Genome scan for loci predisposing to anxiety disorders using a novel multivariate approach

Strong evidence for a chromosome 4 risk locus

Belhassen Kaabi, Joel Gelernter, Scott W. Woods, Andrew Goddard, Grier P. Page, Robert C. Elston

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

We conducted a 10-centimorgan linkage autosomal genome scan in a set of 19 extended American pedigrees (219 subjects) ascertained through probands with panic disorder. Several anxiety disorders-including social phobia, agoraphobia, and simple phobia-in addition to panic disorder segregate in these families. In previous studies of this sample, linkage analyses were based separately on each of the individual categorical affection diagnoses. Given the substantial comorbidity between anxiety disorders and their probable shared genetic liability, it is clear that this method discards a considerable amount of information. In this article, we propose a new approach that considers panic disorder, simple phobia, social phobia, and agoraphobia as expressions of the same multivariate, putatively genetically influenced trait. We applied the most powerful multipoint Haseman-Elston method, using the grade of membership score generated from a fuzzy clustering of these phenotypes as the dependent variable in Haseman-Elston regression. One region on chromosome 4q31-q34, at marker D4S413 (with multipoint and single-point nominal P values < .00001), showed strong evidence of linkage (genomewide significance at P< .05). The same region is known to be the site of a neuropeptide Y receptor gene, NPY1R (4q31-q32), that was recently connected to anxiolytic-like effects in rats. Several other regions on four chromosomes (4q21.21-22.3, 5q14.2-14.3, 8p23.1, and 14q22.3-23.3) met criteria for suggestive linkage (multipoint nominal P values < .01). Family-by-family analysis did not show any strong evidence of heterogeneity. Our findings support the notion that the major anxiety disorders, including phobias and panic disorder, are complex traits that share at least one susceptibility locus. This method could be applied to other complex traits for which shared genetic-liability factors are thought to be important, such as substance dependencies.

Original languageEnglish
Pages (from-to)543-553
Number of pages11
JournalAmerican Journal of Human Genetics
Volume78
Issue number4
DOIs
StatePublished - Apr 2006

Fingerprint

Chromosomes, Human, Pair 4
Panic Disorder
Anxiety Disorders
Genome
Agoraphobia
Chromosomes
Neuropeptide Y Receptors
Phobic Disorders
Anti-Anxiety Agents
Pedigree
Cluster Analysis
Comorbidity
Phenotype
Genes
Social Phobia
Specific Phobia

ASJC Scopus subject areas

  • Genetics

Cite this

Genome scan for loci predisposing to anxiety disorders using a novel multivariate approach : Strong evidence for a chromosome 4 risk locus. / Kaabi, Belhassen; Gelernter, Joel; Woods, Scott W.; Goddard, Andrew; Page, Grier P.; Elston, Robert C.

In: American Journal of Human Genetics, Vol. 78, No. 4, 04.2006, p. 543-553.

Research output: Contribution to journalArticle

Kaabi, Belhassen ; Gelernter, Joel ; Woods, Scott W. ; Goddard, Andrew ; Page, Grier P. ; Elston, Robert C. / Genome scan for loci predisposing to anxiety disorders using a novel multivariate approach : Strong evidence for a chromosome 4 risk locus. In: American Journal of Human Genetics. 2006 ; Vol. 78, No. 4. pp. 543-553.
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