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Genome-wide association study of behavioral, physiological and gene expression traits in outbred CFW mice

Nature Genetics volume 48, pages 919–926 (2016)Cite this article

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Abstract

Although mice are the most widely used mammalian model organism, genetic studies have suffered from limited mapping resolution due to extensive linkage disequilibrium (LD) that is characteristic of crosses among inbred strains. Carworth Farms White (CFW) mice are a commercially available outbred mouse population that exhibit rapid LD decay in comparison to other available mouse populations. We performed a genome-wide association study (GWAS) of behavioral, physiological and gene expression phenotypes using 1,200 male CFW mice. We used genotyping by sequencing (GBS) to obtain genotypes at 92,734 SNPs. We also measured gene expression using RNA sequencing in three brain regions. Our study identified numerous behavioral, physiological and expression quantitative trait loci (QTLs). We integrated the behavioral QTL and eQTL results to implicate specific genes, including Azi2 in sensitivity to methamphetamine and Zmynd11 in anxiety-like behavior. The combination of CFW mice, GBS and RNA sequencing constitutes a powerful approach to GWAS in mice.

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Figure 1: Components of the study.
Figure 2: Genetic characteristics of the CFW mouse population.
Figure 3: QTLs for physiological and behavioral traits.
Figure 4: Overview of eQTL mapping.

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Acknowledgements

The authors wish to acknowledge technical assistance from: D. Godfrey, S. Lionikaite, V. Lionikaite, A.S. Lionikiene and J. Zekos as well as technical and intellectual input from M. Abney, J. Borevitz, K. Broman, N. Cai, R. Cheng, N. Cox, R. Davies, J. Flint, L. Goodstadt, P. Grabowski, B. Harr, E. Leffler, R. Mott, J. Nicod, J. Novembre, A. Price, M. Stephens, D. Weeks and X. Zhou. This project was funded by NIH R01GM097737 and P50DA037844 (A.A.P.), NIH T32DA07255 (C.C.P.), NIH T32GM07197 (N.M.G.), NIH R01AR056280 (D.A.B.), NIH R01AR060234 (C.L.A.-B.), the Fellowship from the Human Frontiers Science Program (P.C.) and the Howard Hughes Medical Institute (J.K.P.).

Author information

Author notes

  1. Clarissa C Parker, Shyam Gopalakrishnan and Peter Carbonetto: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Human Genetics, University of Chicago, Chicago, Illinois, USA

    Clarissa C Parker, Shyam Gopalakrishnan, Peter Carbonetto, Natalia M Gonzales, Emily Leung, Yeonhee J Park, Emmanuel Aryee, Joe Davis & Abraham A Palmer

  2. Department of Psychology, Middlebury College, Middlebury, Vermont, USA

    Clarissa C Parker

  3. Program in Neuroscience, Middlebury College, Middlebury, Vermont, USA

    Clarissa C Parker

  4. Natural History Museum of Denmark, Copenhagen University, Copenhagen, Denmark

    Shyam Gopalakrishnan

  5. AncestryDNA, San Francisco, California, USA

    Peter Carbonetto

  6. Department of Biobehavioral Health, Pennsylvania State University, University Park, Pennsylvania, USA

    David A Blizard

  7. Center for Musculoskeletal Research, University of Rochester, Rochester, New York, USA

    Cheryl L Ackert-Bicknell

  8. Department of Orthopedics and Rehabilitation, University of Rochester, Rochester, New York, USA

    Cheryl L Ackert-Bicknell

  9. School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK

    Arimantas Lionikas

  10. Department of Genetics, Stanford University, Palo Alto, California, USA

    Jonathan K Pritchard

  11. Department of Biology, Stanford University, Palo Alto, California, USA

    Jonathan K Pritchard

  12. Howard Hughes Medical Institute, Stanford University, Palo Alto, California, USA

    Jonathan K Pritchard

  13. Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, Illinois, USA

    Abraham A Palmer

  14. Department of Psychiatry, University of California, San Diego, La Jolla, California, USA.,

    Abraham A Palmer

  15. Institute for Genomic Medicine, University of California, San Diego, La Jolla, California, USA.,

    Abraham A Palmer

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  1. Clarissa C Parker
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  13. Abraham A Palmer
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Contributions

A.A.P. conceived the study. C.C.P. and A.A.P. supervised the project. S.G. and P.C. designed and implemented the statistical and bioinformatics analyses with contributions from C.C.P., J.K.P. and A.A.P. N.M.G. designed and executed the RNA-seq and GBS protocols with assistance from E.A. and J.D. C.C.P. performed the behavioral phenotyping with assistance from E.L. and Y.J.P. A.L. performed the muscle and bone phenotyping with input from D.A.B. C.L.A.-B. performed the BMD phenotyping. C.C.P., S.G., P.C. and A.A.P. wrote the manuscript, with input from all co-authors.

Corresponding author

Correspondence to Abraham A Palmer.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Note and Supplementary Figures 1–29. (PDF 8502 kb)

Supplementary Table 1

Summary of phenotypes. (XLSX 15 kb)

Supplementary Table 2

GWAS results. (XLSX 17 kb)

Supplementary Table 3

The number of expression QTLs (eQTLs) found in the three brain tissues assayed. (XLSX 10 kb)

Supplementary Table 4

Discordance rates when comparing GBS and MegaMUGA genotypes using 24 subjects genotyped using both platforms. (XLSX 10 kb)

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Parker, C., Gopalakrishnan, S., Carbonetto, P. et al. Genome-wide association study of behavioral, physiological and gene expression traits in outbred CFW mice. Nat Genet 48, 919–926 (2016). https://doi.org/10.1038/ng.3609

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  • DOI: https://doi.org/10.1038/ng.3609

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