title: Characterization of genome-methylome interactions in 22 nuclear pedigrees.
abstract: Genetic polymorphisms can shape the global landscape of DNA methylation, by either changing substrates for DNA methyltransferases or altering the DNA binding affinity of cis-regulatory proteins. The interactions between CpG methylation and genetic polymorphisms have been previously investigated by methylation quantitative trait loci (mQTL) and allele-specific methylation (ASM) analysis. However, it remains unclear whether these approaches can effectively and comprehensively identify all genetic variants that contribute to the inter-individual variation of DNA methylation levels. Here we used three independent approaches to systematically investigate the influence of genetic polymorphisms on variability in DNA methylation by characterizing the methylation state of 96 whole blood samples in 52 parent-child trios from 22 nuclear pedigrees. We performed targeted bisulfite sequencing with padlock probes to quantify the absolute DNA methylation levels at a set of 411,800 CpG sites in the human genome. With mid-parent offspring analysis (MPO), we identified 10,593 CpG sites that exhibited heritable methylation patterns, among which 70.1% were SNPs directly present in methylated CpG dinucleotides. We determined the mQTL analysis identified 49.9% of heritable CpG sites for which regulation occurred in a distal cis-regulatory manner, and that ASM analysis was only able to identify 5%. Finally, we identified hundreds of clusters in the human genome for which the degree of variation of CpG methylation, as opposed to whether or not CpG sites were methylated, was associated with genetic polymorphisms, supporting a recent hypothesis on the genetic influence of phenotypic plasticity. These results show that cis-regulatory SNPs identified by mQTL do not comprise the full extent of heritable CpG methylation, and that ASM appears overall unreliable. Overall, the extent of genome-methylome interactions is well beyond what is detectible with the commonly used mQTL and ASM approaches, and is likely to include effects on plasticity.
authors.affiliation: Department of Bioengineering, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Nongluk
authors.initials: N
authors.lastname: Plongthongkum
authors.affiliation: Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Kristel R
authors.initials: KR
authors.lastname: van Eijk
authors.affiliation: Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Behavior, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Simone
authors.initials: S
authors.lastname: de Jong
authors.affiliation: Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Behavior, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Tina
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Computer Science, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Jae Hoon
authors.initials: JH
authors.lastname: Sul
authors.affiliation: Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Marco P M
authors.initials: MP
authors.lastname: Boks
authors.affiliation: Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: René S
authors.initials: RS
authors.lastname: Kahn
authors.affiliation: Department of Bioengineering, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Ho-Lim
authors.initials: HL
authors.lastname: Fung
authors.affiliation: Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Behavior, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California, United States of America; Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Roel A
authors.initials: RA
authors.lastname: Ophoff
authors.affiliation: Department of Bioengineering, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Kun
authors.initials: K
authors.lastname: Zhang
mesh_terms: D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D015894:Genome, Human / Q000235:genetics*; D023281:Genomics; D006801:Humans; D008297:Male; D009679:Nuclear Family; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics