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Genome-Wide Association (GWA) Studies. National Human Genome Research Institute. U.S. Department of Health and Human Services National Institutes of Health National Human Genome Research Institute. National Institutes of Health.

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genome wide association gwa studies

Genome-Wide Association (GWA) Studies

National Human Genome Research Institute

U.S. Department of Health and Human Services

National Institutes of Health

National Human Genome Research Institute

National Institutes of Health

Teri A. Manolio, M.D., Ph.D.Senior Advisor to the Director, NHGRI,

for Population Genomics

Director, Office of Population Genomics

U.S. Department of Health and Human Services

there s a revolution going on
There’s a revolution going on…

Williard, AM. Spirit of ‘76

there s a revolution going on1
There’s a revolution going on…
  • Technologic advances now allow us to measure hundreds of thousands of variable points across human genome
    • Relatively low cost
    • Relatively little DNA
  • Can be applied to unrelated individuals studied over years or decades
  • Can identify multitude of subtle genetic effects increasing risk of “complex” disease

Williard, AM. Spirit of ‘76

what is a gwa study

What is a GWA Study?

  • Method for interrogating all 10 million variable points across human genome
  • Variation inherited in groups, or blocks, so not all 10 million points have to be tested
  • Blocks are shorter (so need to test more points) the less closely people are related
  • Technology now allows studies in unrelated persons, assuming ~10,000 base pair lengths in common (300,000 - 500,000 markers)
slide5

Mapping the Relationships Among SNPs

Christensen and Murray, N Engl J Med 2007; 356:1094-1097.

slide6

One SNP May Serve as Proxy for Many

Christensen and Murray, N Engl J Med 2007; 356:1094-1097.

progress in genotyping technology
Progress in Genotyping Technology

102

ABI

TaqMan

ABI

SNPlex

10

Cost per genotype (Cents, USD)

Illumina

Golden Gate

Affymetrix

MegAllele

Affymetrix

10K

Illumina

Infinium/Sentrix

Perlegen

1

Affymetrix

100K/500K

Nb of

SNPs

1

10

102

103

104

105

106

2001

2005

Courtesy S. Chanock, NCI

slide8

Continued Progress in Genotyping Technology

Affymetrix

500K

Illumina

550K

Illumina

650Y

Illumina

317K

Cost per person (USD)

July 2005

Oct 2006

Courtesy S. Gabriel, Broad/MIT

measures of association the odds ratio
Measures of Association: The Odds Ratio
  • Odds are related to probability: odds = p/(1-p)
    • If probability of horse winning race is 50%, odds are 1/1
    • If probability of horse winning race is 25%, odds are 1/3 for win or 3 to 1 against win
  • If probability of exposed person getting disease is 25%, odds = p/(1-p) = 25/75 = 1/3
  • When don’t have denominators for risk estimates, can calculate odds ratio = cross-product ratio (“ad/bc”); computationally easier
  • If disease is rare, odds ratio approximates relative risk but always overestimates effect
association of rsxxxx3207 alleles with occurrence of myocardial infarction
Association of rsxxxx3207 Alleles with Occurrence of Myocardial Infarction

Helgadottir et al, Sciencexpress 3 May 2007.

association of rsxxxx3207 alleles with occurrence of myocardial infarction1
Association of rsxxxx3207 Alleles with Occurrence of Myocardial Infarction

Embargoed until May 3, 2007

Helgadottir et al, Sciencexpress 3 May 2007.

this is a tsunami of data
This is a tsunami of data…

Hokusai, K. The Great Wave

this is a tsunami of data1
This is a tsunami of data…
  • New approaches needed for accessing, manipulating, visualizing
  • Requires entirely new perspective
  • Recognize potential for differences to be observed by chance alone

Hokusai, K. The Great Wave

slide18

P Values of GWA Scan for Age-Related Macular Degeneration

Klein et al, Science 2005; 308:385-389.

slide19

Genome-Wide Scan for Type 2 Diabetes in a Scandinavian Cohort

http://www.broad.mit.edu/diabetes/scandinavs/type2.html

p values for 8q24 snps most strongly associated with prostate cancer
P-values for 8q24 SNPs Most Strongly Associated with Prostate Cancer

Haiman et al, Nat Genet 2007; 39:638-44.

p values for chromosome 11 snps most strongly associated with diabetes
P-values for Chromosome 11 SNPs Most Strongly Associated with Diabetes

Scott et al, Sciencexpress 26 April 2007.

of 600 gene disease associations only 6 significant in 75 of identified studies
Of 600 Gene-Disease Associations, Only 6 Significant in > 75% of Identified Studies

Hirschhorn J et al, Genet Med 2002; 4:45-61.

aspects of gwa studies that make data sharing crucial
Aspects of GWA Studies that Make Data Sharing Crucial
  • Expensive, generate many “false positives”
  • Replication held as sine qua non of valid association
  • Large sample sizes and multiple studies needed to replicate findings
  • Massive data sets, analysis requires huge and specialized effort
  • Better analytic methods needed
  • Once genome is measured can be related to just about anything
the revolution is here
The revolution is here…

Williard, AM. Spirit of ‘76

the revolution is here1
The revolution is here…
  • Extensive characterization of individual person’s genome now feasible
  • Can be applied to unrelated individuals
  • Many existing studies have carefully characterized thousands of persons
  • New approaches to manipulating and interpreting data needed
  • Responsible and widespread data sharing key to fully exploring GWA datasets
  • Collaboration for replication and functional determination is crucial

Williard, AM. Spirit of ‘76

measures of public health impact population attributable risk
Measures of Public Health Impact: Population Attributable Risk
  • Measures the proportion of disease that would be eliminated if particular causal factor were eliminated
  • Directly related to prevalence of risk factor and risk it conveys
  • Almost always over-estimates proportion attributable to risk factor
gwa genotyping data chromosome 22 one person
GWA Genotyping Data, Chromosome 22, One Person

412 1 T C G G G G A A A A C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T …

chromosome 22 one person continued
Chromosome 22, One Person, Continued

…G A A A A C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T TC C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T …

chromosome 22 one person continued1
Chromosome 22, One Person, Continued…

…A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T TC C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T T T C C A A A A T C A G C C T C T T T C T C T T A G C C C A A A A T C A G C C T C T T T C T C T T A G C C A G A A T C C A A A A T C A G C C T C …