Fine mapping of a region on chromosome 8p gives evidence for a QTL contributing to individual differences in an anxiety-related personality trait: TPQ harm avoidance.

The chromosome 8p region is of interest in human behavioral genetics since it harbors a susceptibility region not only for schizophrenia but also for anxiety-related personality traits such as harm avoidance and neuroticism. Towards verifying our preliminary linkage finding of a QTL for TPQ harm avoidance at chromosome 8p, we have now genotyped altogether 24 micro-satellite markers in 377 families. Using three methods (maximum likelihood binomial or MLB, MERLIN, and an associated one parameter model), we observed significant results (P values from 0.002 to 0.0004) for linkage to harm avoidance in this region. A peak multipoint LOD score of 2.76 (P value 0.0002) was obtained with the MLB method. The region-wide empirical P value was 0.002 [0.001-0.0046]. Although, the peak position varied somewhat according to the method (D8S1048 for MLB, D8S1463 for the two other methods), for three methods D8S1810 ( approximately 60 cM) is within 1-2 cM of the peak for harm avoidance. This marker is of particular interest since it is proximate (<0.5 cM) of the core haplotype that in several recent studies show significant association with schizophrenia near neuroregulin 1. Although association studies with microsatellite markers need to be interpreted cautiously, using the Haplotype Trend Regression test one marker, D8S499 ( approximately 60 cM), showed an empirical P value of 2 x 10(-5) for allele 3, which confers a decreased harm avoidance score. Altogether, the current linkage and association results suggest the possibility that the same locus near the neuroregulin 1 gene on chromosome 8p confers risk for both an anxiety-related personality trait as well as schizophrenia. We hypothesize that this common genetic factor may contribute to emotional liability during early development, which constitutes a predisposing factor for major psychosis.

Tridimensional personality questionnaire trait of harm avoidance (anxiety proneness) is linked to a locus on chromosome 8p21.

Human personality traits are moderately heritable but only recently have specific polymorphisms been associated with particular personality dimensions especially anxiety-related and novelty-seeking traits. The first genome-wide scan for personality traits was recently carried out by Cloninger et al. [1998: Am J Med Genet 81:313-317] and his colleagues and they reported that a region on 8p21 showed linkage to TPQ Harm Avoidance, an anxiety-related personality trait. Towards replicating and extending these results, we examined both 8p21 and two additional chromosomal regions (1q21-24 and 22q12-13) for linkage to TPQ personality traits by genotyping at least three microsatellite markers in each region in a group of 384 sibling pairs. We found evidence for linkage to TPQ HA at 8p21-23 (Lod score = 2.907) confirming in an independent sample the initial findings by Cloninger and his colleagues.