Genome-wide Association Analysis of Eye Movement Dysfunction in Schizophrenia

Masataka Kikuchi,Hidenaga Yamamori,Akihiro Nakaya,Michiko Fujimoto,Kenichiro Miura,Kentaro Morita,Masashi Ikeda,Ryota Hashimoto,Yuka Yasuda

doi:10.1038/s41598-018-30646-9

Abstract

Eye movements are considered endophenotypes of schizophrenia. However, the genetic factors underlying eye movement are largely unknown. In this study, we explored the susceptibility loci for four eye movement scores: the scanpath length during the free viewing test (SPL), the horizontal position gain during the fast Lissajous paradigm of the smooth pursuit test (HPG), the duration of fixations during the far distractor paradigm of the fixation stability test (DF) and the integrated eye movement score of those three scores (EMS). We found 16 SNPs relevant to the HPG that were located in 3 genomic regions (1q21.3, 7p12.1 and 20q13.12) in the patient group; however, these SNPs were intronic or intergenic SNPs. To determine whether these SNPs occur in functional non-coding regions (i.e., enhancer or promoter regions), we examined the chromatin status on the basis of publicly available epigenomic data from 127 tissues or cell lines. This analysis suggested that the SNPs on 1q21.3 and 20q13.12 are in enhancer or promoter regions. Moreover, we performed an analysis of expression quantitative trait loci (eQTL) in human brain tissues using a public database. Finally, we identified significant eQTL effects for all of the SNPs at 1q21.3 and 20q13.12 in particular brain regions.

Highlights

Schizophrenia is a psychiatric disease with a lifetime prevalence of 0.30–0.66%1
We used the three eye movement scores reported in our previous study that best distinguished between healthy controls and schizophrenic individuals[17]
We explored susceptibility loci for three eye movement scores (SPL, HPG and DF) and the integrated eye movement score (EMS)

Summary

Introduction

Schizophrenia is a psychiatric disease with a lifetime prevalence of 0.30–0.66%1. The diagnostic criteria for schizophrenia are based on subjective symptoms, including delusions, hallucinations and thought insertion, and objective symptoms, including disorganized speech and bewilderment. Predictive pursuit gain in the smooth pursuit test has a very high heritability (heritability = 0.9)[22], indicating that genetic factors underlie abnormalities in eye movement It remains unknown whether patients with schizophrenia are predisposed to dysfunctional eye movements. We performed a GWAS to identify SNPs associated with the following eye movement scores: the scanpath length during the free viewing test (SPL); the horizontal position gain during the fast Lissajous paradigm of the smooth pursuit test (HPG); and the duration of fixations during the far distractor paradigm of the fixation stability test (DF). S100A10 expression is lower in lymphoblastoid cell lines from patients with schizophrenia than in those from controls[31] Cadherins such as CDH22 are involved in synaptic plasticity, which may contribute to learning and memory[32]. To examine the functions of these SNPs in detail, our bioinformatics analyses showed that these SNPs were located in functional non-coding regions, such as enhancers or promoters, and affect the expression level of surrounding genes in specific brain regions

Methods

Results

Conclusion