Collective interaction effects associated with mammalian behavioral traits reveal genetic factors connecting fear and hemostasis

Hyung Jun Woo, J. Reifman

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Investigation of the genetic architectures that influence the behavioral traits of animals can provide important insights into human neuropsychiatric phenotypes. These traits, however, are often highly polygenic, with individual loci contributing only small effects to the overall association. The polygenicity makes it challenging to explain, for example, the widely observed comorbidity between stress and cardiac disease. Methods: We present an algorithm for inferring the collective association of a large number of interacting gene variants with a quantitative trait. Using simulated data, we demonstrate that by taking into account the non-uniform distribution of genotypes within a cohort, we can achieve greater power than regression-based methods for high-dimensional inference. Results: We analyzed genome-wide data sets of outbred mice and pet dogs, and found neurobiological pathways whose associations with behavioral traits arose primarily from interaction effects: γ-carboxylated coagulation factors and downstream neuronal signaling were highly associated with conditioned fear, consistent with our previous finding in human post-traumatic stress disorder (PTSD) data. Prepulse inhibition in mice was associated with serotonin transporter and platelet homeostasis, and noise-induced fear in dogs with hemostasis. Conclusions: Our findings suggest a novel explanation for the observed comorbidity between PTSD/anxiety and cardiovascular diseases: key coagulation factors modulating hemostasis also regulate synaptic plasticity affecting the learning and extinction of fear.

Original languageEnglish (US)
Article number175
Pages (from-to)175
JournalBMC Psychiatry
Volume18
Issue number1
DOIs
StatePublished - Jun 5 2018

Bibliographical note

Funding Information:
This work was supported by the U.S. Army Medical Research and Materiel Command (Ft. Detrick, Maryland). The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the U.S. Army or of the U.S. Department of Defense. This paper has been approved for public release with unlimited distribution. The funding body was not involved in any of the following aspects of the research: study design; data collection, analysis, and interpretation; writing of the manuscript; any other function beyond direct funding of the research or its presentation.

Publisher Copyright:
© 2018 The Author(s).

PubMed: MeSH publication types

  • Journal Article
  • Research Support, U.S. Gov't, Non-P.H.S.

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