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Genome-Wide Association for Fear Conditioning in an Advanced Intercross Mouse Line

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Abstract

Fear conditioning (FC) may provide a useful model for some components of post-traumatic stress disorder (PTSD). We used a C57BL/6J × DBA/2J F2 intercross (n = 620) and a C57BL/6J × DBA/2J F8 advanced intercross line (n = 567) to fine-map quantitative trait loci (QTL) associated with FC. We conducted an integrated genome-wide association analysis in QTLRel and identified five highly significant QTL affecting freezing to context as well as four highly significant QTL associated with freezing to cue. The average percent decrease in QTL width between the F2 and the integrated analysis was 59.2%. Next, we exploited bioinformatic sequence and expression data to identify candidate genes based on the existence of non-synonymous coding polymorphisms and/or expression QTLs. We identified numerous candidate genes that have been previously implicated in either fear learning in animal models (Bcl2, Btg2, Dbi, Gabr1b, Lypd1, Pam and Rgs14) or PTSD in humans (Gabra2, Oprm1 and Trkb); other identified genes may represent novel findings. The integration of F2 and AIL data maintains the advantages of studying FC in model organisms while significantly improving resolution over previous approaches.

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Acknowledgments

The authors would like to thank Jackie Lim, Ryan Walters, and Garrett Birkhoff for their assistance in behavioral testing. Access to amygdala microarray data for the BXD strains was provided by Drs. Khyobeni Mozhui and Rob Williams. The authors would like to acknowledge GeneNetwork (http://www.genenetwork.org) for providing bioinformatic tools and public data that have contributed to this manuscript. This work was supported by NIH grants R01MH079103, R21DA024845, R01DA021336 (AAP), and T32DA07255 (CCP).

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Authors and Affiliations

  1. Department of Human Genetics, University of Chicago, 920 E 58th St., CLSC-507D, Chicago, IL, 60637, USA

    Clarissa C. Parker, Greta Sokoloff, Riyan Cheng & Abraham A. Palmer

  2. Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, IL, 60637, USA

    Abraham A. Palmer

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  1. Clarissa C. Parker
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  2. Greta Sokoloff
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Correspondence to Abraham A. Palmer.

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Edited by Tamara Phillips.

Electronic supplementary material

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10519_2011_9524_MOESM1_ESM.pdf

Supplemental Table 1. eQTLs for freezing to tone day 1. Table displays the gene symbol, chromosome and Mb location, mean expression levels, peak LOD score, and peak LOD location for each eQTL. (PDF 66 kb)

10519_2011_9524_MOESM2_ESM.pdf

Supplemental Table 2. eQTLs for freezing to context day 2. Table displays the gene symbol, chromosome and Mb location, mean expression levels, peak LOD score, and peak LOD location for each eQTL. (PDF 217 kb)

10519_2011_9524_MOESM3_ESM.pdf

Supplemental Table 3. eQTLs for freezing to cue day 3. Table displays the gene symbol, chromosome and Mb location, mean expression levels, peak LOD score, and peak LOD location for each eQTL. (PDF 126 kb)

10519_2011_9524_MOESM4_ESM.pdf

Supplemental Table 4. Non-synonymous coding SNPs in freezing to tone day 1 QTLs. Table displays the chromosome, bp position, gene name, gene symbol, and number of coding SNPs present. Symbols represent the presence of SNPS resulting in the following mutations: #=stop-lost, *=stop-gain, $=essential splice site. (PDF 215 kb)

10519_2011_9524_MOESM5_ESM.pdf

Supplemental Table 5. Non-synonymous coding SNPs in freezing to context QTLs. Table displays the chromosome, bp position, gene name, gene symbol, and number of coding SNPs present. Symbols represent the presence of SNPS resulting in the following mutations: #=stop-lost, *=stop-gain, $=essential splice site. (PDF 367 kb)

10519_2011_9524_MOESM6_ESM.pdf

Supplemental Table 6. Non-synonymous coding SNPs in freezing to cue QTLs. Table displays the chromosome, gene name, gene symbol, and number of coding SNPs present. Symbols represent the presence of SNPS resulting in the following mutations: #=stop-lost, *=stop-gain, $=essential splice site. (PDF 299 kb)

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Parker, C.C., Sokoloff, G., Cheng, R. et al. Genome-Wide Association for Fear Conditioning in an Advanced Intercross Mouse Line. Behav Genet 42, 437–448 (2012). https://doi.org/10.1007/s10519-011-9524-8

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