title: Liver and adipose expression associated SNPs are enriched for association to type 2 diabetes.
abstract: Genome-wide association studies (GWAS) have demonstrated the ability to identify the strongest causal common variants in complex human diseases. However, to date, the massive data generated from GWAS have not been maximally explored to identify true associations that fail to meet the stringent level of association required to achieve genome-wide significance. Genetics of gene expression (GGE) studies have shown promise towards identifying DNA variations associated with disease and providing a path to functionally characterize findings from GWAS. Here, we present the first empiric study to systematically characterize the set of single nucleotide polymorphisms associated with expression (eSNPs) in liver, subcutaneous fat, and omental fat tissues, demonstrating these eSNPs are significantly more enriched for SNPs that associate with type 2 diabetes (T2D) in three large-scale GWAS than a matched set of randomly selected SNPs. This enrichment for T2D association increases as we restrict to eSNPs that correspond to genes comprising gene networks constructed from adipose gene expression data isolated from a mouse population segregating a T2D phenotype. Finally, by restricting to eSNPs corresponding to genes comprising an adipose subnetwork strongly predicted as causal for T2D, we dramatically increased the enrichment for SNPs associated with T2D and were able to identify a functionally related set of diabetes susceptibility genes. We identified and validated malic enzyme 1 (Me1) as a key regulator of this T2D subnetwork in mouse and provided support for the association of this gene to T2D in humans. This integration of eSNPs and networks provides a novel approach to identify disease susceptibility networks rather than the single SNPs or genes traditionally identified through GWAS, thereby extracting additional value from the wealth of data currently being generated by GWAS.
authors.affiliation: Department of Genetics, Rosetta Inpharmatics, Seattle, Washington, United States of America.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhong
authors.forename: John
authors.initials: J
authors.lastname: Beaulaurier
authors.forename: Pek Yee
authors.initials: PY
authors.lastname: Lum
authors.forename: Cliona
authors.initials: C
authors.lastname: Molony
authors.forename: Xia
authors.initials: X
authors.lastname: Yang
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Macneil
authors.forename: Drew T
authors.initials: DT
authors.lastname: Weingarth
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Danielle
authors.initials: D
authors.lastname: Greenawalt
authors.forename: Radu
authors.initials: R
authors.lastname: Dobrin
authors.forename: Ke
authors.initials: K
authors.lastname: Hao
authors.forename: Sangsoon
authors.initials: S
authors.lastname: Woo
authors.forename: Christine
authors.initials: C
authors.lastname: Fabre-Suver
authors.forename: Su
authors.initials: S
authors.lastname: Qian
authors.forename: Michael R
authors.initials: MR
authors.lastname: Tota
authors.forename: Mark P
authors.initials: MP
authors.lastname: Keller
authors.forename: Christina M
authors.initials: CM
authors.lastname: Kendziorski
authors.forename: Brian S
authors.initials: BS
authors.lastname: Yandell
authors.forename: Victor
authors.initials: V
authors.lastname: Castro
authors.forename: Alan D
authors.initials: AD
authors.lastname: Attie
authors.forename: Lee M
authors.initials: LM
authors.lastname: Kaplan
authors.forename: Eric E
authors.initials: EE
authors.lastname: Schadt
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D055106:Genome-Wide Association Study; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D020641:Polymorphism, Single Nucleotide; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C416371:PRDM16 protein, human; C521133:Prdm16 protein, mouse; D014157:Transcription Factors
references.citation: Nature. 2008 Mar 27;452(7186):423-8
references.pmid: 18344981
references.citation: Am J Physiol. 1997 Oct;273(4):E708-13
references.pmid: 9357799
references.citation: Nat Rev Genet. 2007 Sep;8(9):657-62
references.pmid: 17703236
references.citation: Diabetes. 2009 Jun;58(6):1463-7
references.pmid: 19252133
references.citation: Nature. 2008 Mar 27;452(7186):429-35
references.pmid: 18344982
references.citation: Am J Ther. 2005 Nov-Dec;12(6):491-8
references.pmid: 16280642
references.citation: Biochemistry. 1980 Oct 28;19(22):5098-103
references.pmid: 6779864
references.citation: Biostatistics. 2008 Oct;9(4):621-34
references.pmid: 18310059
references.citation: Nat Genet. 2005 Nov;37(11):1224-33
references.pmid: 16200066
references.citation: FASEB J. 2004 Feb;18(2):415-7
references.pmid: 14688200
references.citation: N Engl J Med. 2009 Apr 23;360(17):1759-68
references.pmid: 19369657
references.citation: Basic Clin Pharmacol Toxicol. 2008 Jul;103(1):36-42
references.pmid: 18346052
references.citation: Nat Genet. 2007 Jul;39(7):857-64
references.pmid: 17554260
references.citation: Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):10878-82
references.pmid: 7971976
references.citation: J Proteome Res. 2009 Apr;8(4):1682-93
references.pmid: 19714809
references.citation: Science. 2007 Jun 1;316(5829):1341-5
references.pmid: 17463248
references.citation: Nature. 2004 Aug 12;430(7001):743-7
references.pmid: 15269782
references.citation: Nat Genet. 2008 May;40(5):638-45
references.pmid: 18372903
references.citation: Science. 2008 Nov 7;322(5903):881-8
references.pmid: 18988837
references.citation: Cytogenet Genome Res. 2004;105(2-4):363-74
references.pmid: 15237224
references.citation: N Engl J Med. 2007 Aug 2;357(5):443-53
references.pmid: 17634449
references.citation: Bioinformatics. 2006 May 1;22(9):1111-21
references.pmid: 16522673
references.citation: N Engl J Med. 2009 Apr 23;360(17):1696-8
references.pmid: 19369660
references.citation: Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17402-7
references.pmid: 17090670
references.citation: Nat Genet. 2008 Jul;40(7):854-61
references.pmid: 18552845
references.citation: Science. 2002 Aug 30;297(5586):1551-5
references.pmid: 12202830
references.citation: Science. 2006 Nov 10;314(5801):992-3
references.pmid: 17053109
references.citation: Toxicol Appl Pharmacol. 2008 Mar 15;227(3):400-16
references.pmid: 18191166
references.citation: Science. 2007 Jun 1;316(5829):1331-6
references.pmid: 17463246
references.citation: J Biol Chem. 1995 Aug 25;270(34):20051-8
references.pmid: 7650022
references.citation: Science. 2007 Aug 17;317(5840):944-7
references.pmid: 17641165
references.citation: Nature. 2007 Jul 26;448(7152):470-3
references.pmid: 17611496
references.citation: Diabetes. 2002 Jan;51(1):7-18
references.pmid: 11756317
references.citation: Nature. 2009 May 7;459(7243):108-12
references.pmid: 19295514
references.citation: Nat Genet. 2007 Oct;39(10):1202-7
references.pmid: 17873877
references.citation: Obesity (Silver Spring). 2006 Jun;14(6):974-9
references.pmid: 16861601
references.citation: Heredity (Edinb). 1992 Oct;69(4):315-24
references.pmid: 16718932
references.citation: Nature. 2007 Jun 7;447(7145):661-78
references.pmid: 17554300
references.citation: Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2498-502
references.pmid: 9482914
references.citation: J Clin Endocrinol Metab. 1995 May;80(5):1584-90
references.pmid: 7745004
references.citation: Apoptosis. 2009 Dec;14(12):1484-95
references.pmid: 19421860
references.citation: Anim Genet. 2006 Feb;37(1):28-32
references.pmid: 16441292
references.citation: Stat Appl Genet Mol Biol. 2005;4:Article17
references.pmid: 16646834
references.citation: FASEB J. 2001 Feb;15(2):312-21
references.pmid: 11156947
references.citation: J Clin Endocrinol Metab. 2002 Sep;87(9):4407-10
references.pmid: 12213908
references.citation: Diabetes. 2000 Nov;49(11):1946-54
references.pmid: 11078464
references.citation: Nature. 2007 Feb 22;445(7130):881-5
references.pmid: 17293876
references.citation: N Engl J Med. 2009 Apr 23;360(17):1701-3
references.pmid: 19369656
references.citation: Am J Physiol Endocrinol Metab. 2009 Apr;296(4):E917-24
references.pmid: 19176350
references.citation: Science. 2006 Nov 10;314(5801):989-92
references.pmid: 17053108
references.citation: Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9440-5
references.pmid: 12883005
references.citation: J Biol Chem. 2002 Dec 27;277(52):50230-6
references.pmid: 12006582
references.citation: Genetics. 1995 Jul;140(3):1111-27
references.pmid: 7672582
references.citation: Nature. 2003 Mar 20;422(6929):297-302
references.pmid: 12646919
references.citation: Nat Genet. 2005 Jul;37(7):710-7
references.pmid: 15965475
references.citation: PLoS Genet. 2006 Feb;2(2):e15
references.pmid: 16462940
references.citation: PLoS Biol. 2008 May 6;6(5):e107
references.pmid: 18462017
references.citation: Metabolism. 1992 Oct;41(10):1134-6
references.pmid: 1406300
references.citation: Curr Protoc Bioinformatics. 2003 Aug;Chapter 7:Unit 7.4
references.pmid: 18428707
references.citation: Nat Genet. 2009 Apr;41(4):415-23
references.pmid: 19270708
references.citation: Am J Hum Genet. 2004 Dec;75(6):1094-105
references.pmid: 15514893
references.citation: Genome Res. 2008 May;18(5):706-16
references.pmid: 18347327