title: Mendelian inheritance of trimodal CpG methylation sites suggests distal cis-acting genetic effects.
abstract: Environmentally influenced phenotypes, such as obesity and insulin resistance, can be transmitted over multiple generations. Epigenetic modifications, such as methylation of DNA cytosine-guanine (CpG) pairs, may be carriers of inherited information. At the population level, the methylation state of such "heritable" CpG sites is expected to follow a trimodal distribution, and their mode of inheritance should be Mendelian.
  
  
  
  Using the Illumina Infinium 450 K DNA methylation array, we determined DNA CpG-methylation in blood cells from a family cohort 123 individuals of Arab ethnicity, including 18 elementary father-mother-child trios, we asked whether Mendelian inheritance of CpG methylation is observed, and most importantly, whether it is independent of any genetic signals. Using 40× whole genome sequencing, we therefore excluded all CpG sites with possibly confounding genetic variants (SNP) within the binding regions of the Illumina probes.
  
  
  
  We identified a total of 955 CpG sites that displayed a trimodal distribution and confirmed trimodality in a study of 1805 unrelated Caucasians. Of 955 CpG sites, 99.9% observed a strict Mendelian pattern of inheritance and had no SNP within +/-110 nucleotides of the CpG site by design. However, in 97% of these cases a distal cis-acting SNP within a +/-1 Mbp window was found that explained the observed CpG distribution, excluding the hypothesis of epigenetic inheritance for these clear-cut trimodal sites. Using power analysis, we showed that in 46% of all cases, the closest CpG-associated SNP was located more than 1000 bp from the CpG site.
  
  
  
  Our findings suggest that CpG methylation is maintained over larger genomic distances. Furthermore, nearly half of the SNPs associated with these trimodal sites were also associated with the expression of nearby genes (P= 4.08 × 10-6), implying a regulatory effect of these trimodal CpG sites.
authors.affiliation: Department of Physiology and Biophysics, Weill Cornell Medical College in Qatar, Education City, PO Box 24144, Doha, Qatar ; Computer Engineering Department, Virginia Tech, Blacksburg, VA 24060 USA.
authors.forename: Shaza B
authors.initials: SB
authors.lastname: Zaghlool
authors.affiliation: Department of Genomics of Common Disease, Imperial College London, London, UK ; Research Division, Qatar Science Leadership Program, Qatar Foundation, Doha, Qatar ; Department of Biomedical Sciences, College of Health Sciences at Qatar University, Doha, Qatar.
authors.forename: Mashael
authors.initials: M
authors.lastname: Al-Shafai
authors.affiliation: Department of Genomics of Common Disease, Imperial College London, London, UK ; Research Division, Qatar Science Leadership Program, Qatar Foundation, Doha, Qatar.
authors.forename: Wadha A
authors.initials: WA
authors.lastname: Al Muftah
authors.affiliation: Department of Physiology and Biophysics, Weill Cornell Medical College in Qatar, Education City, PO Box 24144, Doha, Qatar.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany ; Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany ; Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Waldenberger
authors.affiliation: Department of Twin Research & Genetic Epidemiology, King's College London, London, SE1 7EH UK.
authors.forename: Mario
authors.initials: M
authors.lastname: Falchi
authors.affiliation: Department of Physiology and Biophysics, Weill Cornell Medical College in Qatar, Education City, PO Box 24144, Doha, Qatar.
authors.forename: Karsten
authors.initials: K
authors.lastname: Suhre
mesh_terms: D000328:Adult; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D040941:Heredity; D006801:Humans; D008297:Male; D057182:Mendelian Randomization Analysis / Q000379:methods*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011780:Qatar / Q000208:ethnology; D017422:Sequence Analysis, DNA / Q000379:methods*; D055815:Young Adult
keywords: CpG; DNA methylation; Epigenetics; Genetic variance; Mendelian inheritance; Trimodal distribution