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Genome-wide association study in a rat model of temperament identifies multiple loci for exploratory locomotion and anxiety-like traits

Common genetic factors likely contribute to multiple psychiatric diseases including mood and substance use disorders. Certain stable, heritable traits reflecting temperament, termed externalizing or internalizing, play a large role in modulating vulnerability to these disorders. To model these herit...

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Autores principales: Chitre, Apurva S., Hebda-Bauer, Elaine K., Blandino, Peter, Bimschleger, Hannah, Nguyen, Khai-Minh, Maras, Pamela, Li, Fei, Ozel, A. Bilge, Pan, Yanchao, Polesskaya, Oksana, Cheng, Riyan, Flagel, Shelly B., Watson, Stanley J., Li, Jun, Akil, Huda, Palmer, Abraham A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9873817/
https://www.ncbi.nlm.nih.gov/pubmed/36712851
http://dx.doi.org/10.3389/fgene.2022.1003074
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author Chitre, Apurva S.
Hebda-Bauer, Elaine K.
Blandino, Peter
Bimschleger, Hannah
Nguyen, Khai-Minh
Maras, Pamela
Li, Fei
Ozel, A. Bilge
Pan, Yanchao
Polesskaya, Oksana
Cheng, Riyan
Flagel, Shelly B.
Watson, Stanley J.
Li, Jun
Akil, Huda
Palmer, Abraham A.
author_facet Chitre, Apurva S.
Hebda-Bauer, Elaine K.
Blandino, Peter
Bimschleger, Hannah
Nguyen, Khai-Minh
Maras, Pamela
Li, Fei
Ozel, A. Bilge
Pan, Yanchao
Polesskaya, Oksana
Cheng, Riyan
Flagel, Shelly B.
Watson, Stanley J.
Li, Jun
Akil, Huda
Palmer, Abraham A.
author_sort Chitre, Apurva S.
collection PubMed
description Common genetic factors likely contribute to multiple psychiatric diseases including mood and substance use disorders. Certain stable, heritable traits reflecting temperament, termed externalizing or internalizing, play a large role in modulating vulnerability to these disorders. To model these heritable tendencies, we selectively bred rats for high and low exploration in a novel environment [bred High Responders (bHR) vs. Low Responders (bLR)]. To identify genes underlying the response to selection, we phenotyped and genotyped 538 rats from an F(2) cross between bHR and bLR. Several behavioral traits show high heritability, including the selection trait: exploratory locomotion (EL) in a novel environment. There were significant phenotypic and genetic correlations between tests that capture facets of EL and anxiety. There were also correlations with Pavlovian conditioned approach (PavCA) behavior despite the lower heritability of that trait. Ten significant and conditionally independent loci for six behavioral traits were identified. Five of the six traits reflect different facets of EL that were captured by three behavioral tests. Distance traveled measures from the open field and the elevated plus maze map onto different loci, thus may represent different aspects of novelty-induced locomotor activity. The sixth behavioral trait, number of fecal boli, is the only anxiety-related trait mapping to a significant locus on chromosome 18 within which the Pik3c3 gene is located. There were no significant loci for PavCA. We identified a missense variant in the Plekhf1 gene on the chromosome 1:95 Mb QTL and Fancf and Gas2 as potential candidate genes that may drive the chromosome 1:107 Mb QTL for EL traits. The identification of a locomotor activity-related QTL on chromosome 7 encompassing the Pkhd1l1 and Trhr genes is consistent with our previous finding of these genes being differentially expressed in the hippocampus of bHR vs. bLR rats. The strong heritability coupled with identification of several loci associated with exploratory locomotion and emotionality provide compelling support for this selectively bred rat model in discovering relatively large effect causal variants tied to elements of internalizing and externalizing behaviors inherent to psychiatric and substance use disorders.
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spelling pubmed-98738172023-01-26 Genome-wide association study in a rat model of temperament identifies multiple loci for exploratory locomotion and anxiety-like traits Chitre, Apurva S. Hebda-Bauer, Elaine K. Blandino, Peter Bimschleger, Hannah Nguyen, Khai-Minh Maras, Pamela Li, Fei Ozel, A. Bilge Pan, Yanchao Polesskaya, Oksana Cheng, Riyan Flagel, Shelly B. Watson, Stanley J. Li, Jun Akil, Huda Palmer, Abraham A. Front Genet Genetics Common genetic factors likely contribute to multiple psychiatric diseases including mood and substance use disorders. Certain stable, heritable traits reflecting temperament, termed externalizing or internalizing, play a large role in modulating vulnerability to these disorders. To model these heritable tendencies, we selectively bred rats for high and low exploration in a novel environment [bred High Responders (bHR) vs. Low Responders (bLR)]. To identify genes underlying the response to selection, we phenotyped and genotyped 538 rats from an F(2) cross between bHR and bLR. Several behavioral traits show high heritability, including the selection trait: exploratory locomotion (EL) in a novel environment. There were significant phenotypic and genetic correlations between tests that capture facets of EL and anxiety. There were also correlations with Pavlovian conditioned approach (PavCA) behavior despite the lower heritability of that trait. Ten significant and conditionally independent loci for six behavioral traits were identified. Five of the six traits reflect different facets of EL that were captured by three behavioral tests. Distance traveled measures from the open field and the elevated plus maze map onto different loci, thus may represent different aspects of novelty-induced locomotor activity. The sixth behavioral trait, number of fecal boli, is the only anxiety-related trait mapping to a significant locus on chromosome 18 within which the Pik3c3 gene is located. There were no significant loci for PavCA. We identified a missense variant in the Plekhf1 gene on the chromosome 1:95 Mb QTL and Fancf and Gas2 as potential candidate genes that may drive the chromosome 1:107 Mb QTL for EL traits. The identification of a locomotor activity-related QTL on chromosome 7 encompassing the Pkhd1l1 and Trhr genes is consistent with our previous finding of these genes being differentially expressed in the hippocampus of bHR vs. bLR rats. The strong heritability coupled with identification of several loci associated with exploratory locomotion and emotionality provide compelling support for this selectively bred rat model in discovering relatively large effect causal variants tied to elements of internalizing and externalizing behaviors inherent to psychiatric and substance use disorders. Frontiers Media S.A. 2023-01-11 /pmc/articles/PMC9873817/ /pubmed/36712851 http://dx.doi.org/10.3389/fgene.2022.1003074 Text en Copyright © 2023 Chitre, Hebda-Bauer, Blandino, Bimschleger, Nguyen, Maras, Li, Ozel, Pan, Polesskaya, Cheng, Flagel, Watson, Li, Akil and Palmer. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Chitre, Apurva S.
Hebda-Bauer, Elaine K.
Blandino, Peter
Bimschleger, Hannah
Nguyen, Khai-Minh
Maras, Pamela
Li, Fei
Ozel, A. Bilge
Pan, Yanchao
Polesskaya, Oksana
Cheng, Riyan
Flagel, Shelly B.
Watson, Stanley J.
Li, Jun
Akil, Huda
Palmer, Abraham A.
Genome-wide association study in a rat model of temperament identifies multiple loci for exploratory locomotion and anxiety-like traits
title Genome-wide association study in a rat model of temperament identifies multiple loci for exploratory locomotion and anxiety-like traits
title_full Genome-wide association study in a rat model of temperament identifies multiple loci for exploratory locomotion and anxiety-like traits
title_fullStr Genome-wide association study in a rat model of temperament identifies multiple loci for exploratory locomotion and anxiety-like traits
title_full_unstemmed Genome-wide association study in a rat model of temperament identifies multiple loci for exploratory locomotion and anxiety-like traits
title_short Genome-wide association study in a rat model of temperament identifies multiple loci for exploratory locomotion and anxiety-like traits
title_sort genome-wide association study in a rat model of temperament identifies multiple loci for exploratory locomotion and anxiety-like traits
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9873817/
https://www.ncbi.nlm.nih.gov/pubmed/36712851
http://dx.doi.org/10.3389/fgene.2022.1003074
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