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Common Disease Findings (case study on diabetes)

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.

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Common Disease Findings (case study on diabetes)

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  1. Common Disease Findings (case study on diabetes) GWAS Workshop Francis S. Collins, M.D., Ph.D. National Human Genome Research Institute May 1, 2007

  2. 1994 2004 Estimates of Diagnosed Diabetes Among Adults in the U.S. No Data <4% 4-4.9% 5-5.9% ≥6%

  3. genetic defects obesity impaired insulin secretion HYPERGLYCEMIA BETA-CELL EXHAUSTION TYPE 2 DIABETES Diabetes Pathophysiology Genetic Predisposition Environment Beta-cell Dysfunction Insulin Resistance poor glucose utilization

  4. 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)

  5. 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

  6. FUSION Two-Stage GWA Study of T2DStage 1: GWAStage 2: Validation of best hits • 80% power to detect: • Stage 1: OR = 1.4 - 1.5 • Stage 1 + 2: OR = 1.3 - 1.4

  7. GWA Genotyping of Stage 1 Samples • 317,503 SNPs genotyped on Illumina HumanHap300 BeadChip at the Center for Inherited Disease Research (CIDR) • Dropped 1,868 SNPs from analysis Failed to meet expectations for Hardy-Weinberg < 90% successful genotypes > 3 Mendelian or duplicate sample errors < 10 detections of the rare allele

  8. FUSION Stage 1 Association Results 1161 Finnish T2D cases + 1174 Finnish normal glucose tolerant controls -log10(p-value) No results meet genome-wide significance (p < 1.7 x 10-7)

  9. TCF7L2 PPARG KCNJ11 Known associations can serve as positive controls 1161 Finnish T2D cases + 1174 Finnish normal glucose tolerant controls -log10(p-value)

  10. Sweden United States (off map) Poland # cases + controls FUSION S1: 1161 + 1174 S2: 1215 + 1258 DGI S1: 1464 + 1467 S2: 5065 + 5785 WTCCC/UKT2D S1: 1924 + 2938 S2: 3757 + 5346 Three Groups Working Together Totals S1 = 4549 + 5579 S2 = 10053 + 12389 (n=32,554)

  11. 49 TCF7L2 15 KCNJ11 10 PPARG 5 0 Combined Results Now Highly Significant // -log10(p-value) Chromosome

  12. Top 10 Results From Combined Analysis

  13. Top 10 Results From Combined Analysis

  14. Top 10 Results From Combined Analysis

  15. 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

  16. rs13266634 is in the coding region of SLC30A8, and changes a highly conserved arginine to a tryptophan

  17. SLC30A8 - Beta Cell Zinc Transporter Chimienti (2005) BioMetals 18:313

  18. 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

  19. Embargoed until 5 PM Thursday May 3!

  20. 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

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