Meta-analyses of genome-wide linkage scans of anxiety-related phenotypes

Abstract

Genetic factors underlying trait neuroticism, reflecting a tendency towards negative affective states, may overlap genetic susceptibility for anxiety disorders and help explain the extensive comorbidity amongst internalizing disorders. Genome-wide linkage (GWL) data from several studies of neuroticism and anxiety disorders have been published, providing an opportunity to test such hypotheses and identify genomic regions that harbor genes common to these phenotypes. In all, 11 independent GWL studies of either neuroticism (n ¼ 8) or anxiety disorders (n ¼ 3) were collected, which comprised of 5341 families with 15 529 individuals. The rank-based genome scan meta-analysis (GSMA) approach was used to analyze each trait separately and combined, and global correlations between results were examined. False discovery rate (FDR) analysis was performed to test for enrichment of significant effects. Using 10 cM intervals, bins nominally significant for both GSMA statistics, P SR and P OR , were found on chromosomes 9, 11, 12, and 14 for neuroticism and on chromosomes 1, 5, 15, and 16 for anxiety disorders. Genome-wide, the results for the two phenotypes were significantly correlated, and a combined analysis identified additional nominally significant bins. Although none reached genome-wide significance, an excess of significant P SR P-values were observed, with 12 bins falling under a FDR threshold of 0.50. As demonstrated by our identification of multiple, consistent signals across the genome, meta-analytically combining existing GWL data is a valuable approach to narrowing down regions relevant for anxiety-related phenotypes. This may prove useful for prioritizing emerging genome-wide association data for anxiety disorders.

Genetics of anxiety disorders: Genetic epidemiological and molecular studies in humans

“…For AD, similar analysis using a smaller set of samples found suggestive evidence for linkage on chromosomes 1, 5, 15, and 16. The results for AD and neuroticism were moderately but significantly correlated …”

“…conducted linkage analyses of phobic disorder in a set of pedigrees ascertained for PD and reported linkage on chromosome 3q for agoraphobia, 14q for specific phobia, and 16q for social phobia . A recent meta‐analysis of all available genome‐wide linkage studies of anxious temperament (neuroticism) using eight independent samples with over 14 000 subjects supported linkage on chromosomes 9, 11, 12, and 14 . For AD, similar analysis using a smaller set of samples found suggestive evidence for linkage on chromosomes 1, 5, 15, and 16.…”

Psychiatric disorders and left-handedness in children living in an urban environment

“…Genes and environmental factors influence the occurrence of both lefthandedness and mental health disorders. Genes implicated in anxiety and depression include the following: CRHR1, the Corticotropin Releasing Hormone Receptor-1, 5-HTTLPR, the 5-HydroxyTryptamine (serotonin) Transporter Gene-Linked Polymorphic Region gene, and BDNF, the brain-derived neurotropic factor gene, among others (Boulle et al, 2012;Rogers et al, 2013;Webb et al, 2012). Environmental factors, such as maltreatment and violence exposure, also place individuals at higher risk for the development of depression, anxiety and posttraumatic stress (Anda et al, 2007;Rogers et al, 2013).…”

Genome-Wide and Gene-Based Association Studies of Anxiety Disorders in European and African American Samples

“…Recent studies have indicated that both dopamine and serotonin partially exert their actions by modulating the activity of AKT [42], [43]. Furthermore, chromosome 4q32 region was suggested to be associated with ADs (PD, SAD, and phobia) in a previous linkage study [44], although this region was not confirmed in a recent meta-analysis of linkage data for ADs [45].…”