Lecture6_Jul30

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


Source Bioscience


Macular degeneration





116’204 SNPs

nominal p-value

Robert J. Klein et al. Science 308, 385 (2005)

116’204 SNPs

nominal p-value



Robert J. Klein et al. Science 308, 385 (2005)

increased by a factor of 7.4 (95% CI 2.9-19)



Linkage disequilibrium

(D’)



- white, not of Hispanic origin - same proportion of males and females - same proportion of smokers / nonsmokers

Why is this important?



Cases (n=96): - evidence of sight-threatening AMD

Controls (n=50): - no evidence of AMD - older than cases




~750K SNPs




SNPs

How?



SNPs

HapMap



SNPs

HapMap

What is the goal of the HapMap and how does it achieve that?



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




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




(2) SNP type many individuals



(2) SNP type many individuals

Original cost: $100’000’000 current: $20’000


Yoruba Han~ Northern European Japanese




Yoruba

Han

Japanese

~ Northern European

“The birthplace of humanity is in Africa”




Yoruba

Han

Japanese

~ Northern European

“The birthplace of humanity is in Africa”

~ Luhya

~Mexican

Tuscan

~Gujarat





(2) SNP type many individuals (3) Determine LD between SNPs


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


Nature 426, 789-796 (2003)


Nature 467, 52–58 (2010)

Yoruba

African American

Luhya


Nature 467, 52–58 (2010)

Yoruba

African American

Luhya

Problem with GWAS in African populations


Nature 467, 52–58 (2010)

Yoruba

African American

Luhya

More diversity, ascertainment bias, and lower LD

Documents

Lecture6_Jul30