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Parent of Origin Genetic Effects on Methylation in Humans Are Common

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Parent of Origin Genetic Effects on Methylation in Humans Are Common Edinburgh Research Explorer Parent of origin genetic effects on methylation in humans are common and influence complex trait variation Citation for published version: Zeng, Y, Amador, C, Xia, C, Marioni, R, Sproul, D, Walker, RM, Morris, SW, Bretherick, A, Canela-Xandri, O, Boutin, TS, Clark, DW, Campbell, A, Rawlik, K, Hayward, C, Nagy, R, Tenesa, A, Porteous, DJ, Wilson, JF, Deary, IJ, Evans, KL, McIntosh, AM, Navarro, P & Haley, CS 2019, 'Parent of origin genetic effects on methylation in humans are common and influence complex trait variation', Nature Communications, vol. 10, 1383. https://doi.org/10.1038/s41467-019-09301-y Digital Object Identifier (DOI): 10.1038/s41467-019-09301-y Link: Link to publication record in Edinburgh Research Explorer Document Version: Publisher's PDF, also known as Version of record Published In: Nature Communications General rights Copyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s) and / or other copyright owners and it is a condition of accessing these publications that users recognise and abide by the legal requirements associated with these rights. Take down policy The University of Edinburgh has made every reasonable effort to ensure that Edinburgh Research Explorer content complies with UK legislation. If you believe that the public display of this file breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 26. Sep. 2021 ARTICLE https://doi.org/10.1038/s41467-019-09301-y OPEN Parent of origin genetic effects on methylation in humans are common and influence complex trait variation Yanni Zeng1, Carmen Amador 1, Charley Xia1,2, Riccardo Marioni3,4, Duncan Sproul 1,5, Rosie M. Walker3,4, Stewart W. Morris4, Andrew Bretherick1, Oriol Canela-Xandri1,2, Thibaud S. Boutin 1, David W. Clark6, Archie Campbell 4, Konrad Rawlik 2, Caroline Hayward 1, Reka Nagy1, Albert Tenesa 1,2, David J. Porteous 3,4, James F. Wilson 1,6, Ian J. Deary3,7, Kathryn L. Evans3,4, Andrew M. McIntosh 3,8, Pau Navarro 1 & Chris S. Haley 1,2 1234567890():,; Parent-of-origin effects (POE) exist when there is differential expression of alleles inherited from the two parents. A genome-wide scan for POE on DNA methylation at 639,238 CpGs in 5,101 individuals identifies 733 independent methylation CpGs potentially influenced by POE at a false discovery rate ≤ 0.05 of which 331 had not previously been identified. Cis and trans methylation quantitative trait loci (mQTL) regulate methylation variation through POE at 54% (399/733) of the identified POE-influenced CpGs. The combined results provide strong evidence for previously unidentified POE-influenced CpGs at 171 independent loci. Methy- lation variation at 14 of the POE-influenced CpGs is associated with multiple metabolic traits. A phenome-wide association analysis using the POE mQTL SNPs identifies a previously unidentified imprinted locus associated with waist circumference. These results provide a high resolution population-level map for POE on DNA methylation sites, their local and distant regulators and potential consequences for complex traits. 1 MRC Human Genetic Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK. 2 The Roslin Institute and Royal (Dick) School of Veterinary Sciences, University of Edinburgh, Edinburgh EH25 9RG, UK. 3 Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK. 4 Centre for Genomic and Experimental Medicine, IGMM, University of Edinburgh, Edinburgh EH4 2XU, UK. 5 Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, UK. 6 Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh EH8 9AG, UK. 7 Department of Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK. 8 Division of Psychiatry, University of Edinburgh, Edinburgh EH10 5HF, UK. Correspondence and requests for materials should be addressed to C.S.H. (email: [email protected]) NATURE COMMUNICATIONS | (2019) 10:1383 | https://doi.org/10.1038/s41467-019-09301-y | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-09301-y NA methylation plays a crucial role in regulating gene SNPs which play a regulatory role in DNA methylation through expression and maintaining genomic stability1. Inter- POEs also have significant associations in GWAS performed D 13 individual variation of DNA methylation levels at CpG using an additive model . Combining these with previous sites (henceforth methylation CpGs) has been associated with observations that disease-associated loci are enriched in reg- complex diseases, quantitative traits, environmental exposures ulatory regions23, analyses that link POE regulation to DNA and the aging process2–6. Previous studies have estimated that on methylation and POE regulation to complex traits potentially average across sites, 19% of variation in DNA methylation level is provide important insights for the understanding of both non- contributed by the additive genetic effects7. A number of genetic additive genetic and epigenetic control mechanisms for complex variants have been shown to regulate methylation CpGs (such traits and diseases. variants being termed methylation quantitative trait loci (mQTL)) We propose here a variance component method to detect in an additive manner, acting locally (cis) or distantly (trans)8,9. signatures of POEs caused by imprinting in the human DNA In contrast, shared family environment has been shown to have a methylome, by identifying methylation CpGs showing an unu- relatively smaller overall contribution (3% on average across sites) sually increased full-sibling and/or one-parent–offspring simi- to variation in DNA methylation7,10. larity. Using this method, we perform a genome-wide scan for DNA methylation can also be affected by parent-of-origin POE on each of 639,238 methylation CpGs in a homogenous effects (POEs), which are non-additive genetic effects that man- Scottish sample (N = 5101) with complex pedigree structure24,in ifest as phenotypic differences depending on the allelic parent-of- which both previously unknown and known POE-influenced origin11. There are several possible causes of observed POEs, CpG sites are identified. We then perform a POE–mQTL analysis but the most common is genomic imprinting11. These POEs to identify local and distant regulatory genetic variants of caused by imprinting can lead to different phenotypic patterns, methylation at the POE-influenced CpG sites identified in the including classical paternal or maternal imprinting, and other variance component analyses. This is followed by an analysis to complex forms (Supplementary Fig. 1)11. (We use the standard identify complex traits associated with the detected POE- definition of maternal imprinting, where the maternal allele is influenced methylation CpGs. We also use identified silenced and the paternal expressed and vice versa for paternal POE–mQTL SNPs to guide a phenome-wide association analysis, imprinting.) Although previous studies estimated the number of through which we identify one locus affecting waist cir- imprinted expressed genes in the human genome at around cumference through a previously unidentified POE, demonstrat- 10012, POEs caused by imprinting can spread to wider genomic ing that the use of methylation data and the proposed set of regions through regulatory variants located in imprinted regions analyses contribute to increase our understanding of the non- transmitting the POEs to their genomic targets (Supplemen- additive genetic control of complex traits. tary Fig. 1)13,14. POEs caused by imprinting have been detected at the DNA methylation, gene expression and phenotypic – Results levels13 15. The precise regulation of expression of genes influ- Overview of the study design. Table 1 shows a summary of the enced by imprinting is crucial for embryonic development, fi metabolism and behavioural traits, and the effect can last into study design. An established ve-component variance component 16–18 analysis accounting for genetic and environmental variation was later life . Given the regulatory role of DNA methylation on fi gene expression, the identification of POEs on DNA methylation rst used to partition DNA methylation variation for each mea- is of particular importance to facilitate understanding of the sured CpG. Following this, a two-stage pipeline was applied to identify potential POE-influenced methylation CpGs among all molecular mechanism of the POEs observed at the gene expres- fi sion or phenotypic level16. measured CpGs. The rst stage applied a POE variance compo- fi nent method that targeted the localisation of POE-influenced Recent progress has been made towards pro ling genome-wide – imprinted regions and POE caused by imprinting in DNA methylation CpGs. The second stage applied a POE mQTL methylation13,19–21. Imprinted regions can be identified by (parent-of-origin effect mQTL) analysis that accounted for POE fi to localise the SNPs that introduce the POE on the identified CpG bisul te sequencing detecting CpGs that display imbalanced or fi bimodal methylation between paired chromosomes, which could candidates from the rst stage. This was followed by two addi- 19,21 tional analyses to profile the phenotypic consequence of the POE- be caused by imprinting . POEs in
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