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

Several linkage studies on anxiety have been carried out in samples ascertained through probands with panic disorder. The results indicated that using a broad anxiety phenotype instead of a DSM-IV anxiety disorder diagnosis might enhance the chance of finding a linkage signal. In the current study, a genome-wide linkage analysis was performed on anxiety measured with a self-report questionnaire whose scores are highly correlated with DSM-IV anxiety disorders. The self-report questionnaire was included in five surveys of a longitudinal study of the Netherlands Twin Register. Genotype and phenotype data were available for 1602 twins and siblings. To estimate identity by descent, additional genotype data for 564 parents and 22 siblings were used. Linkage analyses were carried out using MERLIN-regress on the average anxiety scores across time. A linkage signal ( logarithm of odds score 3.4, empirical P-value 0.07) was obtained at chromosome 14 for marker D14S65 at 105 cM (90% confidence interval, 99-115 cM bounded bymarkers D14S1434 and D14S985). This finding replicates a linkage finding for a broad anxiety phenotype in a clinically based sample, indicating that the region might harbor a quantitative trait locus associated with the whole spectrum of general anxiety, that is from the normal to the clinical range. Moreover, genome-wide linkage and association studies on emotionality in mice obtained significant results in a syntenic region on mouse chromosome 12. Two homolog genes lie in this region -Dlk1 (delta-like 1 homolog, Drosophila) and Rtl1 (retrotransposon-like 1). Future association studies of these genes are warranted.