BioVision Alexandria 2010

Linking Genes to Disease:Leveraging the Human Genome

Doug BrutlagProfessor 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 symptomso Treating symptoms most often exacerbates diseaseo Treating the cause cures the diseaseo Knowing a predisposition, one can often prevent the

disease

• Genomics can identify the cause and predisposition to inherited diseases and many infectious diseaseso “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 medicineo One targets the cause of disease rather than symptoms

Online Mendelian Inheritance in Man: OMIM

http://www.ncbi.nlm.nih.gov/omim/

}67% Genes

}33% Phenotypes

Online Mendelian Inheritance in Man: OMIM

http://www.ncbi.nlm.nih.gov/omim/

Genetic Penetrance of Inherited Diseases

• Many Inherited Diseases are Rare, Mendelian and Highly Penetranto Sickle Cell Anemiao Thalassemiaso Huntington’s Diseaseo Color Blindness

• Most Common Diseases are Complex (caused by multiple genes or multiple pathways) and of Low Penetranceo Familialo Predisposition to Diseaseo Very Large Environmental and Behavioral Componento Many Complex Diseases can be Avoided with Diet,

Nutrition, Exercise or Behavioral Modificationo Many Complex Diseases can also be Monitored by

Increased Vigilance

Common Gene VariationAssociated 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

PhenotypePeptic ulcerIDDM*Alzheimer dementiaDeep venous thrombosis*Falciparum malaria*AIDS*Colorectal cancer*NIDDM*

Variant B DR3,4 E4 Leiden βS

Δ32 3920A 12A

© Gibson & Muse, A Primer of Genome Science

2007 Scientific Breakthrough of the Year

Genome-Wide Association StudiesUsing 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 PopulationSNP chip Expression

andcDNA Levels

Courtesy of Daniel Newburger

AA AG GG

The Wellcome Trust Case Control Consortium Genome-wide association study of 14,000 cases

ofseven common diseases and 3,000 shared

controlsNature 447, 661-678 (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 Catalogwww.genome.gov/GWAStudies

Study Designs in Genome-Wide Association Studies

• Genome-Wide Association Studies Make No Assumptions about Disease Mechanism or Cause

• Case-Control Populationso Homogeneity of Cases and Controlso Population Stratificationo Accurate Diagnosis of the Diseaseo Optimal for Rare Diseaseso Biased Towards Most Prevalent Form of Disease

• Cohorts in a Medical Studyo Better Characterized than Populationso Can focus on Subpopulations and Ethnic Subgroups

• Families and Trioso Highest Genetic Homogeneityo Most Sensitive to Genotyping Errors

Pearson, T. A. et al. JAMA 2008;299:1335-1344

Do genetic differences between ethnic groups contribute to differences in fatty

liver disease? Normal Steatosis Steatohepatitis Cirrhosis

10-20%

1-2%

HispanicsEuropean-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 10-10

Chromosome

5.4 x 10-6

© Helen 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) Variationso High Numbers of Genetic Subpopulations due to

Multiple Migrations and Invasionso 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, 747-753 (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 Indicateo Genes and Regions to Analyze by Resequencing for Causal Alleleso Subpopulations That May be Enriched for Causal or Preventive Alleleso Genes and Gene Products for Functional and Structural Studieso Genes to Examine for Regulatory Studies

• Genome-Wide Association Studies Coupled with Proper Biological and Structural Studies can Lead to:o Unexpected Causes for Diseaseo Novel Mechanisms for Disease (missense mutations, regulatory changes,

alternative splicing, copy number variation etc.)o Multiple Pathways and Multiple Genes Involved in Diseaseo Novel Diagnostics and Prognosiso Novel Treatments

Thank You!