Genome-wide association study of seasonal affective disorder

Kwo Wei David Ho,Jess Fiedorowicz,Douglas F Levinson,Myrna M Weissman,Shizhong Han,James B Potash,Benjamin Hing,Jakob V Nielsen,Dubravka Jancic

doi:10.1038/s41398-018-0246-z

Abstract

Family and twin studies have shown a genetic component to seasonal affective disorder (SAD). A number of candidate gene studies have examined the role of variations within biologically relevant genes in SAD susceptibility, but few genome-wide association studies (GWAS) have been performed to date. The authors aimed to identify genetic risk variants for SAD through GWAS. The authors performed a GWAS for SAD in 1380 cases and 2937 controls of European-American (EA) origin, selected from samples for GWAS of major depressive disorder and of bipolar disorder. Further bioinformatic analyses were conducted to examine additional genomic and biological evidence associated with the top GWAS signals. No susceptibility loci for SAD were identified at a genome-wide significant level. The strongest association was at an intronic variant (rs139459337) within ZBTB20 (odds ratio (OR) = 1.63, p = 8.4 × 10−7), which encodes a transcriptional repressor that has roles in neurogenesis and in adult brain. Expression quantitative trait loci (eQTL) analysis showed that the risk allele “T” of rs139459337 is associated with reduced mRNA expression of ZBTB20 in human temporal cortex (p = 0.028). Zbtb20 is required for normal murine circadian rhythm and for entrainment to a shortened day. Of the 330 human orthologs of murine genes directly repressed by Zbtb20, there were 32 associated with SAD in our sample (at p < 0.05), representing a significant enrichment of ZBTB20 targets among our SAD genetic association signals (fold = 1.93, p = 0.001). ZBTB20 is a candidate susceptibility gene for SAD, based on a convergence of genetic, genomic, and biological evidence. Further studies are necessary to confirm its role in SAD.

Highlights

Seasonal affective disorder (SAD) is a form of mood disorder that typically occurs in late fall and winter when periods of daylight are shortest
The genotyping focused on European ancestry subjects with Bipolar I (BPI) disorder from among those collected by the National Institute of Mental Health (NIMH) Genetics Initiative for Bipolar Disorder in five waves at 11 sites across the United States, as described elsewhere in detail[16]
We carried out meta-analysis based on effect size and Enrichment analysis for ZBTB20 candidate target genes We examined whether ZBTB20 candidate target genes were enriched for genes associated with SAD

Summary

Introduction

Seasonal affective disorder (SAD) is a form of mood disorder that typically occurs in late fall and winter when periods of daylight are shortest. And twin studies of SAD have suggested a genetic component to its etiology. Studies of the relatives of SAD probands have shown higher than expected rates of the disorder in these family members, with rates in the range of 14–26%2–4. A twin study demonstrated that genetic effects account for at least 29% of the variance in seasonality, including mood variation[5]. Association studies using the candidate gene approach have been applied to investigate the role of genetic variation within biologically relevant genes in SAD susceptibility. Variants in genes related to serotonergic transmission, such as the serotonin transporter gene SLC6A46 and the 5-HT2A receptor gene HTR2A, have been associated with SAD at a suggestive level of significance[7,8].

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Results

Conclusion