Liver and adipose expression associated SNPs are enriched for association to type 2 diabetes.
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.
Zhong
Hua
H
Department of Genetics, Rosetta Inpharmatics, Seattle, Washington, United States of America.
Beaulaurier
John
J
Lum
Pek Yee
PY
Molony
Cliona
C
Yang
Xia
X
Macneil
Douglas J
DJ
Weingarth
Drew T
DT
Zhang
Bin
B
Greenawalt
Danielle
D
Dobrin
Radu
R
Hao
Ke
K
Woo
Sangsoon
S
Fabre-Suver
Christine
C
Qian
Su
S
Tota
Michael R
MR
Keller
Mark P
MP
Kendziorski
Christina M
CM
Yandell
Brian S
BS
Castro
Victor
V
Attie
Alan D
AD
Kaplan
Lee M
LM
Schadt
Eric E
EE
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
D004268:DNA-Binding Proteins; C416371:PRDM16 protein, human; C521133:Prdm16 protein, mouse; D014157:Transcription Factors
Nature. 2008 Mar 27;452(7186):423-8
18344981
Am J Physiol. 1997 Oct;273(4):E708-13
9357799
Nat Rev Genet. 2007 Sep;8(9):657-62
17703236
Diabetes. 2009 Jun;58(6):1463-7
19252133
Nature. 2008 Mar 27;452(7186):429-35
18344982
Am J Ther. 2005 Nov-Dec;12(6):491-8
16280642
Biochemistry. 1980 Oct 28;19(22):5098-103
6779864
Biostatistics. 2008 Oct;9(4):621-34
18310059
Nat Genet. 2005 Nov;37(11):1224-33
16200066
FASEB J. 2004 Feb;18(2):415-7
14688200
N Engl J Med. 2009 Apr 23;360(17):1759-68
19369657
Basic Clin Pharmacol Toxicol. 2008 Jul;103(1):36-42
18346052
Nat Genet. 2007 Jul;39(7):857-64
17554260
Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):10878-82
7971976
J Proteome Res. 2009 Apr;8(4):1682-93
19714809
Science. 2007 Jun 1;316(5829):1341-5
17463248
Nature. 2004 Aug 12;430(7001):743-7
15269782
Nat Genet. 2008 May;40(5):638-45
18372903
Science. 2008 Nov 7;322(5903):881-8
18988837
Cytogenet Genome Res. 2004;105(2-4):363-74
15237224
N Engl J Med. 2007 Aug 2;357(5):443-53
17634449
Bioinformatics. 2006 May 1;22(9):1111-21
16522673
N Engl J Med. 2009 Apr 23;360(17):1696-8
19369660
Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17402-7
17090670
Nat Genet. 2008 Jul;40(7):854-61
18552845
Science. 2002 Aug 30;297(5586):1551-5
12202830
Science. 2006 Nov 10;314(5801):992-3
17053109
Toxicol Appl Pharmacol. 2008 Mar 15;227(3):400-16
18191166
Science. 2007 Jun 1;316(5829):1331-6
17463246
J Biol Chem. 1995 Aug 25;270(34):20051-8
7650022
Science. 2007 Aug 17;317(5840):944-7
17641165
Nature. 2007 Jul 26;448(7152):470-3
17611496
Diabetes. 2002 Jan;51(1):7-18
11756317
Nature. 2009 May 7;459(7243):108-12
19295514
Nat Genet. 2007 Oct;39(10):1202-7
17873877
Obesity (Silver Spring). 2006 Jun;14(6):974-9
16861601
Heredity (Edinb). 1992 Oct;69(4):315-24
16718932
Nature. 2007 Jun 7;447(7145):661-78
17554300
Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2498-502
9482914
J Clin Endocrinol Metab. 1995 May;80(5):1584-90
7745004
Apoptosis. 2009 Dec;14(12):1484-95
19421860
Anim Genet. 2006 Feb;37(1):28-32
16441292
Stat Appl Genet Mol Biol. 2005;4:Article17
16646834
FASEB J. 2001 Feb;15(2):312-21
11156947
J Clin Endocrinol Metab. 2002 Sep;87(9):4407-10
12213908
Diabetes. 2000 Nov;49(11):1946-54
11078464
Nature. 2007 Feb 22;445(7130):881-5
17293876
N Engl J Med. 2009 Apr 23;360(17):1701-3
19369656
Am J Physiol Endocrinol Metab. 2009 Apr;296(4):E917-24
19176350
Science. 2006 Nov 10;314(5801):989-92
17053108
Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9440-5
12883005
J Biol Chem. 2002 Dec 27;277(52):50230-6
12006582
Genetics. 1995 Jul;140(3):1111-27
7672582
Nature. 2003 Mar 20;422(6929):297-302
12646919
Nat Genet. 2005 Jul;37(7):710-7
15965475
PLoS Genet. 2006 Feb;2(2):e15
16462940
PLoS Biol. 2008 May 6;6(5):e107
18462017
Metabolism. 1992 Oct;41(10):1134-6
1406300
Curr Protoc Bioinformatics. 2003 Aug;Chapter 7:Unit 7.4
18428707
Nat Genet. 2009 Apr;41(4):415-23
19270708
Am J Hum Genet. 2004 Dec;75(6):1094-105
15514893
Genome Res. 2008 May;18(5):706-16
18347327