A genome-wide screen for acrophobia susceptibility loci in a Finnish isolate

Abstract

Acrophobia, an abnormal fear of heights, is a specific phobia characterized as apprehension cued by the occurrence or anticipation of elevated spaces. It is considered a complex trait with onset influenced by both genetic and environmental factors. Identification of genetic risk variants would provide novel insight into the genetic basis of the fear of heights phenotype and contribute to the molecular-level understanding of its aetiology. Genetic isolates may facilitate identification of susceptibility alleles due to reduced genetic heterogeneity. We took advantage of an internal genetic isolate in Finland in which a distinct acrophobia phenotype appears to be segregating in pedigrees originally ascertained for schizophrenia. We conducted parametric, nonparametric, joint linkage and linkage disequilibrium analyses using a microsatellite marker panel, genotyped in families to search for chromosomal regions correlated with acrophobia. Our results implicated a few regions with suggestive evidence for linkage on chromosomes 4q28 (LOD = 2.17), 8q24 (LOD = 2.09) and 13q21-q22 (LOD = 2.22). We observed no risk haplotypes shared between different families. These results suggest that genetic predisposition to acrophobia in this genetic isolate is unlikely to be mediated by a small number of shared high-risk alleles, but rather has a complex genetic architecture.

Figure 1. Pedigree structure of the most extended acrophobia pedigree with the largest number of affected individuals.

Figure 2. Schematic flowchart of conducted analyses.

The name of the software used is given in brackets.

Figure 3. Results from multipoint nonparametric analysis with NPL_ALL model (SimWalk2).

The upper panel shows comorbid acrophobia and schizophrenia sample, while the lower panel shows pure acrophobia sample.

Figure 4. Results from multipoint nonparametric analysis with NPL_PAIR model (SimWalk2).

The upper panel shows comorbid acrophobia and schizophrenia sample, while the lower panel shows pure acrophobia sample.

Figure 5. Results from linkage disequilibrium conditional on linkage analysis (PSEUDOMARKER).

Recessive analysis is shown with triangles and dominant analysis with dots. The upper panel shows comorbid acrophobia and schizophrenia sample, while the lower panel shows pure acrophobia sample.