Abstract
Epigenetic variation in peripheral tissues is being widely studied as a molecular biomarker of complex disease and disease-related exposures. To date, few studies have examined differences in DNA methylation associated with attention-deficit hyperactivity disorder (ADHD). In this study, we profiled genetic and methylomic variation across the genome in saliva samples from children (age 7–12 years) with clinically established ADHD (N = 391) and nonpsychiatric controls (N = 213). We tested for differentially methylated positions (DMPs) associated with both ADHD diagnosis and ADHD polygenic risk score, by using linear regression models including smoking, medication effects, and other potential confounders in our statistical models. Our results support previously reported associations between ADHD and DNA methylation levels at sites annotated to VIPR2, and identify several novel disease-associated DMPs (p < 1e–5), although none of them were genome-wide significant. The two top-ranked, ADHD-associated DMPs (cg17478313 annotated to SLC7A8 and cg21609804 annotated to MARK2) are also significantly associated with nearby SNPs (p = 1.2e–46 and p = 2.07e–59), providing evidence that disease-associated DMPs are under genetic control. We also report a genome-wide significant association between ADHD polygenic risk and variable DNA methylation at a site annotated to the promoter of GART and SON (p = 6.71E–8). Finally, we show that ADHD-associated SNPs colocalize with SNPs associated with methylation levels in saliva. This is the first large-scale study of DNA methylation in children with ADHD. Our results represent novel epigenetic biomarkers for ADHD that may be useful for patient stratification, reinforce the importance of genetic effects on DNA methylation, and provide plausible molecular mechanisms for ADHD risk variants.
Highlights
Attention-deficit hyperactivity disorder (ADHD) has a substantial heritable component, with genetic factors interacting with early-life environmental exposures to mediate risk[1,2]
We report here the first large-scale epigenome-wide association study (EWAS) of children with ADHD and extend our previous study to incorporate analyses of genetic effects in the context of variable DNA methylation, exploring both methylation quantitative trait loci (mQTL) and polygenic risk burden derived from GWAS
Boys were overrepresented in the ADHD group and we adjusted all results for sex
Summary
Attention-deficit hyperactivity disorder (ADHD) has a substantial heritable component, with genetic factors interacting with early-life environmental exposures to mediate risk[1,2]. The specific mechanisms by which genetic risk factors influence ADHD are not known, recent evidence supports a role for non-sequence-based (i.e., regulatory) genomic variation in neuropsychiatric phenotypes[5,6,7,8]. Epigenetic studies of mental disorders have focused primarily on DNA methylation, the bestcharacterized and most stable epigenetic modification. It acts to influence gene expression via physical disruption of transcription factor binding and the attraction of methyl-binding proteins that initiate chromatin compaction and gene silencing[11]. Many of the environmental risk factors associated with
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
