title: Expression quantitative trait analyses to identify causal genetic variants for type 2 diabetes susceptibility.
abstract: Type 2 diabetes (T2D) is a common metabolic disorder which is caused by multiple genetic perturbations affecting different biological pathways. Identifying genetic factors modulating the susceptibility of this complex heterogeneous metabolic phenotype in different ethnic and racial groups remains challenging. Despite recent success, the functional role of the T2D susceptibility variants implicated by genome-wide association studies (GWAS) remains largely unknown. Genetic dissection of transcript abundance or expression quantitative trait (eQTL) analysis unravels the genomic architecture of regulatory variants. Availability of eQTL information from tissues relevant for glucose homeostasis in humans opens a new avenue to prioritize GWAS-implicated variants that may be involved in triggering a causal chain of events leading to T2D. In this article, we review the progress made in the field of eQTL research and knowledge gained from those studies in understanding transcription regulatory mechanisms in human subjects. We highlight several novel approaches that can integrate eQTL analysis with multiple layers of biological information to identify ethnic-specific causal variants and gene-environment interactions relevant to T2D pathogenesis. Finally, we discuss how the eQTL analysis mediated search for "missing heritability" may lead us to novel biological and molecular mechanisms involved in susceptibility to T2D.
authors.affiliation: Swapan Kumar Das, Neeraj Kumar Sharma, Section on Endocrinology and Metabolism, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, United States.
authors.forename: Swapan Kumar
authors.initials: SK
authors.lastname: Das
authors.affiliation: Swapan Kumar Das, Neeraj Kumar Sharma, Section on Endocrinology and Metabolism, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, United States.
authors.forename: Neeraj Kumar
authors.initials: NK
authors.lastname: Sharma
keywords: Expression quantitative trait locus; Expression regulatory SNPs; Gene-environment interaction; Genome-wide association study; Single nucleotide polymorphisms; Type 2 diabetes
references.citation: Diabetes Res Clin Pract. 2007 Sep;77(3):389-98
references.pmid: 17275945
references.citation: Nature. 2008 Mar 27;452(7186):423-8
references.pmid: 18344981
references.citation: Genetica. 2009 Jun;136(2):333-40
references.pmid: 18668207
references.citation: Genome Med. 2011 Nov 29;3(11):76
references.pmid: 22126607
references.citation: Diabetes. 1996 Jun;45(6):742-8
references.pmid: 8635647
references.citation: Physiol Genomics. 2013 Jul 2;45(13):509-20
references.pmid: 23673729
references.citation: Am J Hum Genet. 2012 Jan 13;90(1):7-24
references.pmid: 22243964
references.citation: Dis Model Mech. 2011 Mar;4(2):155-64
references.pmid: 21324932
references.citation: Nat Biotechnol. 2012 Nov;30(11):1095-106
references.pmid: 23138309
references.citation: Genome Res. 2012 Mar;22(3):528-38
references.pmid: 22113879
references.citation: PLoS Genet. 2012;8(4):e1002639
references.pmid: 22532805
references.citation: Pharmacogenomics. 2011 Dec;12(12):1695-715
references.pmid: 22118053
references.citation: Nat Genet. 2012 Oct;44(10):1084-9
references.pmid: 22941192
references.citation: PLoS Genet. 2010 May 06;6(5):e1000932
references.pmid: 20463879
references.citation: Diabetes. 2008 Aug;57(8):2220-5
references.pmid: 18443202
references.citation: Nature. 2009 May 28;459(7246):587-91
references.pmid: 19349959
references.citation: PLoS Genet. 2010 Jun 03;6(6):e1000976
references.pmid: 20532202
references.citation: PLoS Genet. 2010 Sep 30;6(9):e1001144
references.pmid: 20941394
references.citation: Nat Genet. 2012 Sep;44(9):981-90
references.pmid: 22885922
references.citation: Nat Genet. 2013 Oct;45(10):1238-1243
references.pmid: 24013639
references.citation: Science. 2013 Nov 8;342(6159):747-9
references.pmid: 24136359
references.citation: Am J Hum Genet. 2012 Jun 8;90(6):1046-63
references.pmid: 22658545
references.citation: Pediatr Diabetes. 2013 Mar;14(2):90-6
references.pmid: 23350725
references.citation: Curr Diab Rep. 2007 Apr;7(2):154-64
references.pmid: 17425920
references.citation: Cellscience. 2006 Apr 30;2(4):100-131
references.pmid: 16892160
references.citation: J Clin Endocrinol Metab. 2011 Feb;96(2):E394-403
references.pmid: 21084393
references.citation: Science. 2013 Nov 8;342(6159):744-7
references.pmid: 24136355
references.citation: PLoS Genet. 2008 Oct;4(10):e1000214
references.pmid: 18846210
references.citation: PLoS Comput Biol. 2011 Jan 20;7(1):e1001057
references.pmid: 21283776
references.citation: Genome Biol. 2012 Jan 31;13(1):R7
references.pmid: 22293038
references.citation: Nat Rev Genet. 2009 Mar;10(3):184-94
references.pmid: 19223927
references.citation: Diabetologia. 2008 Jul;51(7):1100-10
references.pmid: 18504548
references.citation: Nat Genet. 2014 Feb;46(2):136-143
references.pmid: 24413736
references.citation: Cell. 2012 Dec 21;151(7):1595-607
references.pmid: 23260145
references.citation: Sci Transl Med. 2012 Sep 26;4(153):153ps18
references.pmid: 23019654
references.citation: Diabetes Care. 2013 Jun;36(6):1789-96
references.pmid: 23704681
references.citation: PLoS Comput Biol. 2010 Apr 08;6(4):e1000737
references.pmid: 20386736
references.citation: J Clin Endocrinol Metab. 2010 Mar;95(3):1450-7
references.pmid: 20097709
references.citation: Nat Rev Genet. 2011 Apr;12(4):277-82
references.pmid: 21386863
references.citation: J Clin Endocrinol Metab. 2011 Aug;96(8):E1308-13
references.pmid: 21593104
references.citation: Diabetes. 2009 Jun;58(6):1463-7
references.pmid: 19252133
references.citation: Am J Hum Genet. 2012 Sep 7;91(3):466-77
references.pmid: 22958899
references.citation: Bioinformatics. 2012 May 15;28(10):1353-8
references.pmid: 22492648
references.citation: Pharmacogenomics. 2011 Aug;12(8):1161-91
references.pmid: 21843065
references.citation: Annu Rev Nutr. 2013;33:349-71
references.pmid: 23642200
references.citation: Diabetes. 2011 Mar;60(3):1019-29
references.pmid: 21266331
references.citation: PLoS Genet. 2011 Feb 03;7(2):e1002003
references.pmid: 21304890
references.citation: Bioinformatics. 2012 Jun 15;28(12):i121-6
references.pmid: 22689751
references.citation: PLoS Genet. 2010 Aug 26;6(8):
references.pmid: 20865176
references.citation: PLoS Biol. 2008 Apr 15;6(4):e83
references.pmid: 18416601
references.citation: Bioinformatics. 2010 Jan 15;26(2):259-62
references.pmid: 19933162
references.citation: Am J Hum Genet. 2008 Mar;82(3):631-40
references.pmid: 18313023
references.citation: Nat Genet. 2008 Jul;40(7):904-8
references.pmid: 18568024
references.citation: Nature. 2008 Mar 27;452(7186):429-35
references.pmid: 18344982
references.citation: Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9362-7
references.pmid: 19474294
references.citation: PLoS Genet. 2011 Jul;7(7):e1002144
references.pmid: 21811411
references.citation: Genome Res. 2013 May;23(5):800-11
references.pmid: 23512712
references.citation: Proc Natl Acad Sci U S A. 2010 Sep 21;107(38):16465-70
references.pmid: 20810919
references.citation: Pharmacogenet Genomics. 2012 Jul;22(7):484-97
references.pmid: 22437669
references.citation: PLoS Comput Biol. 2007 Apr 13;3(4):e69
references.pmid: 17432931
references.citation: Nat Genet. 2007 Feb;39(2):226-31
references.pmid: 17206142
references.citation: Popul Health Metr. 2010 Oct 22;8:29
references.pmid: 20969750
references.citation: Nature. 2010 Apr 1;464(7289):773-7
references.pmid: 20220756
references.citation: Trends Genet. 2011 Mar;27(3):107-15
references.pmid: 21216485
references.citation: Genome Res. 2014 Jan;24(1):14-24
references.pmid: 24092820
references.citation: Cell. 2013 Feb 14;152(4):673-84
references.pmid: 23415219
references.citation: Cell. 2013 Mar 14;152(6):1237-51
references.pmid: 23498934
references.citation: Mol Genet Metab. 2010 May;100(1):77-82
references.pmid: 20138556
references.citation: Int J Obes (Lond). 2013 Sep;37(9):1211-20
references.pmid: 23357958
references.citation: Nat Genet. 2013 Feb;45(2):124-30
references.pmid: 23263488
references.citation: Am J Hum Genet. 2014 Feb 6;94(2):186-97
references.pmid: 24439111
references.citation: Cell Metab. 2013 Feb 5;17(2):157-9
references.pmid: 23395164
references.citation: Diabetes. 2014 Mar;63(3):1154-65
references.pmid: 24306210
references.citation: Nat Biotechnol. 2012 Feb 26;30(3):271-7
references.pmid: 22371084
references.citation: Mol Cell Endocrinol. 2014 Jan 25;382(1):726-739
references.pmid: 23587769
references.citation: Am J Hum Genet. 2012 Mar 9;90(3):410-25
references.pmid: 22325160
references.citation: PLoS Genet. 2011 Jan 20;7(1):e1001279
references.pmid: 21283786
references.citation: PLoS Biol. 2010 Sep 14;8(9):
references.pmid: 20856902
references.citation: Nat Genet. 2013 Jun;45(6):580-5
references.pmid: 23715323
references.citation: Nat Biotechnol. 2012 Feb 26;30(3):265-70
references.pmid: 22371081
references.citation: Nat Rev Genet. 2009 Aug;10(8):565-77
references.pmid: 19584810
references.citation: Nature. 2012 Sep 6;489(7414):57-74
references.pmid: 22955616
references.citation: Nat Genet. 2007 Oct;39(10):1217-24
references.pmid: 17873874
references.citation: BMC Med Genomics. 2009 Dec 31;2:72
references.pmid: 20043853
references.citation: Hum Mol Genet. 2012 Oct 15;21(R1):R18-23
references.pmid: 22936690
references.citation: Sci Transl Med. 2012 Jan 4;4(115):115rv1
references.pmid: 22218693
references.citation: Nat Protoc. 2012 Feb 16;7(3):500-7
references.pmid: 22343431
references.citation: Nutr Metab Cardiovasc Dis. 2013 Jun;23(6):550-6
references.pmid: 22402060
references.citation: Am J Hum Genet. 2013 Nov 7;93(5):779-97
references.pmid: 24210251
references.citation: Nat Genet. 2006 Mar;38(3):320-3
references.pmid: 16415884
references.citation: Diabetes. 2012 Jun;61(6):1642-7
references.pmid: 22474029
references.citation: Nature. 2007 Jul 26;448(7152):470-3
references.pmid: 17611496
references.citation: PLoS Genet. 2013;9(9):e1003803
references.pmid: 24068968
references.citation: Nature. 2013 Sep 26;501(7468):506-11
references.pmid: 24037378
references.citation: Eur J Pharmacol. 2011 Sep;668 Suppl 1:S108-16
references.pmid: 21816149
references.citation: Diabetes. 2012 Nov;61(11):2657-8
references.pmid: 23093653
references.citation: Nat Rev Genet. 2010 Apr;11(4):259-72
references.pmid: 20212493
references.citation: Pharmacogenomics. 2012 Feb;13(3):343-52
references.pmid: 22304583
references.citation: Nat Genet. 2007 Oct;39(10):1202-7
references.pmid: 17873877
references.citation: Nat Genet. 2010 Jul;42(7):579-89
references.pmid: 20581827
references.citation: Bioinformatics. 2012 Feb 1;28(3):451-2
references.pmid: 22171328
references.citation: Nat Genet. 2007 Oct;39(10):1208-16
references.pmid: 17873875
references.citation: Nat Rev Genet. 2012 Feb 14;13(3):215-20
references.pmid: 22330769
references.citation: J Mol Endocrinol. 2011 Sep 30;47(3):251-9
references.pmid: 21798992
references.citation: Stat Appl Genet Mol Biol. 2005;4:Article17
references.pmid: 16646834
references.citation: Nat Rev Genet. 2006 Oct;7(10):812-20
references.pmid: 16983377
references.citation: PLoS Genet. 2010 Apr 01;6(4):e1000895
references.pmid: 20369022
references.citation: Diabetes. 2013 Mar;62(3):965-76
references.pmid: 23193183
references.citation: Cell. 2013 Sep 26;155(1):21-6
references.pmid: 24074858
references.citation: Cell Metab. 2008 Sep;8(3):186-200
references.pmid: 18762020
references.citation: Am J Hum Genet. 2010 Mar 12;86(3):399-410
references.pmid: 20170901
references.citation: Cell Metab. 2012 Jul 3;16(1):122-34
references.pmid: 22768844
references.citation: Genetics. 2008 Dec;180(4):1909-25
references.pmid: 18791227
references.citation: Nat Genet. 2013 Sep;45(9):1021-1028
references.pmid: 23892608
references.citation: Science. 2012 Sep 7;337(6099):1190-5
references.pmid: 22955828
references.citation: Diabetologia. 2012 Aug;55(8):2205-13
references.pmid: 22584726
references.citation: Science. 2010 Apr 9;328(5975):232-5
references.pmid: 20299548
references.citation: PLoS Genet. 2011 Jul;7(7):e1002162
references.pmid: 21750684
references.citation: PLoS Genet. 2011 May;7(5):e1002078
references.pmid: 21637794
references.citation: PLoS One. 2011;6(8):e23480
references.pmid: 21912597
references.citation: PLoS Genet. 2007 Sep;3(9):1724-35
references.pmid: 17907809
references.citation: Am J Hum Genet. 2013 May 2;92(5):667-80
references.pmid: 23643380
references.citation: Wiley Interdiscip Rev Syst Biol Med. 2010 Jan-Feb;2(1):3-22
references.pmid: 20836007
references.citation: Nature. 2003 Jun 5;423(6940):599-602
references.pmid: 12789325
references.citation: PLoS One. 2010 May 20;5(5):e10746
references.pmid: 20505766
references.citation: Nat Genet. 2005 Jul;37(7):710-7
references.pmid: 15965475
references.citation: Nature. 2009 Oct 8;461(7265):747-53
references.pmid: 19812666
references.citation: Nat Rev Genet. 2006 Nov;7(11):862-72
references.pmid: 17047685
references.citation: PLoS Genet. 2012 Jan;8(1):e1002431
references.pmid: 22275870
references.citation: PLoS Biol. 2008 May 6;6(5):e107
references.pmid: 18462017
references.citation: PLoS Genet. 2010 Apr 01;6(4):e1000888
references.pmid: 20369019
references.citation: N Engl J Med. 2011 Mar 24;364(12):1104-15
references.pmid: 21428766
references.citation: Hum Genet. 2013 May;132(5):495-508
references.pmid: 23334806
references.citation: Trends Genet. 2005 Nov;21(11):616-23
references.pmid: 16154229
references.citation: Nature. 2012 Sep 6;489(7414):109-13
references.pmid: 22955621
references.citation: Curr Diab Rep. 2010 Dec;10(6):476-84
references.pmid: 20820957
references.citation: Cell. 2013 Apr 25;153(3):707-20
references.pmid: 23622250
references.citation: Am J Hum Genet. 2008 May;82(5):1101-13
references.pmid: 18439551
references.citation: Bioinformatics. 2010 Oct 1;26(19):2474-6
references.pmid: 20702402
references.citation: PLoS Genet. 2005 Dec;1(6):e78
references.pmid: 16362079
references.citation: Am J Hum Genet. 2007 Sep;81(3):427-37
references.pmid: 17701890
references.citation: PLoS One. 2012;7(1):e29348
references.pmid: 22272232
references.citation: J Clin Endocrinol Metab. 2007 Dec;92(12):4656-63
references.pmid: 17878257
references.citation: Nat Rev Genet. 2009 Sep;10(9):595-604
references.pmid: 19636342
references.citation: Genome Res. 2011 Jul;21(7):1008-16
references.pmid: 21602305