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Genome-Wide Association Studies: Hunting for Genes in the New Millennium

Genome-Wide Association Studies: Hunting for Genes in the New Millennium. National Human Genome Research Institute. U.S. Department of Health and Human Services National Institutes of Health National Human Genome Research Institute. National Institutes of Health.

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Genome-Wide Association Studies: Hunting for Genes in the New Millennium

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  1. Genome-Wide Association Studies: Hunting for Genes in the New Millennium National Human Genome Research Institute U.S. Department of Health and Human Services National Institutes of Health National Human Genome Research Institute National Institutes of Health Teri A. Manolio, M.D., Ph.D.Director, Office of Population Genomics Senior Advisor to the Director, NHGRI, for Population Genomics November 20, 2008 U.S. Department of Health and Human Services

  2. We Live in Interesting Times… “‘May he live in interesting times.’ Like it or not we live in interesting times.” --Robert Kennedy, June 7, 1966 May you come to the attention of those in authority. May you find what you are looking for. Wikipedia, accessed 11Sep07

  3. 2008 first quarter 2007 second quarter 2007 third quarter 2006 2005 2008 second quarter 2008 third quarter 2007 fourth quarter 2007 first quarter Manolio, Brooks, Collins, J. Clin. Invest., May 2008

  4. 2007: The Year of GWA Studies Pennisi E, Science 2007; 318:1842-43.

  5. Macular Degeneration • Exfoliation Glaucoma • Lung Cancer • Prostate Cancer • Breast Cancer • Colorectal Cancer • Bladder Cancer • Neuroblastoma • Melanoma • TP53 Cancer Predispos’n • 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)

  6. “There have been few, if any, similar bursts of discovery in the history of medical research…” Hunter DJ and Kraft P, N Engl J Med 2007; 357:436-439.

  7. What is a Genome-Wide Association Study? • Method for interrogating all 10 million variable points across human genome • Variation inherited in groups, or blocks, so not all 10 million points have to be tested • Blocks are shorter (so need to test more points) the less closely people are related • Technology now allows studies in unrelated persons, assuming 5,000 – 10,000 base pair lengths in common (300,000 – 1,000,000 markers)

  8. DNA on Chromosome 7 GAAATAATTAATGTTTTCCTTCCTTCTCCTATTTTGTCCTTTACTTCAATTTATTTATTTATTATTAATATTATTATTTTTTGAGACGGAGTTTC/ACTCTTGTTGCCAACCTGGAGTGCAGTGGCGTGATCTCAGCTCACTGCACACTCCGCTTTCCTGGTTTCAAGCGATTCTCCTGCCTCAGCCTCCTGAGTAGCTGGGACTACAGTCACACACCACCACGCCCGGCTAATTTTTGTATTTTTAGTAGAGTTGGGGTTTCACCATGTTGGCCAGACTGGTCTCGAACTCCTGACCTTGTGATCCGCCAGCCTCTGCCTCCCAAAGAGCTGGGATTACAGGCGTGAGCCACCGCGCTCGGCCCTTTGCATCAATTTCTACAGCTTGTTTTCTTTGCCTGGACTTTACAAGTCTTACCTTGTTCTGCC/TTCAGATATTTGTGTGGTCTCATTCTGGTGTGCCAGTAGCTAAAAATCCATGATTTGCTCTCATCCCACTCCTGTTGTTCATCTCCTCTTATCTGGGGTCACA/CTATCTCTTCGTGATTGCATTCTGATCCCCAGTACTTAGCATGTGCGTAACAACTCTGCCTCTGCTTTCCCAGGCTGTTGATGGGGTGCTGTTCATGCCTCAGAAAAATGCATTGTAAGTTAAATTATTAAAGATTTTAAATATAGGAAAAAAGTAAGCAAACATAAGGAACAAAAAGGAAAGAACATGTATTCTAATCCATTATTTATTATACAATTAAGAAATTTGGAAACTTTAGATTACACTGCTTTTAGAGATGGAGATGTAGTAAGTCTTTTACTCTTTACAAAATACATGTGTTAGCAATTTTGGGAAGAATAGTAACTCACCCGAACAGTG/TAATGTGAATATGTCACTTACTAGAGGAAAGAAGGCACTTGAAAAACATCTCTAAACCGTATAAAAACAATTACATCATAATGATGAAAACCCAAGGAATTTTTTTAGAAAACATTACCAGGGCTAATAACAAAGTAGAGCCACATGTCATTTATCTTCCCTTTGTGTCTGTGTGAGAATTCTAGAGTTATATTTGTACATAGCATGGAAAAATGAGAGGCTAGTTTATCAACTAGTTCATTTTTAAAAGTCTAACACATCCTAGGTATAGGTGAACTGTCCTCCTGCCAATGTATTGCACATTTGTGCCCAGATCCAGCATAGGGTATGTTTGCCATTTACAAACGTTTATGTCTTAAGAGAGGAAATATGAAGAGCAAAACAGTGCATGCTGGAGAGAGAAAGCTGATACAAATATAAAT/GAAACAATAATTGGAAAAATTGAGAAACTACTCATTTTCTAAATTACTCATGTATTTTCCTAGAATTTAAGTCTTTTAATTTTTGATAAATCCCAATGTGAGACAAGATAAGTATTAGTGATGGTATGAGTAATTAATATCTGTTATATAATATTCATTTTCATAGTGGAAGAAATAAAATAAAGGTTGTGATGATTGTTGATTATTTTTTCTAGAGGGGTTGTCAGGGAAAGAAATTGCTTTTT SNPs 1 / 300 bases

  9. Mapping the Relationships Among SNPs Christensen and Murray, N Engl J Med 2007; 356:1094-97.

  10. Chromosome 9p21 Region Associated with MI Samani N et al, N Engl J Med 2007; 357:443-453.

  11. Distances Among East Coast Cities

  12. Distances Among East Coast Cities

  13. Distances Among East Coast Cities

  14. Provi- dence New York Phila- delphia Balti- more Wash- ington Boston Distances Among East Coast Cities

  15. Distances Among East Coast Cities

  16. Mapping the Relationships Among SNPs Christensen and Murray, N Engl J Med 2007; 356:1094-97.

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

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

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

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

  21. 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%

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

  23. A HapMap for More Efficient Association Studies: Goals • Use just the density of SNPs needed to find associations between SNPs and diseases • Do not miss chromosomal regions with disease association • Produce a tool to assist in finding genes affecting health and disease • Use more SNPs for complete genome coverage of populations of recent African ancestry populations due to shorter LD

  24. Progress in Genotyping Technology 102 ABI TaqMan ABI SNPlex 10 Cost per genotype (Cents, USD) Illumina Golden Gate Affymetrix MegAllele Affymetrix 10K Illumina Infinium/Sentrix Perlegen 1 Affymetrix 100K/500K Nb of SNPs 1 10 102 103 104 105 106 2001 2005 Courtesy S. Chanock, NCI

  25. Continued Progress in Genotyping Technology Affymetrix 500K Illumina 550K Illumina 650Y Illumina 317K Cost per person (USD) July 2005 Oct 2006 Courtesy S. Gabriel, Broad/MIT

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

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

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

  29. Nicotine Dependence among Smokers Bierut LJ et al, Hum Molec Genet 2007; 16:24-35.

  30. Genome-Wide Scan for Type 2 Diabetes in a Scandinavian Cohort http://www.broad.mit.edu/diabetes/scandinavs/type2.html

  31. Genome-Wide Scan for Crohn Disease in Belgian Cases and Controls Libioulle C et al, PLoS Genet; 2007 Apr 20;3(4):e58.

  32. Genome-Wide Scan for Type 2 Diabetes in French Case-Control Study Sladek R et al, Nature 2007; 445, 881-885.

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

  34. Genome-Wide Scan for Breast Cancer in Postmenopausal Women Hunter DJ et al, Nat Genet 2007; 39:870-874.

  35. -Log10 P Values for SNP Associations with Myocardial Infarction Samani N et al., N Engl J Med 2007; 357:443-53.

  36. Association Signal for Coronary Artery Disease on Chromosome 9 Samani N et al., N Engl J Med 2007; 357:443-53.

  37. Region of Chromosome 1 Showing Strong Association with Inflammatory Bowel Disease Duerr R et al., Science 2006; 314:1461-63.

  38. Unique Aspects of GWA Studies • Permit examination of inherited genetic variability at unprecedented level of resolution • Permit "agnostic" genome-wide evaluation • Once genome measured, can be related to any trait • Most robust associations in GWA studies have not been with genes previously suspected of association with the disease • Some associations in regions not even known to harbor genes “The chief strength of the new approach also contains its chief problem: with more than 500,000 comparisons per study, the potential for false positive results is unprecedented.” Hunter DJ and Kraft P,N Engl J Med 2007; 357:436-439.

  39. Larson, G. The Complete Far Side. 2003.

  40. Number of New, Significant Gene-Disease Associations by Year, 1984 - 2000 Hirschhorn J et al, Genet Med 2002; 4:45-61.

  41. Of 600 Gene-Disease Associations, Only 6 Significant in > 75% of Identified Studies Hirschhorn J et al., Genet Med 2002; 4:45-61.

  42. Reports For and Against Associations of Variants with Carotid Atherosclerosis Manolio et al., ATVB 2004; 24:1567-77.

  43. May 1999 Am J Hum Genet July 2004 Nat Genet July 2006 Am J Hum Genet July 2004 J. Hirschhorn and D. Altshuler J Clin Endo Metab 2002 PLoS Biol Sept 2005

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

  45. 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.

  46. Replication Strategy for Prostate Cancer Study in CGEMS Initial Study 1,150 cases / 1,150 controls >500,000 Tag SNPs Replication Study #1 3,000 cases / 3,000 controls ~24,000 SNPs Replication Study #2 2,400 cases / 2,400 controls ~1,500 SNPs 200+ New ht-SNPs Replication Study #3 2,500 cases / 2,500 controls 25-50 Loci Hoover R, Epidemiology 2007; 18:13-17.

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

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

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

  50. 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.

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