STRONG EVIDENCE FOR A CHROMOSOME 4 RISK LOCUS PREDISPOISNG TO ANXIETY DISORDERS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We conducted a 10 cM linkage autosomal genome scan in a set of 19 American extended pedigrees (219 subjects) ascertained through probands with panic disorder. Several anxiety disorders, including social phobia, agoraphobia, and simple phobias - in addition to panic disorder- segregate in these families. In previous analyses on this sample, linkage analyses were based separately on each of the individual categorical affection diagnoses. Considering the substantial comorbidity between anxiety disorders and their probable shared genetic liability, it is clear that this method discards a considerable amount of information. We proposed 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 multipoint Haseman-Elston method, using the grades of membership generated from a fuzzy clustering of these phenotypes as the dependent variable in Haseman-Elston regression. One region on chromosome 4q31-q34 around marker D4S413 (multipoint and single-point nominal p-values <0.00001) showed strong evidence of linkage (genome-wide significant at p<0.05). The same region is known to be the site of a neuropeptide Y receptor gene NPY1R (4q31-q32) that was recently implicated in anxiolytic-like effects in rats. 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.