Doug Brutlag 2011 Genomics & Medicine Doug Brutlag Professor Emeritus of Biochemistry & Medicine Stanford University School of Medicine Personal Genomics The Lancet 2010, 375:

Doug Brutlag 2011 Low Heritability of Common SNPs Rare High Penetrance Variants Carry High Risk Common SNPs Carry Low Risk Multiple Variants May Increase Risk Synergistically Common SNPs Associated with Genes Containing High Risk Alleles Common SNPs Associations can Suggest Regions to Sequence in Cohorts or Trios or Subpopulations Manolio et al. Nature 461, (2009) Odds Ratio

Doug Brutlag 2011 Disease Genes are Often Enriched in Subpopulations Subpopulations are often enriched for disease alleles Subpopulations can cause synthetic SNP associations Focusing on a subpopulations will eliminate synthetic SNP associations Focusing on subpopulations eliminates need for population stratification adjustments Egypt is a haplotype heaven! –Highest frequency of genetic (SNP) variations –High numbers of genetic subpopulations due to multiple migrations and invasions –Greeks, Romans, Turks, Persians etc.

Doug Brutlag 2011 Summary of Genome-Wide Association Studies Genome-wide association studies make no assumptions about disease mechanism or cause Genome-wide association studies usually discover only genetic correlations, not causal mutations Genome-wide associations suggest: –Genes and regions one must analyze by re-sequencing for causal alleles –Subpopulations that may be enriched for causal or preventive alleles –Genes and gene products for functional and structural studies –Genes to examine for regulatory studies Genome-wide association studies coupled with proper biological and structural studies can lead to: –Unexpected causes for disease –Novel mechanisms for disease (missense mutations, regulatory changes, alternative splicing, copy number variation etc.) –Multiple genes and multiple pathways involved in disease –Novel diagnostics and prognosis –Novel treatments

Doug Brutlag 2011 Genetic Loci Associated with Hypertriglyceridemia

Doug Brutlag 2011 Novel Rare Variants in GWAS Genes for Hypertriglyceridemia

Doug Brutlag 2011 Rare Variant Accumulation in Hypertriglyceridemia

Doug Brutlag 2011 So What Can We Learn from Personal Genomics? Disease risk for common diseases –Genetic predisposition towards a disease (relative risk or odds ratio) –Genetic versus environmental contributions to disease (penetrance) –How to alter your environment and behavior to avoid the disease Disease Carrier status –Premarital genetic counseling –Preimplantation genetic diagnosis –Neonatal diagnosis Amniocentesis Chorion villus sampling (CVS) Fetal cells in pregnant mothers blood Familial traits, diseases and relationships –Known family diseases (breast cancers, colorectal cancer, lysosome storage diseases, etc.) –Paternity (10% of people do not know their true biological father) –Maternity (about 1% of people do not know their true biological mother) –Inbreeding and incest lead to increased homozygosity and recessive diseases –Orphans can find family relations Pharmacogenomics and Pharmacogenetics: Drug susceptibility –Efficacy of common drugs –Adverse reactions to common drugs Ancestry –One can follow maternal line using mitochondrial DNA SNPs –Males can follow paternal line using Y chromosome SNPs –Shared haplotypes with recent relatives (up to 5 th cousins)

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Doug Brutlag 2011 Choice of GWAS Studies Common traits of broad interest –Prevalence of > 1% –Report Mendelian traits when possible –Focus on drug responses Avoid false discoveries –Large case-control studies > 750 cases –Highly significant expectation values (<0.01 errors) –Published in reputable journals –Studies that have been replicated May impute highly linked missing SNPs Calculate likelihood and odds ratio using customers ethnicity as detected Distinguish preliminary studies (non-replicated or smaller sample sizes) from established research.

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Doug Brutlag 2011 Clopidogrel (Plavix®) Efficacy

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Doug Brutlag andMe Maternal Inheritance

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Doug Brutlag 2011 What is a Fifth CousinWhat is a Fifth Cousin?

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Doug Brutlag 2011 INFORMED Medical Decisions

Doug Brutlag 2011 INFORMED for 23andMe Customers

Doug Brutlag 2011 Navigenics

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Doug Brutlag 2011 Navigenics

Doug Brutlag 2011 Navigenics

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Doug Brutlag 2011 Navigenics

Doug Brutlag 2011 Navigenics

Doug Brutlag 2011 Navigenics

Doug Brutlag 2011 Navigenics

Doug Brutlag 2011 Navigenics Compass Program

Doug Brutlag 2011 Navigenics Conditions Covered

Doug Brutlag 2011 DNAdirect: Clinical Genetic Testing

Doug Brutlag 2011 DNAdirect: Clinical Genetic Testing

Doug Brutlag 2011 Personal Genomics References Clinical Assessment Incorporating a Personal Genome. Ashley, E. et al. (2010) Lancet 375, Emerging genomic applications in coronary artery disease. Damani SB, Topal EJ, JACC Cardiovasc. Intervention (2011). 4: Topal EJ, JACC Cardiovasc. Intervention (2011). 4: Clinical applicability of sequence variations in genes related to drug metabolism. Stojiljkovic M, Patrinos GP, Pavlovic S. (2011) Curr Drug Metab. 1;12(5): Clinical pharmacogenetics and potential application in personalized medicine. Zhou et al., (2008) Curr Drug Metab. 9(8): Genes, mutations, and human inherited disease at the dawn of the age of personalized genomics. Cooper et al (2010) Hum Mutat. 31(6):631-55personalized genomics. Cooper et al (2010) Hum Mutat. 31(6): Web-based, participant-driven studies yield novel genetic associations for common traits. Eriksson et al. (2010) PLoS Genetics 6, e