common disease findings (case study on diabetes)
DESCRIPTION
Common Disease Findings (case study on diabetes). GWAS Workshop Francis S. Collins, M.D., Ph.D. National Human Genome Research Institute May 1, 2007. 1994. 2004. Estimates of Diagnosed Diabetes Among Adults in the U.S. - PowerPoint PPT PresentationTRANSCRIPT
Common Disease Findings (case study on diabetes)
GWAS Workshop
Francis S. Collins, M.D., Ph.D.National Human Genome Research Institute
May 1, 2007
No Data <4% 4-4.9% 5-5.9% ≥6%
19941994 20042004
Estimates of Diagnosed Diabetes Among Adults in the U.S.
Diabetes Pathophysiology
Genetic Predisposition Environmentgenetic defects
Beta-cell Dysfunction Insulin Resistance
impaired insulin secretion
poor glucose utilization
obesity
TYPE 2 DIABETES
BETA-CELL EXHAUSTION
HYPERGLYCEMIA
Type 2 Diabetes:“The geneticist’s nightmare”
• Family history as a substantial risk factor– Relative risk to a sibling ~3
• Environment as a major contributor• Family linkage studies relatively disappointing• Validated genes prior to 2007:
– PPARG (candidate gene)
– KCNJ11 (candidate gene)
– TCF7L2 (linkage study)
Applying Genome Wide Association to Type 2 Diabetes
• Three groups, each with 1000 – 1500 cases and 1000 – 3000 controls in Stage 1:– FUSION (Boehnke, Bergman, Collins, Mohlke, Tuomilehto)– Diabetes Genetics Initiative of Broad, Novartis, and Lund
(Altshuler, Groop)– Wellcome Trust Case Control Consortium/UK Type 2
Diabetes Consortium (McCarthy, Hattersley, Donnelly)
• Genotyped with Illumina 317K or Affy 500K panel• Compared results across all three studies• Followed up promising signals in Stage 2 validation set
FUSION Two-Stage GWA Study of T2DStage 1: GWA
Stage 2: Validation of best hits
Cases
NGT
Controls Total
Familial /
population-based cases (%)
Stage 1 1161 1174 2335 68/32
Stage 2 1215 1258 2489 0/100
Total 2392 2432 4824 27/73
80% power to detect:• Stage 1: OR = 1.4 - 1.5 • Stage 1 + 2: OR = 1.3 - 1.4
• 317,503 SNPs genotyped on Illumina HumanHap300 BeadChip at the Center for Inherited Disease Research (CIDR)
• Dropped 1,868 SNPs from analysisFailed to meet expectations for Hardy-Weinberg< 90% successful genotypes> 3 Mendelian or duplicate sample errors< 10 detections of the rare allele
GWA Genotyping of Stage 1 Samples
FUSION Stage 1 Association Results-l
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1161 Finnish T2D cases + 1174 Finnish normal glucose tolerant controls
No results meet genome-wide significance (p < 1.7 x 10-7)
Known associations can serve as positive controls-l
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KCNJ11PPARG
1161 Finnish T2D cases + 1174 Finnish normal glucose tolerant controls
Three Groups Working Together
Sweden
Poland
United States
(off map)
# cases + controls
FUSIONS1: 1161 + 1174S2: 1215 + 1258
DGIS1: 1464 + 1467S2: 5065 + 5785
WTCCC/UKT2DS1: 1924 + 2938S2: 3757 + 5346
Totals S1 = 4549 + 5579S2 = 10053 + 12389 (n=32,554)
Combined Results Now Highly Significant-l
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Chromosome
15
10
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0
49 TCF7L2
KCNJ11
PPARG
//
Top 10 Results From Combined Analysis
FUSION DGI WTCCC/UKT2D All Samples
Gene OR p-value OR p-value OR p-value OR p-value
TCF7L2 1.34 1.3 x 10-8 1.38 2.3 x 10-31 1.37 6.7 x 10-13 1.37 1.0 x 10-48
IGF2BP2 1.18 2.1 x 10-4 1.17 1.7 x 10-9 1.11 1.6 x 10-4 1.14 8.9 x 10-16
CDKN2A/B 1.20 .0022 1.20 5.4 x 10-8 1.19 4.9 x 10-7 1.20 7.8 x 10-15
FTO 1.11 0.016 1.03 0.25 1.23 7.3 x 10-14 1.17 1.3 x 10-12
CDKAL1 1.12 0.0095 1.08 0.0024 1.16 1.3 x 10-8 1.12 4.1 x 10-11
KCNJ11 1.11 0.013 1.15 1.0 x 10-7 1.15 0.0013 1.14 6.7 x 10-11
HHEX 1.10 0.026 1.14 1.7 x 10-4 1.13 4.6 x 10-6 1.13 5.7 x 10-10
SLC30A8 1.18 7.0 x 10-5 1.07 0.047 1.12 7.0 x 10-5 1.12 5.3 x 10-8
Chr 11 1.48 5.7 x 10-8 1.16 0.12 1.13 0.068 1.23 4.3 x 10-7
PPARG 1.20 0.0014 1.09 0.019 1.23 0.0013 1.14 1.7 x 10-6
Top 10 Results From Combined Analysis
FUSION DGI WTCCC/UKT2D All Samples
Gene OR p-value OR p-value OR p-value OR p-value
TCF7L2 1.34 1.3 x 10-8 1.38 2.3 x 10-31 1.37 6.7 x 10-13 1.37 1.0 x 10-48
IGF2BP2 1.18 2.1 x 10-4 1.17 1.7 x 10-9 1.11 1.6 x 10-4 1.14 8.9 x 10-16
CDKN2A/B 1.20 .0022 1.20 5.4 x 10-8 1.19 4.9 x 10-7 1.20 7.8 x 10-15
FTO 1.11 0.016 1.03 0.25 1.23 7.3 x 10-14 1.17 1.3 x 10-12
CDKAL1 1.12 0.0095 1.08 0.0024 1.16 1.3 x 10-8 1.12 4.1 x 10-11
KCNJ11 1.11 0.013 1.15 1.0 x 10-7 1.15 0.0013 1.14 6.7 x 10-11
HHEX 1.10 0.026 1.14 1.7 x 10-4 1.13 4.6 x 10-6 1.13 5.7 x 10-10
SLC30A8 1.18 7.0 x 10-5 1.07 0.047 1.12 7.0 x 10-5 1.12 5.3 x 10-8
Chr 11 1.48 5.7 x 10-8 1.16 0.12 1.13 0.068 1.23 4.3 x 10-7
PPARG 1.20 0.0014 1.09 0.019 1.23 0.0013 1.14 1.7 x 10-6
Top 10 Results From Combined Analysis
FUSION DGI WTCCC/UKT2D All Samples
Gene OR p-value OR p-value OR p-value OR p-value
TCF7L2 1.34 1.3 x 10-8 1.38 2.3 x 10-31 1.37 6.7 x 10-13 1.37 1.0 x 10-48
IGF2BP2 1.18 2.1 x 10-4 1.17 1.7 x 10-9 1.11 1.6 x 10-4 1.14 8.9 x 10-16
CDKN2A/B 1.20 .0022 1.20 5.4 x 10-8 1.19 4.9 x 10-7 1.20 7.8 x 10-15
FTO 1.11 0.016 1.03 0.25 1.23 7.3 x 10-14 1.17 1.3 x 10-12
CDKAL1 1.12 0.0095 1.08 0.0024 1.16 1.3 x 10-8 1.12 4.1 x 10-11
KCNJ11 1.11 0.013 1.15 1.0 x 10-7 1.15 0.0013 1.14 6.7 x 10-11
HHEX 1.10 0.026 1.14 1.7 x 10-4 1.13 4.6 x 10-6 1.13 5.7 x 10-10
SLC30A8 1.18 7.0 x 10-5 1.07 0.047 1.12 7.0 x 10-5 1.12 5.3 x 10-8
Chr 11 1.48 5.7 x 10-8 1.16 0.12 1.13 0.068 1.23 4.3 x 10-7
PPARG 1.20 0.0014 1.09 0.019 1.23 0.0013 1.14 1.7 x 10-6
How could IGF2BP2 be related to diabetes?
• IGF2BP2 codes for the insulin-like growth factor 2 mRNA binding protein 2
• But we know very little about what this does
• A related gene, IGF2BP1, codes for a protein that binds to the upstream leader sequence of the insulin-like growth factor 2 (IGF2) mRNA and regulates IGF2 protein production
• IGF2 is involved in development, growth, and stimulation of insulin action
rs13266634is in the codingregion of SLC30A8, andchanges a highlyconservedarginine to atryptophan
SLC30A8 - Beta Cell Zinc Transporter
Chimienti (2005) BioMetals 18:313
SNPs Upstream of CDKN2A/B
• Cyclin-dependent kinase inhibitors CDKN2A and CDKN2B, also known as p16INK4a and p15INK4b
• Inhibit the activity of cyclin-dependent protein kinases CDK4 and CDK6, have been implicated repeatedly in cancer.
• Cdk4 activity also influences beta cell proliferation and mass in mice; loss of Cdk4 leads to diabetes
Embargoed until 5 PM Thursday M
ay 3!
SNPs Within Introns of CDKAL1• CDK5 regulatory subunit associated protein 1-like 1
• Shares protein domain similarity with CDK5RAP1, which inhibits CDK5
• CDK5 activity is influenced by glucose, stimulates insulin gene transcription, and may influence other beta cell processes
• Over activity of CDK5 in pancreas may lead to beta cell degeneration