H. Hill Goldsmith, PhD – Slide of the Week

Goldsmith Slide of the Week 2018

Title: Using Discordant MZ Twins and Genome-wide Methylation Analyses to Identify Anxiety-relevant Genes

Legend: Three MZ (genetically identical) twin pairs were chosen to be clearly discordant for childhood cortisol levels and adolescent fMRI patterns in the amygdala that correlated with anxiety symptoms. Based on genome-wide methylation analyses, 230 regions were differentially methylated, with intrapair differences in the same direction  across twin pairs. These regions identified 183 genes. The smoothing plot above shows the location of differentially methylated (y-axis) CpG dinucleotides (x-axis; black tick marks) for one of the identified genes (NAV1). The DNA methylation profile for the high cortisol/reactive amygdalar BOLD signal/anxious twins (red) and their less anxious (blue) cotwins are shown. Each corresponding co-twin is indicated by a different line pattern (pair A = solid; B = dashed; C = dash + dot). The genomic region of significant differential intrapair methylation is highlighted (peach).

Citation: Alisch, RS. Van Hulle, C., Chopra, P., Bhattacharyya, A., Zhang, SC., Davidson, RJ., Kalin, NH., & Goldsmith, HH. (2017). A multi-dimensional characterization of anxiety in monozygotic twin pairs reveals susceptibility loci in human. Translational Psychiatry, 7(12):1282. 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.

About the investigator: Goldsmith’s research concerns children’s emotional development, behavioral challenges and the autism spectrum. The research incorporates perspectives of psychology, genetics, neuroscience, and developmental epidemiology. He is recognized as a leading theorist of human temperament and a key empirical contributor to the fields of developmental behavioral genetics and childhood psychopathology. Goldsmith is Principal Investigator on six external grants, an investigator in three Centers, and a faculty member on three training grants. His highly collaborative research involves many UW faculty and colleagues at other institutions. Visit the Wisconsin Twin Research lab for more information.

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