A multi-dimensional characterization of anxiety in monozygotic twin pairs reveals susceptibility loci in humans

Reid S Alisch,Su-Chun Zhang,Richard J Davidson,H Hill Goldsmith,Carol Van Hulle,Anita Bhattacharyya,Pankaj Chopra,Ned H Kalin

doi:10.1038/s41398-017-0047-9

Abstract

The etiology of individual differences in human anxiousness is complex and includes contributions from genetic, epigenetic (i.e., DNA methylation) and environmental factors. Past genomic approaches have been limited in their ability to detect human anxiety-related differences in these factors. To overcome these limitations, we employed both a multi-dimensional characterization method, to select monozygotic twin pairs discordant for anxiety, and whole genome DNA methylation sequencing. This approach revealed 230 anxiety-related differentially methylated loci that were annotated to 183 genes, including several known stress-related genes such as NAV1, IGF2, GNAS, and CRTC1. As an initial validation of these findings, we tested the significance of an overlap of these data with anxiety-related differentially methylated loci that we previously reported from a key neural circuit of anxiety (i.e., the central nucleus of the amygdala) in young monkeys and found a significant overlap (P-value < 0.05) of anxiety-related differentially methylated genes, including GNAS, SYN3, and JAG2. Finally, sequence motif predictions of all the human differentially methylated regions indicated an enrichment of five transcription factor binding motifs, suggesting that DNA methylation may regulate gene expression by mediating transcription factor binding of these transcripts. Together, these data demonstrate environmentally sensitive factors that may underlie the development of human anxiety.

Highlights

Anxiety is frequently characterized by a negative affective response that is associated with the anticipation of encountering a potential threat[1]
To characterize non-shared environmental influences on measures of human anxiety, including generalized anxiety disorder (GAD), social phobia, hypothalamic–pituitary– adrenal (HPA) activity, and amygdala function, we computed intraclass correlations (ICCs)) to quantify the degree of within-pair similarity between MZ cotwins over a seven-year period[44]
While initial amygdala activation at age 15 was moderately familial (ICC = 0.44, P-value = 0.05; N = 24 pairs), our measure of interest, amygdala recovery, showed low and statistically non-significant twin pair similarity (ICC = −0.19, P-value = 0.75; N = 24 pairs). These data suggest that the time course for recovery is sensitive to a non-shared environment (Supplementary Table 2)

Summary

Introduction

Anxiety is frequently characterized by a negative affective response that is associated with the anticipation of encountering a potential threat[1]. Our recent study in young monkeys, as well as studies in humans, identified differentially methylated genes that are implicated as risk factors for anxiety and depressive disorders[25,26]. These studies support the hypothesis that DNA methylation may have an important role in the risk to develop trait-like anxiety. These studies have relied heavily on the ability to access brain tissue. Focusing studies on anxietyrelated DNA methylation profiles in blood has the potential to provide tools that could be clinically utilized to improve diagnostic and treatment strategies

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