functionality and personality. However, large heterogeneity in its biological effects is observed, which is at least partially due to genetic modifiers. To gain insight into serotonin transporter (SERT)-specific genetic modifiers, we studied an intercross between the Wistar SERT(-/- )rat and the behaviorally and genetically divergent Brown Norway rat, and performed a QTL analysis. RESULTS: In a cohort of >150 intercross SERT(-/- )and control (SERT(+/+)) rats we characterized 12 traits that were previously associated with SERT deficiency, including activity, exploratory pattern, cocaine-induced locomotor activity, and abdominal and subcutaneous fat. Using 325 genetic markers, 10 SERT(-/-)-specific quantitative trait loci (QTLs) for parameters related to activity and exploratory pattern (Chr.1,9,11,14), and cocaine-induced anxiety and locomotor activity (Chr.5,8) were identified. No significant QTLs were found for fat parameters. Using in silico approaches we explored potential causal genes within modifier QTL regions and found interesting candidates, amongst others, the 5-HT1D receptor (Chr. 5), dopamine D2 receptor (Chr. 8), cannabinoid receptor 2 (Chr. 5), and genes involved in fetal development and plasticity (across chromosomes). CONCLUSIONS: We anticipate that the SERT(-/-)-specific QTLs may lead to the identification of new modulators of serotonergic signaling, which may be targets for pharmacogenetic and therapeutic approaches. BioMed Central 2010-05-07 /pmc/articles/PMC2874760/ /pubmed/20459657 http://dx.doi.org/10.1186/1471-2156-11-37 Text en Copyright ©2010 Homberg et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research article
Homberg, Judith
Nijman, Isaäc J
Kuijpers, Sylvia
Cuppen, Edwin
Identification of genetic modifiers of behavioral phenotypes in serotonin transporter knockout rats
title Identification of genetic modifiers of behavioral phenotypes in serotonin transporter knockout rats
title_full Identification of genetic modifiers of behavioral phenotypes in serotonin transporter knockout rats
title_fullStr Identification of genetic modifiers of behavioral phenotypes in serotonin transporter knockout rats
title_full_unstemmed Identification of genetic modifiers of behavioral phenotypes in serotonin transporter knockout rats
title_short Identification of genetic modifiers of behavioral phenotypes in serotonin transporter knockout rats
title_sort identification of genetic modifiers of behavioral phenotypes in serotonin transporter knockout rats
topic Research article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874760/
https://www.ncbi.nlm.nih.gov/pubmed/20459657
http://dx.doi.org/10.1186/1471-2156-11-37
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