Genome Scan for Loci Predisposing to Anxiety Disorders Using a Novel Multivariate Approach: Strong Evidence for a Chromosome 4 Risk Locus

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.

Linkage on chromosome 14 in a genome-wide linkage study of a broad anxiety phenotype

“…This signifies that a linkage signal can be not only due to the disease, but also due to other characteristics of a clinical sample. As our significant linkage result was also previously found in a clinical sample, 12 the region on chromosome 14 is possibly associated with the whole spectrum of general anxiety, that is from the normal to the clinical range.…”

“…For the same region at chromosome 14, Kaabi et al 12 reported a significant linkage result (nominal P = 0.005 and empirical P = 0.04). However, after adjusting for sib-pair age differences, the signal disappeared (nominal P = 0.07, empirical P not given).…”

“…[3][4][5] Several genome-wide linkage studies have tried to identify genomic regions harboring quantitative trait loci (QTLs) that influence the vulnerability for anxiety disorders. All these studies [6][7][8][9][10][11][12][13][14][15] ascertained the pedigrees through probands with panic disorder, except for one study 16 that included pedigrees with at least one member having an anxiety disorder or somatoform pain. Panic disorder is the most frequently analyzed phenotype.…”

“…11,15 Simple phobia and social phobia have each been investigated once. 9,10 Other anxiety phenotypes 12,14,16 have been based on findings from genetic epidemiological studies indicating a common genetic background for anxiety disorders, 4,17 Thorgeirsson et al 16 considered anxiety disorder or somatoform pain as indicators of affection status. Smoller et al 14 and Kaabi et al 12 constructed new phenotypes of anxiety proneness.…”

Meta-analyses of genome-wide linkage scans of anxiety-related phenotypes

“…21 The Yale group has published four analyses of various ANX phenotypes. We used the results from Kaabi et al, 22 which analyzed linkage to a multivariate 'fuzzy clustering' phenotype that combined information from PD and social, specific, and agoraphobias. Finally, we included data from the primary PD linkage analysis published by the Iowa group.…”