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Association of Human DNA Variation with Complex Traits

Association of Human DNA Variation with Complex Traits. David R. Cox M.D., Ph.D. Chief Scientific Officer Perlegen Sciences Inc. david_cox@perlegen.com. Genes, through the proteins they encode, interact with challenges from the environment.

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Association of Human DNA Variation with Complex Traits

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  1. Association of Human DNA Variation with Complex Traits David R. Cox M.D., Ph.D. Chief Scientific Officer Perlegen Sciences Inc. david_cox@perlegen.com

  2. Genes, through the proteins they encode, interact with challenges from the environment

  3. Whole-Genome Patterns of Common Human DNA Variation Have Been Characterized 18 February 2005 …………………………..February, 2005 27 October 2005 ……………..October, 2005

  4. Genetic Association Cases- drug toxicity Controls- no toxicity 40% Green and 60% red 50% Green and 50% red If a segment of the genome is “associated” with toxicity, cases will have a different SNP allele frequency than controls.

  5. Lessons Learned From SNP Association Studies To Date SNP associations can lead to novel biological insights It is not possible to predict the fraction of variation of a complex trait determined by a SNP prior to performing an association study The majority of SNP associations account for a small fraction trait variability

  6. Questions That Remain Unanswered What is the relative role of common versus rare genetic variation in complex human traits? What is the relative role of population specific versus global genetic variation in complex human traits? Which segments of the human genome play the most important role in human phenotype variation? Will genetic associations of modest effect have clinical utility?

  7. How will Genetic Knowledge Impact Health Outcomes and the Practice of Medicine?

  8. Automobiles Not formalized on large scale Mass produced Mass customized Personalized Individualize to small degree Timing Pre-1900 1900-1920 1920-1940 1940-present Basically never… Organization example • None • Rolls-Royce • Ford • General Motors • Rolls Royce Key person • Individuals • Rolls, CS Royce, FH • Henry Ford • Alfred Sloan • - Method of production • Ad-hoc methods • Job-shop • Line • Multiple-line • - Product example • Non-motorized vehicle • Silver Spirit • Model-T • Pontiac • - Visual While mass customization developed soon after mass production, personalization never occurred in auto industry

  9. Clothing Not formalized on large scale Individualized to small degree Mass produced Mass customized Personalized Timing Pre-history Pre-1850 1850-1940 1940-present 2000 (but it didn’t work out…) Organization example • None • Bespoke tailor • US Army • Major retailer • Levi Jeans Co. • IC3D • None • Davies & Son (1803) • Alexander, M (1850) • O’Brien, R & Shelton, WC (1941) Key person Product example • None • Bespoke suit • Civil War uniform • Levi’s personalized jeans • 1950 shirt Visual As with automobiles, apparel became mass customized relatively quickly but has also never become personalized on large scale

  10. Medicine Genetic knowledge will reclassify disease based on biological causality Individuals will receive “group” assignments based on this information

  11. What is the “right” phenotype to study?

  12. A Genome-Wide Association Study of Breast Cancer Douglas F Easton, Alison M Dunning, Karen Pooley, Paul DP Pharoah, Dennis Ballinger, Deborah Thompson, D Gareth Evans, Diana Eccles, Nazneen Rahman, Michael R Stratton, Julian Peto, Olivia Fletcher, David R. Cox, Bruce AJ Ponder, The Breast Cancer Association Consortium

  13. Low Frequency Germline Gene Mutations Associated with Increased Breast Cancer Risk High risk BRCA1, BRCA2 Two-fold risk CHEK2, ATM, BRIP1, and PALB2

  14. Phase I: 227,876 tag SNPs Female controls EPIC (age>50) (n=400) “High-risk” breast cancer cases (n=408) Compare genotype frequencies P<.05? Phase II: 13,023 SNPs 3,916 controls (EPIC) 3,990 breast cancers (ABC) P<.0001? Phase III: 30 SNPs 21,668 invasive breast cancers 20,973 controls (BCAC) 967 carcinoma in-situ cases Study Design

  15. Breast Cancer Association Consortium CNIO, Madrid : Roger Milne Gloria Ribas Ana Gonzalez Javier Benitez SASBAC: Per Hall, Sara Wedren, JJ Liu, Low Yin Lin Copenhagen BCS: Stig Bojesen, Borge Nordestgaard Leiden BCS: Rob Tollenaaer, C.E. Jacobi, J.G.M. Klijn, Peter Devilee Rotterdam BCS: Hanne Meijers-Hiejboer, André Unterlinden Sheffield BCS: Angie Cox Helsinki BCS: Heli Nevanlinna Kuopio BCS: Arto Mannermaa, Veli-Matti Kosma, Vesa Kataja, Jaana Hartikainen GENICA: Hiltrud BrauchHannover BCS: Thilo Dörk Polish BCS: Montse Garcia-Closas kConFab/AOCS: Georgia Chenevix-Trench, Mandy Spurdle, Jonathan Beesley, Xiaoqin Chen ABCFS: John Hopper, Margaret McCredie, Melissa Southey, Graham Giles MCCS: Graham Giles, Melissa Southey, John Hopper, Chris Schroen Nurses Health Study: David Hunter, Sue Hankinson, David Cox Mayo Clinic BCS: Fergus Couch, Ellen Goode, Janet Olson US Radiologic Technologists Study: Alice Sigurdson, Jeff Struewing Multi-ethnic Cohort: Chris Haiman Thailand/IARC: Paul Brennan Soeul Breast Cancer Study: Daehee Kang Taiwan Breast Cancer Study: Chen-Yang Shen

  16. Observed numbers of associations after stage 2 by level of significance, before and after adjustment for population stratification, and expected numbers under the null hypothesis of no association 1Adjusted for inflation of the test statistic by the genomic control method

  17. Five SNPs Selected for Stage 3 With Strong Evidence of Association 2 Minor allele frequency in Search (UK) study. Combined allele frequency from three Asian studies in italics

  18. Results for Five Loci from 22 Studies (21,668 cases/ 20,973 controls)

  19. Odds Ratios for Carcinoma in situ vs Controls

  20. Additive Genetic Variance Predicts A Subset of the Population At Increased Risk For An Adverse Response To Treatment 4 4 2 2 3 3 5 5 1 1 1 1 2 2 3 3 4 4 5 5

  21. Risk Stratifier High risk Risk Low risk

  22. A High Proportion of Women in the General Population Carry the FGFR2 Breast Cancer Risk Allele Copies of FGFR2 Risk Allele 210 14% 47% 39% 10.5% 6.7% 5.5% Frequency In UK Population Breast cancer Risk by age 70

  23. American Cancer Society Guidelinesfor Breast Screening with MRI as anAdjunct to Mammography Debbie Saslow, PhD; Carla Boetes, MD, PhD; Wylie Burke, MD, PhD; Steven Harms, MD; Martin O. Leach, PhD; Constance D. Lehman, MD, PhD; Elizabeth Morris, MD; Etta Pisano,MD; Mitchell Schnall, MD, PhD; Stephen Sener, MD; Robert A. Smith, PhD; Ellen Warner,MD; Martin Yaffe, PhD; Kimberly S. Andrews; Christy A. Russell, MD (for the American Cancer Society Breast Cancer Advisory Group) ABSTRACT New evidence on breast Magnetic Resonance Imaging (MRI) screening has become available since the American Cancer Society (ACS) last issued guidelines for the early detection of breast cancer in 2003. A guideline panel has reviewed this evidence and developed new recommendations for women at different defined levels of risk. Screening MRI is recommended for women with an approximately 20–25% or greater lifetime risk of breast cancer, including women with a strong family history of breast or ovarian cancer and women who were treated for Hodgkin disease. There are several risk subgroups for which the available data are insufficient to recommend for or against screening, including women with a personal history of breast cancer, carcinoma in situ, atypical hyperplasia, and extremely dense breasts on mammography. Diagnostic uses of MRI were not considered to be within the scope of this review. CA Cancer J Clin 2007;57:75–89.

  24. The Missing Piece An international network collecting long term treatment outcomes for a wide range of disorders Genetic association analysis using data collected by such a network would provide an important scientific body of knowledge that could be used to improve treatment efficacy and to reduce adverse treatment events in individual patients

  25. Prohibiting Genetic Discrimination Kathy L. Hudson Ph.D.

  26. The Enhancing Drug Safety and Innovation Act of 2007 Passed the US Senate with a vote of 93 to 1. Requires the FDA to link electronic health care database to answer questions about the safety of drugs on the market. Gives FDA the authority to require a drug company to conduct any post-approval study necessary to answer a question that the FDA’s own surveillance system will not answer

  27. Conclusions Rosiglitazone was associated with a significant increase in the risk of myocardial infarction and with an increase in the risk of death from cardiovascular causes that had borderline significance. Our study was limited by a lack of access to original source data, which would have enabled time-to-event analysis. Despite these limitations, patients and providers should consider the potential for serious adverse cardiovascular effects of treatment with rosiglitazone for type 2 diabetes. Online May 21, 2007 N ENGL J MED 10.1056/NEJMoa072761

  28. Conclusions Genetic knowledge can be used in conjunction with other risk factors to help individual patients and their physicans to choose between exisitng treatment options, thereby maximizing treatment efficacy and minimizing adverse events Large scale outcome studies, performed as an intergral component of the healthcare system, will be essential for the short term application of genetic knowledge to human health outcomes.

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