The corticotropin-releasing hormone gene and behavioral inhibition in children at risk for panic disorder.
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.
Smoller
Jordan W
JW
Department of Psychiatry, Massachusetts General Hospital, Boston 02114, USA. jsmoller@hms.harvard.edu
Yamaki
Lesley H
LH
Fagerness
Jesen A
JA
Biederman
Joseph
J
Racette
Stephanie
S
Laird
Nan M
NM
Kagan
Jerome
J
Snidman
Nancy
N
Faraone
Stephen V
SV
Hirshfeld-Becker
Dina
D
Tsuang
Ming T
MT
Slaugenhaupt
Susan A
SA
Rosenbaum
Jerrold F
JF
Sklar
Pamela B
PB
D002648:Child; D002874:Chromosome Mapping; D003346:Corticotropin-Releasing Hormone / Q000235:genetics*; D005192:Family Health; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007266:Inhibition, Psychological; D015810:Linkage Disequilibrium; D008297:Male; D016584:Panic Disorder / Q000235:genetics* / Q000503:physiopathology*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D012306:Risk; D012307:Risk Factors
D003346:Corticotropin-Releasing Hormone