Abstract
Genome-wide association studies (GWAS) have remarkably advanced insight into the genetic basis of schizophrenia (SCZ). Still, most of the functional variance in disease risk remains unexplained. Hence, there is a growing need to map genetic variability-to-genes-to-functions for understanding the pathophysiology of SCZ and the development of better treatments. Genetic variation can regulate various cellular functions including DNA methylation, an epigenetic mark with important roles in transcription and the mediation of environmental influences. Methylation quantitative trait loci (meQTLs) are derived by mapping levels of DNA methylation in genetically different, genotyped individuals and define loci at which DNA methylation is influenced by genetic variation. Recent evidence points to an abundance of meQTLs in brain tissues whose functional contributions to development and mental diseases are still poorly understood. Interestingly, fetal meQTLs reside in regulatory domains affecting methylome reconfiguration during early brain development and are enriched in loci identified by GWAS for SCZ. Moreover, fetal meQTLs are preserved in the adult brain and could trace early epigenomic deregulation during vulnerable periods. Overall, these findings highlight the role of fetal meQTLs in the genetic risk for and in the possible neurodevelopmental origin of SCZ.
Highlights
Schizophrenia (SCZ) is a chronic, debilitating disease characterized by the presence of positive, negative, and cognitive symptoms that affect multiple aspects of mental activity, including perception, thought, attention, memory, and emotion
These fetal brain meQTLs were enriched in regulatory domains, including DNase I hypersensitive sites, repressive histone marks, transcription factor (TF) binding sites, and significantly overlapped with eQTLs, all of these findings are in accord with previous studies [60,67]
SCZ, CCCTC-binding factor (CTCF) hasIn been recently an integrated approach for pathways and genes pathway approach for pathways and genes affected in Together, these findings a affected in SCZ [75]. These findings suggest a regulatory role for fetal meQTLs and suggest highlight regulatory role for fetal meQTLs and highlight with an important mechanism connecting with CTCF an important mechanism connecting genomic variation to genomic function
Summary
Schizophrenia (SCZ) is a chronic, debilitating disease characterized by the presence of positive, negative, and cognitive symptoms that affect multiple aspects of mental activity, including perception, thought, attention, memory, and emotion. We will firstly discuss the current status of SCZ genetics and the urgent need to map genetic variation-to-genes-to-function. Recent progress on genome-wide functional annotation of DNA sequences opens up the perspective to prioritize genetic variation to define causal variants. We will explore new insights into the role of dynamic DNA methylation and ask how genetic influences on DNA methylation could contribute to the molecular etiology of SCZ. We will analyze current evidence for the presence of methylation quantitative trait loci (meQTLs) in peripheral and, in healthy and diseased brain tissues, and their potential role in transcription and RNA splicing.
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