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Genome-Wide Association (GWA) Studies

Genome-Wide Association (GWA) Studies. 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 (GWA) Studies

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  1. Genome-Wide Association (GWA) Studies 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.Senior Advisor to the Director, NHGRI, for Population Genomics Director, Office of Population Genomics U.S. Department of Health and Human Services

  2. There’s a revolution going on… Williard, AM. Spirit of ‘76

  3. There’s a revolution going on… • Technologic advances now allow us to measure hundreds of thousands of variable points across human genome • Relatively low cost • Relatively little DNA • Can be applied to unrelated individuals studied over years or decades • Can identify multitude of subtle genetic effects increasing risk of “complex” disease Williard, AM. Spirit of ‘76

  4. What is a GWA 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 ~10,000 base pair lengths in common (300,000 - 500,000 markers)

  5. Mapping the Relationships Among SNPs Christensen and Murray, N Engl J Med 2007; 356:1094-1097.

  6. One SNP May Serve as Proxy for Many Christensen and Murray, N Engl J Med 2007; 356:1094-1097.

  7. 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

  8. 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

  9. Intensity Data for Three Combinations of Two Alleles Courtesy, K. Doheny, Johns Hopkins

  10. GWA Genotyping Data, Chromosome 22, Parkinson’s Study http://ccr.coriell.org/ninds/

  11. Association of rs2236639 Alleles with Development of Parkinson Disease (Made Up!)

  12. Measures of Association: The Odds Ratio • Odds are related to probability: odds = p/(1-p) • If probability of horse winning race is 50%, odds are 1/1 • If probability of horse winning race is 25%, odds are 1/3 for win or 3 to 1 against win • If probability of exposed person getting disease is 25%, odds = p/(1-p) = 25/75 = 1/3 • When don’t have denominators for risk estimates, can calculate odds ratio = cross-product ratio (“ad/bc”); computationally easier • If disease is rare, odds ratio approximates relative risk but always overestimates effect

  13. Association of rsxxxx3207 Alleles with Occurrence of Myocardial Infarction Helgadottir et al, Sciencexpress 3 May 2007.

  14. Association of rsxxxx3207 Alleles with Occurrence of Myocardial Infarction Embargoed until May 3, 2007 Helgadottir et al, Sciencexpress 3 May 2007.

  15. This is a tsunami of data… Hokusai, K. The Great Wave

  16. This is a tsunami of data… • New approaches needed for accessing, manipulating, visualizing • Requires entirely new perspective • Recognize potential for differences to be observed by chance alone Hokusai, K. The Great Wave

  17. A Few Epidemiologic Definitions

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

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

  20. P-values for 8q24 SNPs Most Strongly Associated with Prostate Cancer Haiman et al, Nat Genet 2007; 39:638-44.

  21. P-values for Chromosome 11 SNPs Most Strongly Associated with Diabetes Scott et al, Sciencexpress 26 April 2007.

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

  23. Aspects of GWA Studies that Make Data Sharing Crucial • Expensive, generate many “false positives” • Replication held as sine qua non of valid association • Large sample sizes and multiple studies needed to replicate findings • Massive data sets, analysis requires huge and specialized effort • Better analytic methods needed • Once genome is measured can be related to just about anything

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

  25. The revolution is here… Williard, AM. Spirit of ‘76

  26. The revolution is here… • Extensive characterization of individual person’s genome now feasible • Can be applied to unrelated individuals • Many existing studies have carefully characterized thousands of persons • New approaches to manipulating and interpreting data needed • Responsible and widespread data sharing key to fully exploring GWA datasets • Collaboration for replication and functional determination is crucial Williard, AM. Spirit of ‘76

  27. Measures of Public Health Impact: Population Attributable Risk • Measures the proportion of disease that would be eliminated if particular causal factor were eliminated • Directly related to prevalence of risk factor and risk it conveys • Almost always over-estimates proportion attributable to risk factor

  28. GWA Genotyping Data, Chromosome 22, Parkinson’s Study http://ccr.coriell.org/ninds/

  29. GWA Genotyping Data, Chromosome 22, One Person 412 1 T C G G G G A A A A C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T …

  30. Chromosome 22, One Person, Continued …G A A A A C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T TC C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T …

  31. Chromosome 22, One Person, Continued… …A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T TC C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T C C A A A A T C A G C C T C …

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