35
203.343 Advanced Genetics and Genomics Lecture 6 July 30th 2015 Olin Silander

Lecture6_Jul30

Embed Size (px)

DESCRIPTION

SFGD

Citation preview

203.343 Advanced Genetics

and Genomics

Lecture 6

July 30th 2015

Olin Silander

Association Studies

Linkage Studies (pedigrees)

Association Studies (populations)

Association Studies

casecasecasecasecasecase

controlcontrolcontrolcontrolcontrolcontrol

0 1 2 1 0 2 1 0 20 1 2 1 0 2 1 1 12 1 2 1 0 2 0 0 20 2 2 2 1 1 2 0 01 2 2 1 1 2 1 2 20 1 2 0 0 1 0 2 2

1 0 0 0 1 0 2 1 22 1 0 1 0 2 1 0 00 1 0 1 0 2 2 1 21 0 0 2 0 2 1 0 20 1 0 1 0 2 1 0 10 2 0 1 2 1 0 2 2

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

Source Bioscience

Genome Wide Association Studies

Source Bioscience

Genome Wide Association Studies

Macular degeneration

Genome Wide Association Studies

Genome Wide Association Studies

Genome Wide Association Studies

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

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

Genome Wide Association Studies

Linkage disequilibrium

(D’)

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 426, 789-796 (2003)

Genome Wide Association Studies - HapMap

Nature 467, 52–58 (2010)

Yoruba

African American

Luhya

Genome Wide Association Studies - HapMap

Nature 467, 52–58 (2010)

Yoruba

African American

Luhya

Problem with GWAS in African populations

Genome Wide Association Studies - HapMap

Nature 467, 52–58 (2010)

Yoruba

African American

Luhya

More diversity, ascertainment bias, and lower LD