Anxiety: Uncover Roles of Stress Related Genes by Imaging Genetics



Functional and structural changes in components of the neural circuitry involved in anxiety and stress responses can be accessed by brain imaging. Unlike genetic effects on complex behavioral traits of anxiety, which are relatively small and may require large sample sizes to detect, gene effects on the intermediate phenotypes accessed via brain imaging are likely to be more pronounced and more readily detectable. In this chapter, we provide an overview of imaging genetic studies on anxiety and stress related genes. We also discuss in particular the effects of genetic variation of neuropeptide Y (NPY) gene on individual stress responses and emotion accessed by neuroimaging.

Anxiety is a subjectively-experienced setpoint that determines a range of normal behavioral responses, as well pathological variation. Anxiety and mood disorders may result from failure in individual adaptive responses to fear and stress (McEwen, Neuropsychopharmacology 22, 108–124, 2000), where the normal homeostatic setpoint of mood is replaced by an allostatic state marked by chronic anxiety and dysphoria, and vulnerability to stress-induced relapse (McEwen and Stellar, Arch Intern Med 153, 2093–2101, 1993). In humans, anxiety and emotionality (Neuroticism) are moderately to highly heritable traits (0.4–0.6) but also strongly influenced by stress exposures in a pattern consistent with gene x environment interaction (Caspi et al., Science 297, 851–854, 2002). These stress-induced changes are superimposed on genetic differences and are probably dependent on genetic variation in resiliency. While the detection of gene effects on psychiatric measures of complex behaviors such as trait anxiety would require substantially large sample size, it has been noted that allelic effects on fear and stress responses are more readily detectable in relatively small sample size via the changes of the conserved neural components accessed by brain imaging (Hariri et al., Science 297, 400–403, 2002; Heinz et al., Nat Neurosci 8, 20–21, 2005; Pezawas et al., Nat Neurosci 8, 828–834, 2005). Because of this, the functional and structural changes in the components of neural circuitry observed with brain imaging are important intermediate phenotypes and have become effective handles in the studies of the genetics of anxiety and mood disorders.


Nucleus Accumbens Trait Anxiety Amygdala Activation Amygdala Reactivity Pain Stress 
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We thank Guanshan Zhu for his contributions to the NPY haplotype and mRNA expression analyses. We thank Ahmad Hariri, Robert Ferrell, Stephen Manuck, and Sarah M. Brown for the fMRI data. We thank Jon-Kar Zubieta, David Scott, and Christian Stohler for the PET data. We thank Rajita Sinha, Matti Virkkunen, Deborah Mash, and Richard Hauger for their contributions of the various samples analyzed in our study. We also acknowledge Mary-Anne Enoch, Robert Lipsky, Xian-Zhang Hu, Colin Hodgkinson, Ke Xu, Beata Buzas, Qiaoping Yuan, and Pei-Hong Shen for their suggestions and assistance. The NPY study was originally published in Nature, 2008 (Zhou et al. 2008).


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Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Laboratory of Neurogenetics, NIAAA/NIHRockvilleUSA

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