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Association Studies
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Parametric Linkage Analysis
Requires: (1) Pedigree (2) Phenotypes (3) Marker genotypes
Association Studies
Requires: (1) Population (2) Phenotypes (3) Marker genotypes
Genome Wide Association Studies
116’204 SNPs
nominal p-value
Robert J. Klein et al. Science 308, 385 (2005)
116’204 SNPs
nominal p-value
Genome Wide Association Studies
Robert J. Klein et al. Science 308, 385 (2005)
increased by a factor of 7.4 (95% CI 2.9-19)
Genome Wide Association Studies
Requires: (1) Population (2) Phenotypes (3) Marker genotypes
- white, not of Hispanic origin - same proportion of males and females - same proportion of smokers / nonsmokers
Why is this important?
Genome Wide Association Studies
Requires: (1) Population (2) Phenotypes (3) Marker genotypes
Cases (n=96): - evidence of sight-threatening AMD
Controls (n=50): - no evidence of AMD - older than cases
Why is this important?
Genome Wide Association Studies
Requires: (1) Population (2) Phenotypes (3) Marker genotypes
~750K SNPs
Why is this important?
Genome Wide Association Studies
Requires: (1) Population (2) Phenotypes (3) Marker genotypes
SNPs
How?
Genome Wide Association Studies
Requires: (1) Population (2) Phenotypes (3) Marker genotypes
SNPs
HapMap
Genome Wide Association Studies
Requires: (1) Population (2) Phenotypes (3) Marker genotypes
SNPs
HapMap
What is the goal of the HapMap and how does it achieve that?
Genome Wide Association Studies
Requires: (1) Population (2) Phenotypes (3) Marker genotypes
SNPs
HapMap
What is the goal of the HapMap and how does it achieve that?
Goal: catalogue human SNP variation
Genome Wide Association Studies - HapMap
(1) Find individuals that cover the genetic diversity of humans
Goal: catalogue human SNP variation
Genome Wide Association Studies - HapMap
(1) Find individuals that cover the genetic diversity of humans
SNPs originally discovered using a variety of platforms:
- Shotgun sequencing by HapMap groups - Sanger sequencing at Celera (Craig Venter’s company),
Sanger Centre, Washington University (St. Louis), and Whitehead Institute
- The SNP Consortium
Goal: catalogue human SNP variation
Genome Wide Association Studies - HapMap
(1) Find individuals that cover the genetic diversity of humans
(2) SNP type many individuals
Genome Wide Association Studies - HapMap
(1) Find individuals that cover the genetic diversity of humans
(2) SNP type many individuals
Original cost: $100’000’000 current: $20’000
Genome Wide Association Studies - HapMap
Yoruba Han~ Northern European Japanese
(1) Find individuals that cover the genetic diversity of humans
Goal: catalogue human SNP variation
Genome Wide Association Studies - HapMap
Yoruba
Han
Japanese
~ Northern European
“The birthplace of humanity is in Africa”
(1) Find individuals that cover the genetic diversity of humans
Goal: catalogue human SNP variation
Genome Wide Association Studies - HapMap
Yoruba
Han
Japanese
~ Northern European
“The birthplace of humanity is in Africa”
~ Luhya
~Mexican
Tuscan
~Gujarat
(1) Find individuals that cover the genetic diversity of humans
Goal: catalogue human SNP variation
Genome Wide Association Studies - HapMap
(1) Find individuals that cover the genetic diversity of humans
(2) SNP type many individuals (3) Determine LD between SNPs
Genome Wide Association Studies - HapMap
Nature 426, 789-796 (2003)
Patterns of LD are empirically determined to select tag SNPs
LD between nearby markers varies across the genome
Not efficient to use SNPs selected at random or evenly spaced
Genome Wide Association Studies - HapMap
Nature 467, 52–58 (2010)
Yoruba
African American
Luhya
Problem with GWAS in African populations