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Genome-wide association (GWA) studies: Moving from genetic localization to medical applications

Genome-wide association (GWA) studies: Moving from genetic localization to medical applications. Michael Davey, M.D., Ph.D. Portland VAMC & OHSU. Acknowledgment : Genome-Wide Association Studies: The Basics of the Science November 20, 2008 (Webinar) Teri Manolio, M.D., Ph.D.

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Genome-wide association (GWA) studies: Moving from genetic localization to medical applications

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  1. Genome-wide association (GWA) studies: Moving from genetic localization to medical applications Michael Davey, M.D., Ph.D. Portland VAMC & OHSU

  2. Acknowledgment: Genome-Wide Association Studies: The Basics of the Science November 20, 2008 (Webinar) Teri Manolio, M.D., Ph.D. Director of the Office of Population Genomics, NHGRI Manolio 11/20/08

  3. Age-related macular degeneration • Progressive degeneration of photoreceptors • Siblings have 3-6-fold disease risk • Until 2005, thought to be caused by ischemia Soft druzen of macula Swaroop et al, Human Molecular Genetics 16:R174-R182 (2007)

  4. GWA Scan for Age-Related Macular Degeneration Klein et al, Science 2005; 308:385-389.

  5. Single nucleotide polymorphisms (SNPs) • DNA sequence of any 2 people is 99.99% identical • Sites where individuals differ are called single nucleotide polymorphisms (SNPs) • Roughly 10 million such sites in humans

  6. www.hapmap.org Nature 2005; 437:1299-320. Nature 2007; 449:851-61.

  7. HapMap Project • Create a database of patterns of common human sequence variation • Based on “Common Disease – Common Variant” hypothesis -common, interacting allelic variants underlie most common diseases -alleles present in 1-5% of the population -in concert with environmental factors

  8. DNA on Chromosome 7 GAAATAATTAATGTTTTCCTTCCTTCTCCTATTTTGTCCTTTACTTCAATTTATTTATTTATTATTAATATTATTATTTTTTGAGACGGAGTTTC/ACTCTTGTTGCCAACCTGGAGTGCAGTGGCGTGATCTCAGCTCACTGCACACTCCGCTTTCCTGGTTTCAAGCGATTCTCCTGCCTCAGCCTCCTGAGTAGCTGGGACTACAGTCACACACCACCACGCCCGGCTAATTTTTGTATTTTTAGTAGAGTTGGGGTTTCACCATGTTGGCCAGACTGGTCTCGAACTCCTGACCTTGTGATCCGCCAGCCTCTGCCTCCCAAAGAGCTGGGATTACAGGCGTGAGCCACCGCGCTCGGCCCTTTGCATCAATTTCTACAGCTTGTTTTCTTTGCCTGGACTTTACAAGTCTTACCTTGTTCTGCC/TTCAGATATTTGTGTGGTCTCATTCTGGTGTGCCAGTAGCTAAAAATCCATGATTTGCTCTCATCCCACTCCTGTTGTTCATCTCCTCTTATCTGGGGTCACA/CTATCTCTTCGTGATTGCATTCTGATCCCCAGTACTTAGCATGTGCGTAACAACTCTGCCTCTGCTTTCCCAGGCTGTTGATGGGGTGCTGTTCATGCCTCAGAAAAATGCATTGTAAGTTAAATTATTAAAGATTTTAAATATAGGAAAAAAGTAAGCAAACATAAGGAACAAAAAGGAAAGAACATGTATTCTAATCCATTATTTATTATACAATTAAGAAATTTGGAAACTTTAGATTACACTGCTTTTAGAGATGGAGATGTAGTAAGTCTTTTACTCTTTACAAAATACATGTGTTAGCAATTTTGGGAAGAATAGTAACTCACCCGAACAGTG/TAATGTGAATATGTCACTTACTAGAGGAAAGAAGGCACTTGAAAAACATCTCTAAACCGTATAAAAACAATTACATCATAATGATGAAAACCCAAGGAATTTTTTTAGAAAACATTACCAGGGCTAATAACAAAGTAGAGCCACATGTCATTTATCTTCCCTTTGTGTCTGTGTGAGAATTCTAGAGTTATATTTGTACATAGCATGGAAAAATGAGAGGCTAGTTTATCAACTAGTTCATTTTTAAAAGTCTAACACATCCTAGGTATAGGTGAACTGTCCTCCTGCCAATGTATTGCACATTTGTGCCCAGATCCAGCATAGGGTATGTTTGCCATTTACAAACGTTTATGTCTTAAGAGAGGAAATATGAAGAGCAAAACAGTGCATGCTGGAGAGAGAAAGCTGATACAAATATAAAT/GAAACAATAATTGGAAAAATTGAGAAACTACTCATTTTCTAAATTACTCATGTATTTTCCTAGAATTTAAGTCTTTTAATTTTTGATAAATCCCAATGTGAGACAAGATAAGTATTAGTGATGGTATGAGTAATTAATATCTGTTATATAATATTCATTTTCATAGTGGAAGAAATAAAATAAAGGTTGTGATGATTGTTGATTATTTTTTCTAGAGGGGTTGTCAGGGAAAGAAATTGCTTTTT Single Nucleotide Polymorphisms (SNPs) 1 / 300 bases Manolio 11/20/08

  9. } } One Tag SNP May Serve as Proxy for Many Block 1 Block 2 SNP1 ↓ SNP2 ↓ SNP3 ↓ SNP4 ↓ SNP5 ↓ SNP6 ↓ SNP7 ↓ SNP8 ↓ CAGATCGCTGGATGAATCGCATCTGTAAGCAT CGGATTGCTGCATGGATCGCATCTGTAAGCAC CAGATCGCTGGATGAATCGCATCTGTAAGCAT CAGATCGCTGGATGAATCCCATCAGTACGCAT CGGATTGCTGCATGGATCCCATCAGTACGCAT CGGATTGCTGCATGGATCCCATCAGTACGCAC

  10. } } Block 1 Block 2 One Tag SNP May Serve as Proxy for Many SNP6 ↓ SNP7 ↓ SNP8 ↓ SNP1 ↓ SNP2 ↓ SNP3 ↓ SNP4 ↓ SNP5 ↓ CAGATCGCTGGATGAATCGCATCTGTAAGCAT CGGATTGCTGCATGGATCGCATCTGTAAGCAC CAGATCGCTGGATGAATCGCATCTGTAAGCAT CAGATCGCTGGATGAATCCCATCAGTACGCAT CGGATTGCTGCATGGATCCCATCAGTACGCAT CGGATTGCTGCATGGATCCCATCAGTACGCAC

  11. } } Block 1 Block 2 One Tag SNP May Serve as Proxy for Many SNP3 ↓ SNP6 ↓ SNP7 ↓ SNP5 ↓ SNP8 ↓ CAGATCGCTGGATGAATCGCATCTGTAAGCAT CGGATTGCTGCATGGATCGCATCTGTAAGCAC CAGATCGCTGGATGAATCGCATCTGTAAGCAT CAGATCGCTGGATGAATCCCATCAGTACGCAT CGGATTGCTGCATGGATCCCATCAGTACGCAT CGGATTGCTGCATGGATCCCATCAGTACGCAC

  12. } } One Tag SNP May Serve as Proxy for Many Block 1 Block 2 SNP8 ↓ SNP3 ↓ SNP6 ↓ CAGATCGCTGGATGAATCGCATCTGTAAGCAT CGGATTGCTGCATGGATCGCATCTGTAAGCAC CAGATCGCTGGATGAATCGCATCTGTAAGCAT CAGATCGCTGGATGAATCCCATCAGTACGCAT CGGATTGCTGCATGGATCCCATCAGTACGCAT CGGATTGCTGCATGGATCCCATCAGTACGCAC

  13. One Tag SNP May Serve as Proxy for Many Block 1 Block 2 Singleton Frequency GTT 35% CTC 30% GTT 10% GAT 8% CAT 7% CAC 6% other haplotypes 4% Manolio 11/20/08

  14. Biotin-DNA

  15. Each DNA probe represented more than 20 times Zimmer C., Sci Amer 299:68-75 (2008)

  16. Linkage Diagram Relationship among SNPS – “each to each other” Christensen, K. and Murray, JC, NEJM 356:1094-97 (2007)

  17. Distances Among East Coast Cities Manolio 11/20/08

  18. Distances Among East Coast Cities Manolio 11/20/08

  19. Distances Among East Coast Cities Manolio 11/20/08

  20. Provi- dence New York Phila- delphia Balti- more Wash- ington Boston Distances Among East Coast Cities Manolio 11/20/08

  21. Linkage Diagram Relationship among SNPS – “each to each other” Christensen, K. and Murray, JC, NEJM 356:1094-97 (2007)

  22. Method for interrogating all 10 million variable points across human genome (unprecedented level of resolution) • Variation inherited in groups, or blocks, so not all 10 million points have to be tested • 500,000 tag SNPs sufficient for GWS • Agnostic • Associations have been with genes not previously suspected of association with disease • Some associations in regions not even known to harbor genes What is a Genome-Wide Association Study?

  23. GWAS: 4 Parts • Select individuals with disease or trait and a suitable comparison group • Isolate DNA and genotype • Statistical tests for associations • Replicate in an independent population

  24. Statistical Issues Same test 1 million times, setting cut-off critical P<.05 for 1 million SNPs 50,000 associations by chance alone Bonferroni correction P<.05/106, or 5x10-8

  25. TNFAIP3 on 6q23 associated with SLE Graham, RR et al Nat Genet 2008

  26. SNP = Causal Variant • A SNP can “tag along” with the actual causal variant • DNA sequencing in the region often required to identify the change causing disease • Functional studies then required

  27. Association of Alleles and Genotypes of rs1333049 with Myocardial Infarction Samani N et al, N Engl J Med 2007; 357:443-53.

  28. Association of Alleles and Genotypes of rs1333049 with Myocardial Infarction Samani N et al, N Engl J Med 2007; 357:443-53.

  29. Chanock S, Manolio T, et al., Nature 2007; 447:655-60.

  30. Replication, Replication, Replication Initial study: Sufficient description to permit replication • Sources of cases and controls • Participation rates and flow chart of selection • Methods for assessing affected status • Standard “Table 1” including rates of missing data • Assessment of population heterogeneity • Genotyping methods and QC metrics Replication study: • Similar population, similar phenotype • Same genetic model, same SNP, same direction • Adequately powered to detect postulated effect Chanock S, Manolio T, et al., Nature 2007; 447:655-60.

  31. Examples of Multistage Designs in Genome-wide Association Studies Pearson, T. A. et al. JAMA 2008;299:1335-1344.

  32. Replication Strategy in Easton Breast Cancer Study Easton et al, Nature 2007; 447:1087-93.

  33. Replication Strategy in Easton Breast Cancer Study Easton et al, Nature 2007; 447:1087-93.

  34. Replication Strategy in Easton Breast Cancer Study Easton et al, Nature 2007; 447:1087-93.

  35. Replication Strategy in Easton Breast Cancer Study • ABCFS • BCST • COPS • GENICA • HBCS • HBCP • TBCS • KConFab/AOCS • KBCP • LUMCBCS • MCBCS • MCCS • MEC-W • MEC-J • NHS • PBCS • RBCS • SASBAC • SEARCH2 • SEARCH3 • SBCP • SBCS • CNIOBCS • USRT Easton et al, Nature 2007; 447:1087-93.

  36. Publisher GWA Reports, 3/2005 - 9/2008 191 Total Number of Publications Calendar Quarter Manolio 11/20/08

  37. Wellcome Trust Genome-Wide Association Study of Seven Common Diseases WTCCC, Nature 2007; 447:661-678.

  38. 2007: The Year of GWA Studies Pennisi E, Science 2007; 318:1842-43.

  39. Macular Degeneration • Exfoliation Glaucoma • Lung Cancer • Prostate Cancer • Breast Cancer • Colorectal Cancer • Bladder Cancer • Neuroblastoma • Melanoma • TP53 Cancer Predisposing • Chr. Lymph. Leukemia • Inflamm. Bowel Disease • Celiac Disease • Gallstones • Irritable Bowel Syndrome • QT Prolongation • Coronary Disease • Coronary Spasm • Atrial Fibrillation/Flutter • Stroke • Subarachnoid Hemorrhage • Intracranial Aneurysm • Hypertension • Hypt. Diuretic Response • Peripheral Artery Disease • Lipids and Lipoproteins • Warfarin Dosing • Ximelegatran Adv. Resp. • Parkinson Disease • Amyotrophic Lat. Sclerosis • Multiple Sclerosis • MS Interferon-β Response • Prog. Supranuclear Palsy • Alzheimer’s Disease in ε4+ • Cognitive Ability • Memory • Hearing • Restless Legs Syndrome • Nicotine Dependence • Methamphetamine Depend. • Neuroticism • Schizophrenia • Sz. Iloperidone Response • Bipolar Disorder • Family Chaos • Narcolepsy • Attention Deficit Hyperactivity • Personality Traits • Rheumatoid Arthritis • RA Anti-TNF Response • Syst. Lupus Erythematosus • Sarcoidosis • Pulmonary Fibrosis • Psoriasis • HIV Viral Setpoint • Childhood Asthma • Type 1 Diabetes • Type 2 Diabetes • Diabetic Nephropathy • End-St. Renal Disease • Obesity, BMI, Waist, IR • Height • Osteoporosis • Osteoarthritis • Male Pattern Baldness • F-Cell Distribution • Fetal Hgb Levels • C-Reactive Protein • ICAM-1 • Total IgE Levels • Uric Acid Levels, Gout • Protein Levels • Vitamin B12 Levels • Recombination Rate • Pigmentation Diseases and Traits with Published GWA Studies (n = 76, 11/17/08)

  40. NHGRI Catalog of GWA Studies: http://www.genome.gov/gwastudies/ Manolio 11/20/08

  41. Functional Classification of 782 Index SNPs Associated with Complex Traits 37 11 340 2 11 6 22 20 354 0 10 20 30 40 50 60 Percent Manolio 11/20/08

  42. Odds Ratios of Discrete Associations Median = 1.28 // // 3 4 5 6 9 13 20 30 Manolio 11/20/08

  43. Odds Ratios of Discrete Associations // // 3 4 5 6 9 13 20 30 Manolio 11/20/08

  44. Reported Risk Allele Frequencies by Odds Ratios for Discrete Traits 30 25 20 15 10 5 4 3 2 1 Sarasquete Osteonecrosis Thorlieifsson Exfoliation Glaucoma Hakonarson Type 1 DM van Heel Celiac Disease WTCCC Type 1 DM Manolio 11/20/08

  45. Lessons Learned from Initial GWA Studies Manolio 11/20/08

  46. Lessons Learned from Initial GWA Studies Manolio 11/20/08

  47. Lessons Learned from Initial GWA Studies Manolio 11/20/08

  48. Lessons Learned from Initial GWA Studies Manolio 11/20/08

  49. Lessons Learned from Initial GWA Studies Manolio 11/20/08

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