Elsevier

Biological Psychiatry

Volume 57, Issue 12, 15 June 2005, Pages 1485-1492
Biological Psychiatry

Original article
The Corticotropin-Releasing Hormone Gene and Behavioral Inhibition in Children at Risk for Panic Disorder

https://doi.org/10.1016/j.biopsych.2005.02.018Get rights and content

Background

Behavioral inhibition to the unfamiliar (BI) is a heritable temperamental phenotype involving the tendency to display fearful, avoidant, or shy behavior in novel situations. BI is a familial and developmental risk factor for panic and phobic anxiety disorders. We previously observed an association between BI and a microsatellite marker linked to the corticotropin releasing hormone (CRH) gene in children at risk for panic disorder. To evaluate this further, we genotyped additional families for this marker and a panel of markers encompassing the CRH locus.

Methods

Sixty-two families that included parents with panic disorder and children who underwent laboratory-based behavioral observations were studied. Family-based association tests and haplotype analysis were used to evaluate the association between BI and polymorphisms spanning the CRH locus.

Results

We examined a set of markers which we found to reside in a block of strong linkage disequilibrium encompassing the CRH locus. The BI phenotype was associated with the microsatellite marker (p = .0016) and three single nucleotide polymorphisms (SNPs), including a SNP in the coding sequence of the gene (p = .023). Haplotype-specific tests revealed association with a haplotype comprising all of the markers (p = .015).

Conclusions

These results suggest that the CRH gene influences inhibited temperament, a risk factor for panic and phobic anxiety disorders. Genetic studies of anxiety-related temperament represent an important strategy for identifying the genetic basis of anxiety disorders.

Section snippets

Participants

Families were recruited from a sample of 231 families who had participated in a study of children at risk for anxiety disorders conducted at Massachusetts General Hospital (MGH). Details of the study sample and behavioral assessments are provided elsewhere (Rosenbaum et al 2000; Smoller et al 2001). In the children-at-risk study, the proband was a parent who either had a history of treatment for panic disorder or major depression or who was a control with no history of major anxiety syndromes

LD Structure of the CRH Locus

In order to determine the LD relationships among SNPs in and around the CRH gene, markers were genotyped in a panel of 93 individuals from 12 CEPH pedigrees, as described in Methods. Fifty-five SNPs spanning a region of more than 200 kb encompassing the CRH gene were typed, including approximately 155 kb centromeric and 114 kb telomeric of the gene. Figure 1 displays the inter-marker LD (using the D’ statistic) for the 25 SNPs that passed quality control metrics and had a minor allele frequency

Discussion

Although one must always be cautious when interpreting a single study, our results are compelling for several reasons. CRH has been implicated in the neurobiology of anxiety-related behavior and anxious temperament by numerous physiological and genetic studies of experimental animal models (Bakshi and Kalin 2000). The temperamental phenotype BI has been identified as a familial and developmental risk factor for panic and phobic anxiety disorders. We observed associations between markers in and

References (69)

  • J. Kagan et al.

    Early childhood predictors of adult anxiety disorders

    Biol Psychiatry

    (1999)
  • N.H. Kalin et al.

    Cerebrospinal fluid corticotropin-releasing hormone levels are elevated in monkeys with patterns of brain activity associated with fearful temperament

    Biol Psychiatry

    (2000)
  • M. Knapp

    The transmission/disequilibrium test and parental-genotype reconstructionthe reconstruction-combined transmission/disequilibrium test

    Am J Hum Genet

    (1999)
  • C. Lange et al.

    Power calculations for a general class of family-based association testsdichotomous traits

    Am J Hum Genet

    (2002)
  • T.J. Sajdyk et al.

    Role of corticotropin-releasing factor and urocortin within the basolateral amygdala of rats in anxiety and panic responses

    Behav Brain Res

    (1999)
  • C. Schwartz et al.

    Adolescent social anxiety as an outcome of inhibited temperament in childhood

    J Am Acad Child Adolesc Psychiatry

    (1999)
  • C.E. Schwartz et al.

    Differential amygdalar response to novel versus newly familiar neutral facesa functional MRI probe developed for studying inhibited temperament

    Biol Psychiatry

    (2003)
  • K.A. Seth et al.

    Repressor element silencing transcription factor/neuron-restrictive silencing factor (REST/NRSF) can act as an enhancer as well as a repressor of corticotropin-releasing hormone gene transcription

    J Biol Chem

    (2001)
  • G.N. Smagin et al.

    The role of CRH in behavioral responses to stress

    Peptides

    (2001)
  • J. Smoller et al.

    Association of a genetic marker at the corticotropin releasing hormone locus with behavioral inhibition

    Biol Psychiatry

    (2003)
  • R. Spielman et al.

    A sibship test for linkage in the presence of associationthe sib transmission/disequilibrium test

    Am J Hum Genet

    (1998)
  • L.K. Takahashi

    Role of CRF(1) and CRF(2) receptors in fear and anxiety

    Neurosci Biobehav Rev

    (2001)
  • N. Wang et al.

    Distribution of recombination crossovers and the origin of haplotype blocksthe interplay of population history, recombination, and mutation

    Am J Hum Genet

    (2002)
  • S.L. Warren et al.

    Maternal panic disorderinfant temperament, neurophysiology, and parenting behaviors

    J Am Acad Child Adolesc Psychiatry

    (2003)
  • J. Whittaker et al.

    The effect of family structure on linkage tests using allelic association

    Am J Hum Genet

    (1998)
  • S. Arbelle et al.

    Relation of shyness in grade school children to the genotype for the long form of the serotonin transporter promoter region polymorphism

    Am J Psychiatry

    (2003)
  • J.C. Barrett et al.

    Haploviewanalysis and visualization of LD and haplotype maps

    Bioinformatics

    (2005)
  • J. Biederman et al.

    Further evidence of association between behavioral inhibition and social anxiety in children

    Am J Psychiatry

    (2001)
  • K.H. Buetow et al.

    High-throughput development and characterization of a genomewide collection of gene-based single nucleotide polymorphism markers by chip-based matrix-assisted laser desorption/ionization time-of-flight mass spectrometry

    Proc Natl Acad Sci U S A

    (2001)
  • M. Davis

    Functional neuroanatomy of anxiety and feara focus on the amygdala

  • J.M. Gorman et al.

    Neuroanatomical hypothesis of panic disorder, revised

    Am J Psychiatry

    (2000)
  • I.I. Gottesman et al.

    The endophenotype concept in psychiatryetymology and strategic intentions

    Am J Psychiatry

    (2003)
  • J. Gu et al.

    Dinucleotide repeat polymorphism at the CRH gene

    Hum Mol Genet

    (1993)
  • K.E. Habib et al.

    Oral administration of a corticotropin-releasing hormone receptor antagonist significantly attenuates behavioral, neuroendocrine, and autonomic responses to stress in primates

    Proc Natl Acad Sci U S A

    (2000)
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