The Future is The Past: Methylation QTLs in Schizophrenia

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.

Moderating effect of mode of delivery on the genetics of intelligence: Explorative genome‐wide analyses in ALSPAC

“…Other potential mediators between method of delivery and neurodevelopmental phenotypes include epigenetic changes, microbiome composition, and oxidative stress. Epigenetic changes play an important role in synaptic plasticity and memory formation (Grissom, Lubin, Gupta, & Parrish, ) as well as in a number of neuropsychiatric conditions where IQ is affected (Chaste & Leboyer, ; Hoffmann, Ziller, & Spengler, ; Siniscalco, Cirillo, Bradstreet, & Antonucci, ; Walton et al, ). Likewise, changes in methylation profiles have been linked to DCS (Schlinzig et al, ), though another study did not detect an effect between method of delivery and global methylation of DNA in the blood (Virani et al, ).…”

“…Other potential mediators between method of delivery and neu- Hoffmann, Ziller, & Spengler, 2016;Siniscalco, Cirillo, Bradstreet, & Antonucci, 2013;Walton et al, 2016). Likewise, changes in methylation profiles have been linked to DCS (Schlinzig et al, 2009), though another study did not detect an effect between method of delivery and global methylation of DNA in the blood (Virani et al, 2012).…”

Beyond the looking glass: recent advances in understanding the impact of environmental exposures on neuropsychiatric disease

“…Rare variant genetic studies of autism spectrum and bipolar disorders have shown chromatin remodeling genes are more frequently dysregulated among affected individuals [57][58][59][60]. Integration of genetic and epigenetic data has shown that genetic risk variants for ASD, schizophrenia, ADHD, and bipolar disorder control DNA methylation levels more often than non-psychiatric genetic variants [61][62][63][64][65][66][67][68]. Epigenetic changes have also been directly observed in postmortem brain [69][70][71], blood [72][73][74], semen [75,76], saliva [77][78][79], placenta [80], and buccal [81][82][83] tissues in individuals with a psychiatric disorder.…”

Multi‐omics integrative analysis identified SNP‐methylation‐mRNA: Interaction in peripheral blood mononuclear cells

“…Aberrant DNA methylation in cancer was associated with abnormally regulated expression of normal cellular genes . Recently, disrupted DNA methylation patterns were established as a contributor to metabolic syndrome, schizophrenia and inflammatory or autoimmune disorders . The feature and distribution of DNA methylation have been studied in a variety of tissues/cells, and these genome‐wide maps of DNA methylation have revealed interesting features and provided important insights into its potential functions in genome regulation .…”