Abundant Quantitative Trait Loci Exist for DNA Methylation and Gene Expression in Human Brain

被引:608
作者
Gibbs, J. Raphael [1 ,2 ,3 ]
van der Brug, Marcel P. [1 ,4 ]
Hernandez, Dena G. [1 ,2 ,3 ]
Traynor, Bryan J. [1 ]
Nalls, Michael A. [1 ]
Lai, Shiao-Lin [1 ,2 ,3 ]
Arepalli, Sampath [1 ]
Dillman, Allissa [1 ]
Rafferty, Ian P. [1 ]
Troncoso, Juan [5 ]
Johnson, Robert [6 ]
Zielke, H. Ronald [6 ]
Ferrucci, Luigi [7 ]
Longo, Dan L. [8 ]
Cookson, Mark R. [1 ]
Singleton, Andrew B. [1 ]
机构
[1] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA
[2] UCL, Dept Mol Neurosci, Inst Neurol, London, England
[3] UCL, Inst Neurol, Reta Lila Weston Labs, London, England
[4] Scripps Res Inst, Dept Mol & Integrat Neurosci, Jupiter, FL USA
[5] Johns Hopkins Univ, Sch Med, Dept Pathol, Div Neuropathol, Baltimore, MD 21205 USA
[6] Univ Maryland, Sch Med, NICHHD, Brain & Tissue Bank Dev Disorders, Baltimore, MD 21201 USA
[7] NIA, Clin Res Branch, Baltimore, MD 21224 USA
[8] NIA, Lymphocyte Cell Biol Unit, Immunol Lab, NIH, Baltimore, MD 21224 USA
来源
PLOS GENETICS | 2010年 / 6卷 / 05期
基金
美国国家卫生研究院;
关键词
MICROARRAY DATA; GENOME; HAPLOTYPE; PATTERNS; OMNIBUS; DISEASE;
D O I
10.1371/journal.pgen.1000952
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
A fundamental challenge in the post-genome era is to understand and annotate the consequences of genetic variation, particularly within the context of human tissues. We present a set of integrated experiments that investigate the effects of common genetic variability on DNA methylation and mRNA expression in four human brain regions each from 150 individuals (600 samples total). We find an abundance of genetic cis regulation of mRNA expression and show for the first time abundant quantitative trait loci for DNA CpG methylation across the genome. We show peak enrichment for cis expression QTLs to be approximately 68,000 bp away from individual transcription start sites; however, the peak enrichment for cis CpG methylation QTLs is located much closer, only 45 bp from the CpG site in question. We observe that the largest magnitude quantitative trait loci occur across distinct brain tissues. Our analyses reveal that CpG methylation quantitative trait loci are more likely to occur for CpG sites outside of islands. Lastly, we show that while we can observe individual QTLs that appear to affect both the level of a transcript and a physically close CpG methylation site, these are quite rare. We believe these data, which we have made publicly available, will provide a critical step toward understanding the biological effects of genetic variation.
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页数:13
相关论文
共 32 条
[1]   A haplotype map of the human genome [J].
Altshuler, D ;
Brooks, LD ;
Chakravarti, A ;
Collins, FS ;
Daly, MJ ;
Donnelly, P ;
Gibbs, RA ;
Belmont, JW ;
Boudreau, A ;
Leal, SM ;
Hardenbol, P ;
Pasternak, S ;
Wheeler, DA ;
Willis, TD ;
Yu, FL ;
Yang, HM ;
Zeng, CQ ;
Gao, Y ;
Hu, HR ;
Hu, WT ;
Li, CH ;
Lin, W ;
Liu, SQ ;
Pan, H ;
Tang, XL ;
Wang, J ;
Wang, W ;
Yu, J ;
Zhang, B ;
Zhang, QR ;
Zhao, HB ;
Zhao, H ;
Zhou, J ;
Gabriel, SB ;
Barry, R ;
Blumenstiel, B ;
Camargo, A ;
Defelice, M ;
Faggart, M ;
Goyette, M ;
Gupta, S ;
Moore, J ;
Nguyen, H ;
Onofrio, RC ;
Parkin, M ;
Roy, J ;
Stahl, E ;
Winchester, E ;
Ziaugra, L ;
Shen, Y .
NATURE, 2005, 437 (7063) :1299-1320
[2]  
Barrett Tanya, 2006, V338, P175
[3]   CpG island mapping by epigenome prediction [J].
Bock, Christoph ;
Walter, Joern ;
Paulsen, Martina ;
Lengauer, Thomas .
PLOS COMPUTATIONAL BIOLOGY, 2007, 3 (06) :1055-1070
[4]  
CHURCHILL GA, 1994, GENETICS, V138, P963
[5]   Mapping complex disease traits with global gene expression [J].
Cookson, William ;
Liang, Liming ;
Abecasis, Goncalo ;
Moffatt, Miriam ;
Lathrop, Mark .
NATURE REVIEWS GENETICS, 2009, 10 (03) :184-194
[6]   Common Regulatory Variation Impacts Gene Expression in a Cell Type-Dependent Manner [J].
Dimas, Antigone S. ;
Deutsch, Samuel ;
Stranger, Barbara E. ;
Montgomery, Stephen B. ;
Borel, Christelle ;
Attar-Cohen, Homa ;
Ingle, Catherine ;
Beazley, Claude ;
Arcelus, Maria Gutierrez ;
Sekowska, Magdalena ;
Gagnebin, Marilyne ;
Nisbett, James ;
Deloukas, Panos ;
Dermitzakis, Emmanouil T. ;
Antonarakis, Stylianos E. .
SCIENCE, 2009, 325 (5945) :1246-1250
[7]   Gene Expression Omnibus: NCBI gene expression and hybridization array data repository [J].
Edgar, R ;
Domrachev, M ;
Lash, AE .
NUCLEIC ACIDS RESEARCH, 2002, 30 (01) :207-210
[8]   Epigenetics in human disease and prospects for epigenetic therapy [J].
Egger, G ;
Liang, GN ;
Aparicio, A ;
Jones, PA .
NATURE, 2004, 429 (6990) :457-463
[9]   Cluster analysis and display of genome-wide expression patterns [J].
Eisen, MB ;
Spellman, PT ;
Brown, PO ;
Botstein, D .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (25) :14863-14868
[10]   CPG ISLANDS IN VERTEBRATE GENOMES [J].
GARDINERGARDEN, M ;
FROMMER, M .
JOURNAL OF MOLECULAR BIOLOGY, 1987, 196 (02) :261-282