Impact of genetic risk variants of mental disorders on epigenetic regulation: an mqtl approach

Mental disorders (MDx) are common, complex and heritable conditions estimated to be a leading cause of disability worldwide. The last decade of research in genomics of MDx has provided valuable insight into their polygenic genetic architecture involving thousands of risk variants. Despite the success of genomic studies, a significant knowledge gap persists in understanding how these risk variants contribute to the pathophysiology of MDx and in discerning their potential to guide the development of new treatment approaches. One significant challenge is that most of the identified risk variants are non-coding, meaning their influence on MDx does not result from their ability to alter the amino acid sequence. However, the MDx risk variants are often located in regulatory regions of the genome. It is therefore of great interest to study the impact of identified MDx risk variants on DNA methylation (DNAm), the best studied epigenetic modification, playing a pivotal role in the regulation of transcriptomic processes, brain development, and functioning. In this study, we performed methylation Quantitative Trait Loci (mQTL) analyses for common risk variants of MDx, with the aim of improving the functional interpretation of GWAS findings for these disorders. First, DNAm levels quantified at >850,000 loci and genotyping data available from 2,065 neonatal dried blood spots from the Danish iPSYCH2012 cohort were used to create a human neonatal genome-wide mQTL database. The newly created iPSYCH mQTL results were compared to publicly available mQTL data from cord blood, peripheral blood, fetal, and adult brain. Secondly, risk variants from GWASes of five common MDx (ADHD, ASD, major depressive disorder, schizophrenia, and bipolar disorder) were then investigated to establish if they were identified as mQTLs in the available datasets. Genes with DNAm changes due to mQTLs were further subjected to pathway enrichment analyses. Our mQTL analyses of risk variants revealed multiple significant associations. The generated iPSYCH mQTLs were replicated in mQTLs from public repositories across tissue types and developmental stages. The results of this study confirm previously reported associations between the genotype variations of MDx and altered DNAm levels across the genome, as well as highlight novel associations. Notably, our enrichment analyses highlighted several biological processes and pathways, including synapse organization and axon guidance, that may play a crucial role in the development and pathophysiology of MDx, providing a functional context to the genetic findings. This study highlights the importance and advantage of combining genetic and DNAm data in studying molecular etiologies of MDx and supports the use of mQTL analyses in interpretation of GWAS findings of complex conditions. The identified mQTLs and implicated pathways offer promising leads for future research aimed at elucidating the functional consequences of MDx risk variants.