BioVision Alexandria 2010 Linking Genes to Disease: Leveraging the Human Genome Doug Brutlag Professor Emeritus Biochemistry & Medicine (by courtesy)

Preventive Medicine Courtesy of James Liao, Harvard Medical School

The Case for Preventive Medicine Treats the cause of the disease rather than treating the symptoms o Treating symptoms most often exacerbates disease o Treating the cause cures the disease o Knowing a predisposition, one can often prevent the disease Genomics can identify the cause and predisposition to inherited diseases and many infectious diseases o “All medicine may soon become pediatrics” o Paul Wise, Professor of Pediatrics, Stanford Medical School Effects of environment, behavior, accidents, aging, etc. Health care costs can be greatly reduced if o One invests in preventive medicine o One targets the cause of disease rather than symptoms

Online Mendelian Inheritance in Man: OMIM

} 67 % Genes } 33% Phenotypes Online Mendelian Inheritance in Man: OMIM

Genetic Penetrance of Inherited Diseases Many Inherited Diseases are Rare, Mendelian and Highly Penetrant o Sickle Cell Anemia o Thalassemias o Huntington’s Disease o Color Blindness Most Common Diseases are Complex (caused by multiple genes or multiple pathways) and of Low Penetrance o Familial o Predisposition to Disease o Very Large Environmental and Behavioral Component o Many Complex Diseases can be Avoided with Diet, Nutrition, Exercise or Behavioral Modification o Many Complex Diseases can also be Monitored by Increased Vigilance

Common Gene Variation Associated With Disease Case-control studies, comparing the frequencies of common gene variants can identify susceptibility and protective alleles. Many have multiple identified genes (*) Gene ABO HLA APOE F5 HBB CCR5 APC PPARγ Phenotype Peptic ulcer IDDM* Alzheimer dementia Deep venous thrombosis* Falciparum malaria* AIDS* Colorectal cancer* NIDDM* Variant B DR3,4 E4 Leiden β S Δ A 12A © Gibson & Muse, A Primer of Genome Science

2007 Scientific Breakthrough of the Year

Genome-Wide Association Studies Using SNPs to Link Genes to Disease © Gibson & Muse, A Primer of Genome Science

Genome-Wide Association Study: A Brief Primer WTCCC, Nature 2007 Control Population Disease Population SNP chip Courtesy of Daniel Newburger

Expression Quantitative Trait Loci (eQTLs) A Quantitative Gene-Expression Association Modified from WTCCC, Nature 2007 Sample Population SNP chipExpression and cDNA Levels Courtesy of Daniel Newburger AAAGGG

The Wellcome Trust Case Control Consortium Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls Nature 447, (7 June 2007)

Hokusai, K. The Great Wave The Great Wave of GWAS Studies

Published Genome-Wide Associations through 12/2009, 658 published GWA at p<5x10 -8 NHGRI GWA Catalog

Study Designs in Genome-Wide Association Studies Genome-Wide Association Studies Make No Assumptions about Disease Mechanism or Cause Case-Control Populations o Homogeneity of Cases and Controls o Population Stratification o Accurate Diagnosis of the Disease o Optimal for Rare Diseases o Biased Towards Most Prevalent Form of Disease Cohorts in a Medical Study o Better Characterized than Populations o Can focus on Subpopulations and Ethnic Subgroups Families and Trios o Highest Genetic Homogeneity o Most Sensitive to Genotyping Errors Pearson, T. A. et al. JAMA 2008;299:

Do genetic differences between ethnic groups contribute to differences in fatty liver disease? NormalSteatosisSteatohepatitis Cirrhosis 10-20% 1-2% Hispanics European-Americans African-Americans © Helen Hobbs 2009 First Hit Obesity Type 2 diabetes Ethanol Hepatitis C Second Hit Oxidative Stress Lipid Peroxidation Anti-virals Cytokines

Genome-wide Association Study of Liver Triglyceride Levels in Dallas Heart Study Cohort (2,111 patients and 9,299 Non-synonymous SNPs) P=5.9 X Chromosome 5.4 x © Helen Hobbs, Nature Genetics V40, pp 1461, 2008Helen Hobbs, Nature Genetics V40, pp 1461, 2008

Mito PNPLA2 (ATGL) VLDL + Remnants Acetyl CoA PNPLA3 & Hepatic Triglyceride Metabolism Liver Adipose Tissue PNPLA3 (Adiponutrin) Fasting Feeding © Helen Hobbs 2009

Ser47 Asp166 Ile148 Met148 I148M & Catalytic Dyad of PNPLA3 Ser47 Asp166 © Helen Hobbs 2009

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 Egypt is a Haplotype Heaven! o Highest Frequency of Genetic (SNP) Variations o High Numbers of Genetic Subpopulations due to Multiple Migrations and Invasions o Greeks, Romans, Turks, Persians etc.

Low Heritability of Common SNPs Common SNPs Carry Low Risk While Rarer High Penetrance Variants Carry High 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 Manolio et al. Nature 461, (2009)

Summary Genome-Wide Association Studies Make No Assumptions About Disease Mechanism or Cause Genome-Wide Association Studies Usually Discover Only Genetic Correlations, Not Cause Genome-Wide Associations Indicate o Genes and Regions to Analyze by Resequencing for Causal Alleles o Subpopulations That May be Enriched for Causal or Preventive Alleles o Genes and Gene Products for Functional and Structural Studies o Genes to Examine for Regulatory Studies Genome-Wide Association Studies Coupled with Proper Biological and Structural Studies can Lead to: o Unexpected Causes for Disease o Novel Mechanisms for Disease (missense mutations, regulatory changes, alternative splicing, copy number variation etc.) o Multiple Pathways and Multiple Genes Involved in Disease o Novel Diagnostics and Prognosis o Novel Treatments

Thank You!