Genome-wide linkage scan for loci predisposing to social phobia: Evidence for a chromosome 16 risk locus

Objective: Social phobia is a common, sometimes disabling, fear of situations that might entail scrutiny by others. Several anxiety disorders, including social phobia, are genetically influenced. Genetic linkage analysis can provide the means to identify genomic locations harboring susceptibility loci for genetically influenced disorders. Identifying loci for social phobia was the goal of this study. Method: The authors conducted a genome-wide linkage scan, i.e., tested enough genetic markers to query the entire genome, in 17 American pedigrees (163 subjects) ascertained through probands with panic disorder. Several anxiety disorders segregate in these families; diagnoses were based on structured interviews. A total of 422 markers (404 autosomal, 18 on the X chromosome) with an average spacing of less than 10 centimorgans were genotyped. Multipoint lod score and nonparametric (ZIr score) link-age analyses for social phobia were completed with Allegro and Genehunter X software. Results: Evidence for linkage to social phobia for chromosome 16 markers was identified. A Zlr score of 3.41 was observed for chromosome 16 near marker D16S415. The maximum observed lod score was 2.22, also for chromosome 16, between D16S415 and D16S503 (under a model of recessive inheritance). Additional areas of interest were identified on chromosomes 9, 14. and 18. Conclusions: These findings meet conservative criteria for "suggestive" linkage. The gene encoding the norepinephrine transporter protein (SLC6A2) maps to this broad region, making SLC6A2 both a positional and physiological candidate for influencing social phobia risk. To the authors' knowledge, this is the first complete linkage genome scan for this disorder.