title: Genome-wide haplotype analysis of cis expression quantitative trait loci in monocytes.
abstract: In order to assess whether gene expression variability could be influenced by several SNPs acting in cis, either through additive or more complex haplotype effects, a systematic genome-wide search for cis haplotype expression quantitative trait loci (eQTL) was conducted in a sample of 758 individuals, part of the Cardiogenics Transcriptomic Study, for which genome-wide monocyte expression and GWAS data were available. 19,805 RNA probes were assessed for cis haplotypic regulation through investigation of ~2,1 × 10(9) haplotypic combinations. 2,650 probes demonstrated haplotypic p-values >10(4)-fold smaller than the best single SNP p-value. Replication of significant haplotype effects were tested for 412 probes for which SNPs (or proxies) that defined the detected haplotypes were available in the Gutenberg Health Study composed of 1,374 individuals. At the Bonferroni correction level of 1.2 × 10(-4) (~0.05/412), 193 haplotypic signals replicated. 1000 G imputation was then conducted, and 105 haplotypic signals still remained more informative than imputed SNPs. In-depth analysis of these 105 cis eQTL revealed that at 76 loci genetic associations were compatible with additive effects of several SNPs, while for the 29 remaining regions data could be compatible with a more complex haplotypic pattern. As 24 of the 105 cis eQTL have previously been reported to be disease-associated loci, this work highlights the need for conducting haplotype-based and 1000 G imputed cis eQTL analysis before commencing functional studies at disease-associated loci.
authors: INSERM, UMR_S 937, Pierre and Marie Curie University, UPMC, Paris 6, Paris, France.
authors: Sophie
authors: S
authors: Garnier
authors: Vinh
authors: V
authors: Truong
authors: Jessy
authors: J
authors: Brocheton
authors: Tanja
authors: T
authors: Zeller
authors: Maxime
authors: M
authors: Rovital
authors: Philipp S
authors: PS
authors: Wild
authors: Andreas
authors: A
authors: Ziegler
authors: Thomas
authors: T
authors: Munzel
authors: Laurence
authors: L
authors: Tiret
authors: Stefan
authors: S
authors: Blankenberg
authors: Panos
authors: P
authors: Deloukas
authors: Jeannette
authors: J
authors: Erdmann
authors: Christian
authors: C
authors: Hengstenberg
authors: Nilesh J
authors: NJ
authors: Samani
authors: Heribert
authors: H
authors: Schunkert
authors: Willem H
authors: WH
authors: Ouwehand
authors: Alison H
authors: AH
authors: Goodall
authors: François
authors: F
authors: Cambien
authors: David-Alexandre
authors: DA
authors: Trégouët
mesh_terms: D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D009000:Monocytes; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid
references: Nat Rev Genet. 2010 Jun;11(6):446-50
references: 20479774
references: Nature. 2010 Sep 23;467(7314):460-4
references: 20827270
references: Blood. 2010 Jun 10;115(23):4644-50
references: 20212171
references: Nat Rev Genet. 2009 Mar;10(3):184-94
references: 19223927
references: PLoS One. 2011;6(9):e23956
references: 21912656
references: Nat Genet. 2009 Mar;41(3):283-5
references: 19198611
references: Carcinogenesis. 2012 Mar;33(3):598-603
references: 22219177
references: Bioinformatics. 2008 Dec 15;24(24):2938-9
references: 18974171
references: Genet Epidemiol. 2010 Dec;34(8):816-34
references: 21058334
references: Hum Mol Genet. 2008 Oct 15;17(R2):R129-34
references: 18852201
references: Ann Hum Genet. 2004 Mar;68(Pt 2):165-77
references: 15008795
references: Nat Genet. 2007 Oct;39(10):1217-24
references: 17873874
references: PLoS Genet. 2011 Dec;7(12):e1002367
references: 22144904
references: PLoS Genet. 2010 Apr 01;6(4):e1000895
references: 20369022
references: Nat Genet. 2010 Mar;42(3):210-5
references: 20139978
references: Nature. 2009 Oct 8;461(7265):747-53
references: 19812666
references: Bioinformatics. 2008 Jul 1;24(13):1547-8
references: 18467348
references: Genomics. 2011 Nov;98(5):320-6
references: 21763416
references: Nature. 2008 Mar 27;452(7186):423-8
references: 18344981
references: Blood. 2006 Sep 1;108(5):1562-8
references: 16705091
references: Philos Trans A Math Phys Eng Sci. 2005 Aug 15;363(1833):1729-42
references: 16099744
references: Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9362-7
references: 19474294
references: Mol Psychiatry. 2013 Apr;18(4):461-70
references: 22430674
references: Hum Mol Genet. 2009 Oct 15;18(R2):R211-5
references: 19808798
references: Nat Genet. 2011 May 29;43(7):685-9
references: 21623375
references: PLoS One. 2010 May 18;5(5):e10693
references: 20502693
references: Blood. 2005 Jul 1;106(1):135-40
references: 15790782
references: Bioinformatics. 2007 Apr 15;23(8):1038-9
references: 17308338
references: Nature. 2007 Jul 26;448(7152):470-3
references: 17611496
references: Nat Genet. 2007 Oct;39(10):1202-7
references: 17873877
references: Circ Cardiovasc Genet. 2011 Dec;4(6):626-35
references: 21965548
references: Nat Genet. 2010 Mar;42(3):200-2
references: 20173748
references: Arterioscler Thromb Vasc Biol. 2007 Oct;27(10):2250-7
references: 17656673
references: Nat Genet. 2007 Oct;39(10):1208-16
references: 17873875
references: Arterioscler Thromb Vasc Biol. 2004 Apr;24(4):775-81
references: 14962947
references: Nat Genet. 2006 Aug;38(8):904-9
references: 16862161
references: Hum Mol Genet. 2005 Oct 15;14 Spec No. 2:R163-9
references: 16244315
references: Trends Genet. 2001 Jul;17(7):388-91
references: 11418218
references: Hum Mol Genet. 2010 Dec 1;19(23):4745-57
references: 20833654
references: PLoS Biol. 2008 May 6;6(5):e107
references: 18462017
references: PLoS Genet. 2010 Apr 01;6(4):e1000888
references: 20369019
references: Nat Genet. 2011 Aug 28;43(10):984-9
references: 21874001
references: Nucleic Acids Res. 2010 Jan;38(3):e17
references: 19923232