Transcript Linking Genes to Disease:Leveraging the Human Genome

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
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Treating symptoms most often exacerbates disease
Treating the cause cures the disease
Knowing a predisposition, one can often prevent the disease
• Genomics can identify the cause and predisposition to inherited
diseases and many infectious diseases
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“All medicine may soon become pediatrics”
Paul Wise, Professor of Pediatrics, Stanford Medical School
• Effects of environment, behavior, accidents, aging, etc.
• Health care costs can be greatly reduced if
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One invests in preventive medicine
One targets the cause of disease rather than symptoms
Online Mendelian Inheritance in Man: OMIM
http://www.ncbi.nlm.nih.gov/omim/
Online Mendelian Inheritance in Man: OMIM
http://www.ncbi.nlm.nih.gov/omim/
}
67% Genes
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33%
Phenotypes
Genetic Penetrance of Inherited Diseases
• Many Inherited Diseases are Rare, Mendelian and Highly
Penetrant
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Sickle Cell Anemia
Thalassemias
Huntington’s Disease
Color Blindness
• Most Common Diseases are Complex (caused by multiple
genes or multiple pathways) and of Low Penetrance
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Familial
Predisposition to Disease
Very Large Environmental and Behavioral Component
Many Complex Diseases can be Avoided with Diet, Nutrition,
Exercise or Behavioral Modification
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 (*)
Phenotype
Peptic ulcer
IDDM*
Alzheimer dementia
Deep venous thrombosis*
Falciparum malaria*
AIDS*
Colorectal cancer*
NIDDM*
Gene
ABO
HLA
APOE
F5
HBB
CCR5
APC
PPARγ
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 Studies
Using SNPs to Link Genes to Disease
© Gibson & Muse, A Primer of Genome Science
Genome-Wide Association Study:
A Brief Primer
SNP chip
Control
Population
WTCCC,
Nature 2007
Disease
Population
Courtesy of Daniel Newburger
A Quantitative Gene-Expression Association
Sample Population
SNP chip
Expression
cDNA Levels
and
AA
AG
GG
Expression Quantitative Trait Loci (eQTLs)
Modified from WTCCC, Nature 2007
Courtesy of Daniel Newburger
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, 661-678 (7 June 2007)
The Great Wave of GWAS Studies
Hokusai, K. The Great Wave
Published Genome-Wide Associations through 12/2009,
658 published GWA at p<5x10-8
NHGRI GWA Catalog
www.genome.gov/GWAStudies
Study Designs in Genome-Wide Association Studies
• Genome-Wide Association Studies Make No Assumptions
about Disease Mechanism or Cause
• Case-Control Populations
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Homogeneity of Cases and Controls
Population Stratification
Accurate Diagnosis of the Disease
Optimal for Rare Diseases
Biased Towards Most Prevalent Form of Disease
• Cohorts in a Medical Study
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Better Characterized than Populations
Can focus on Subpopulations and Ethnic Subgroups
• Families and Trios
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Highest Genetic Homogeneity
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%
Hispanics
European-Americans
African-Americans
First Hit
•Obesity
• Type 2 diabetes
• Ethanol
• Hepatitis C
Second Hit
• Oxidative Stress
• Lipid Peroxidation
• Anti-virals
• Cytokines
© Helen Hobbs 2009
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
5.4 x 10-6
Chromosome
© Helen Hobbs, Nature Genetics V40, pp 1461, 2008
PNPLA3 & Hepatic Triglyceride Metabolism
Liver
Acetyl CoA
Mito
Remnants
Adipose Tissue
+
PNPLA2 (ATGL)
Fasting
VLDL
PNPLA3 (Adiponutrin)
Feeding
I148M & Catalytic Dyad of PNPLA3
Ile148
Met148
Asp166
Asp166
Ser47
Ser47
© 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!
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Highest Frequency of Genetic (SNP) Variations
High Numbers of Genetic Subpopulations due to Multiple
Migrations and Invasions
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Greeks, Romans, Turks, Persians etc.
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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
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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
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Genes and Regions to Analyze by Resequencing 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:
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Unexpected Causes for Disease
Novel Mechanisms for Disease (missense mutations, regulatory changes, alternative
splicing, copy number variation etc.)
Multiple Pathways and Multiple Genes Involved in Disease
Novel Diagnostics and Prognosis
Novel Treatments
Thank You!