Incorporation of DNA methylation quantitative trait loci (mQTLs) in epigenome-wide association analysis: application to birthweight effects in neonatal whole blood.
Incorporation of DNA methylation quantitative trait loci (mQTLs) in epigenome-wide association analysis: application to birthweight effects in neonatal whole blood.
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DOI：
10.1186/s13148-022-01385-6
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发表时间：
2022-12-01
影响因子：
5.7
通讯作者：
Wiemels, Joseph L.
中科院分区：
文献类型：
--
作者：
Li, Shaobo;Mancuso, Nicholas;Metayer, Catherine;Ma, Xiaomei;de Smith, Adam J.;Wiemels, Joseph L.
关键词：
表观全基因组关联研究（EWAS）有助于确定DNA甲基化与许多临床病理和发育特征之间的关联。由于DNA甲基化受某些基因座遗传变异的影响，EWAS关联可能受到遗传效应的潜在影响。然而，在EWAS评估中纳入遗传变异的价值缺乏正式的评估，特别是对多种族人群。使用来自Illumina Omni Express或Affyestrium PMDA阵列的单核苷酸多态性（SNP）和来自Illumina 450 K或EPIC阵列的来自1638个不同遗传祖先的新生儿的DNA甲基化数据，我们生成了两种阵列类型的DNA甲基化数量性状基因座（mQTL）数据库。然后，我们使用EWAS模型研究了新生儿DNA甲基化与出生体重（包括胎龄）之间的关系，并报告了控制mQTL如何影响EWAS结果。在450 K基因芯片上，平均有15.4%的CpG位点被指定为mQTL，而在EPIC基因芯片上，有23.0%的CpG位点被指定为mQTL（校正后的P值< 0.05）。与SNP相关的CpG在CpG岛海岸区域富集。在EWAS模型中校正出生体重的mQTL有助于提高最高命中的显著性水平。对于与出生体重相关途径（例如营养代谢、生物合成）相关的CpG重叠基因，mQTL的解释比其他随机CpG更显著地改变了它们的回归系数（> 20%）。基因组中约20% CpG的DNA甲基化水平受到常见SNP基因型的影响。当考虑到这些遗传效应时，EWAS模型拟合显着提高。与基因表达控制相关的CpG重叠遗传元件的遗传效应更强。在线版本包含补充材料，可通过10.1186/s13148-022-01385-6获得。
Epigenome-wide association studies (EWAS) have helped to define the associations between DNA methylation and many clinicopathologic and developmental traits. Since DNA methylation is affected by genetic variation at certain loci, EWAS associations may be potentially influenced by genetic effects. However, a formal assessment of the value of incorporating genetic variation in EWAS evaluations is lacking especially for multiethnic populations. Using single nucleotide polymorphism (SNP) from Illumina Omni Express or Affymetrix PMDA arrays and DNA methylation data from the Illumina 450 K or EPIC array from 1638 newborns of diverse genetic ancestries, we generated DNA methylation quantitative trait loci (mQTL) databases for both array types. We then investigated associations between neonatal DNA methylation and birthweight (incorporating gestational age) using EWAS modeling, and reported how EWAS results were influenced by controlling for mQTLs. For CpGs on the 450 K array, an average of 15.4% CpGs were assigned as mQTLs, while on the EPIC array, 23.0% CpGs were matched to mQTLs (adjusted P value < 0.05). The CpGs associated with SNPs were enriched in the CpG island shore regions. Correcting for mQTLs in the EWAS model for birthweight helped to increase significance levels for top hits. For CpGs overlapping genes associated with birthweight-related pathways (nutrition metabolism, biosynthesis, for example), accounting for mQTLs changed their regression coefficients more dramatically (> 20%) than for other random CpGs. DNA methylation levels at circa 20% CpGs in the genome were affected by common SNP genotypes. EWAS model fit significantly improved when taking these genetic effects into consideration. Genetic effects were stronger on CpGs overlapping genetic elements associated with control of gene expression. The online version contains supplementary material available at 10.1186/s13148-022-01385-6.
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影响因子：
64.8
作者：
Horikoshi, Momoko;Beaumont, Robin N.;Day, Felix R.;Warrington, Nicole M.;Kooijman, Marjolein N.;Fernandez-Tajes, Juan;Feenstra, Bjarke;van Zuydam, Natalie R.;Gaulton, Kyle J.;Grarup, Niels;Bradfield, Jonathan P.;Strachan, David P.;Li-Gao, Ruifang;Ahluwalia, Tarunveer S.;Kreiner, Eskil;Rueedi, Rico;Lyytikainen, Leo-Pekka;Cousminer, Diana L.;Wu, Ying;Thiering, Elisabeth;Wang, Carol A.;Have, Christian T.;Hottenga, Jouke-Jan;Vilor-Tejedor, Natalia;Joshi, Peter K.;Boh, Eileen Tai Hui;Ntalla, Ioanna;Pitkanen, Niina;Mahajan, Anubha;van Leeuwen, Elisabeth M.;Joro, Raimo;Lagou, Vasiliki;Nodzenski, Michael;Diver, Louise A.;Zondervan, Krina T.;Bustamante, Mariona;Marques-Vidal, Pedro;Mercader, Josep M.;Bennett, Amanda J.;Rahmioglu, Nilufer;Nyholt, Dale R.;Ma, Ronald C. W.;Tam, Claudia H. T.;Tam, Wing Hung;Ganesh, Santhi K.;van Rooij, Frank J. A.;Jones, Samuel E.;Loh, Po-Ru;Ruth, Katherine S.;Tuke, Marcus A.;Tyrrell, Jessica;Wood, Andrew R.;Yaghootkar, Hanieh;Scholtens, Denise M.;Paternoster, Lavinia;Prokopenko, Inga;Kovacs, Peter;Atalay, Mustafa;Willems, Sara M.;Panoutsopoulou, Kalliope;Wang, Xu;Carstensen, Lisbeth;Geller, Frank;Schraut, Katharina E.;Murcia, Mario;van Beijsterveldt, Catharina E. M.;Willemsen, Gonneke;Appel, Emil V. R.;Fonvig, Cilius E.;Trier, Caecilie;Tiesler, Carla M. T.;Standl, Marie;Kutalik, Zoltan;Bonas-Guarch, Silvia;Hougaard, David M.;Sanchez, Friman;Torrents, David;Waage, Johannes;Hollegaard, Mads V.;de Haan, Hugoline G.;Rosendaal, Frits R.;Medina-Gomez, Carolina;Ring, Susan M.;Hemani, Gibran;McMahon, George;Robertson, Neil R.;Groves, Christopher J.;Langenberg, Claudia;Luan, Jian'an;Scott, Robert A.;Zhao, Jing Hua;Mentch, Frank D.;MacKenzie, Scott M.;Reynolds, Rebecca M.;Lowe, William L.;Toenjes, Anke;Stumvoll, Michael;Lindi, Virpi;Lakka, Timo A.;van Duijn, Cornelia M.;Kiess, Wieland;Koerner, Antje;Sorensen, Thorkild I. A.;Niinikoski, Harri;Pahkala, Katja;Raitakari, Olli T.;Zeggini, Eleftheria;Dedoussis, George V.;Teo, Yik-Ying;Saw, Seang-Mei;Melbye, Mads;Campbell, Harry;Wilson, James F.;Vrijheid, Martine;de Geus, Eco J. C. N.;Boomsma, Dorret I.;Kadarmideen, Haja N.;Holm, Jens-Christian;Hansen, Torben;Sebert, Sylvain;Hattersley, Andrew T.;Beilin, Lawrence J.;Newnham, John P.;Pennell, Craig E.;Heinrich, Joachim;Adair, Linda S.;Borja, Judith B.;Mohlke, Karen L.;Eriksson, Johan G.;Widen, Elisabeth;Kahonen, Mika;Viikari, Jorma S.;Lehtimaki, Terho;Vollenweider, Peter;Bonnelykke, Klaus;Bisgaard, Hans;Mook-Kanamori, Dennis O.;Hofman, Albert;Rivadeneira, Fernando;Uitterlinden, Andre G.;Pisinger, Charlotta;Pedersen, Oluf;Power, Christine;Hyppoenen, Elina;Wareham, Nicholas J.;Hakonarson, Hakon;Davies, Eleanor;Walker, Brian R.;Jaddoe, Vincent W. V.;Jaervelin, Marjo-Riitta;Grant, Struan F. A.;Vaag, Allan A.;Lawlor, Debbie A.;Frayling, Timothy M.;Smith, George Davey;Morris, Andrew P.;Ong, Ken K.;Felix, Janine F.;Timpson, Nicholas J.;Perry, John R. B.;Evans, David M.;McCarthy, Mark I.;Freathy, Rachel M.
通讯作者：
Freathy, Rachel M.
影响因子：
30.8
作者：
Das, Sayantan;Forer, Lukas;Schoenherr, Sebastian;Sidore, Carlo;Locke, Adam E.;Kwong, Alan;Vrieze, Scott I.;Chew, Emily Y.;Levy, Shawn;McGue, Matt;Schlessinger, David;Stambolian, Dwight;Loh, Po-Ru;Iacono, William G.;Swaroop, Anand;Scott, Laura J.;Cucca, Francesco;Kronenberg, Florian;Boehnke, Michael;Abecasis, Goncalo R.;Fuchsberger, Christian
通讯作者：
Fuchsberger, Christian
影响因子：
2.1
作者：
Lind, Lars
通讯作者：
Lind, Lars
影响因子：
64.5
作者：
Hnisz D;Abraham BJ;Lee TI;Lau A;Saint-André V;Sigova AA;Hoke HA;Young RA
通讯作者：
Young RA
影响因子：
5.7
作者：
Moccia C;Popovic M;Isaevska E;Fiano V;Trevisan M;Rusconi F;Polidoro S;Richiardi L
通讯作者：
Richiardi L