admixture mapping n.
Download
Skip this Video
Loading SlideShow in 5 Seconds..
Admixture Mapping PowerPoint Presentation
Download Presentation
Admixture Mapping

Loading in 2 Seconds...

play fullscreen
1 / 12

Admixture Mapping - PowerPoint PPT Presentation


  • 99 Views
  • Uploaded on

Admixture Mapping. Qunyuan Zhang Division of Statistical Genomics GEMS Course M21-621 Computational Statistical Genetics March 24, 2010. dsgweb.wustl.edu/ qunyuan /presentations/AdmixtureMapping2011.pptx. Three Mapping Strategies.

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'Admixture Mapping' - merton


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
admixture mapping

Admixture Mapping

Qunyuan Zhang

Division of Statistical Genomics

GEMS Course M21-621

Computational Statistical Genetics

March 24, 2010

dsgweb.wustl.edu/qunyuan/presentations/AdmixtureMapping2011.pptx

three mapping strategies

Three Mapping Strategies

Linkage Analysis (linkage): genotype & phenotype data from family (or families)

Association Scan (LD): genotype & phenotype data from population(s) or families

Admixture Mapping (LD): genotype data from admixed and ancestral populations, phenotype data from admixed populations

(1) Ancestry-phenotype association mapping

(2) Ancestry info for population structure control

genetic admixture

Ancestral Population 2

Caucasians

Ancestral Population 1

Africans

Admixture Information (Ancestry Analysis)

Admixture Mapping

Admixed Population African Americans

Genetic Admixture

rationale of admixture mapping

Rationale of Admixture Mapping

If a disease has some genetic factors, and the disease gene frequency in pop 2 is higher than in pop 1. After the admixture of pop 1 and 2, the diseased individuals in admixed generations will carry disease genes/alleles that have more ancestry from pop 2 than from pop 1.

If a marker is linked with disease genes, because of linkage disequilibrium, the diseased individuals will also carry the marker copies that have more ancestry from pop 2 than from pop 1.

Inversely, if we find a marker/locus whose ancestry from pop 2 in diseased group is significantly different from that in non-diseased group, we consider this marker/locus to be linked with (or a part of ) disease gene.

advantages of admixture mapping

Advantages of Admixture Mapping

Admixed population has more genetic variation and polymorphism than relatively pure ancestral populations.

Admixture produces new LD in admixed population. Compared with ancestral populations, shorter genetic history of admixture population keeps more LD (long genetic history will destroy LD), In admixed population, LD could be detected for relatively loose linkage.

Ancestry information can be used to control population stratification caused by genetic admixture.

According to simulation, admixture mapping demonstrates higher power than regular methods, needs less sample size.

Flexible design: case-control or case-only, qualitative or quantitative traits, no need of pedigree information

ancestry

Ancestry

Proportion of genetic materials descending from each founding population

Population level : population admixture proportion

Individual level: individual admixture proportion

Individual-locus level: locus-specific ancestry

two ways of using ancestral info

Two Ways of Using Ancestral Info.

Individual Ancestry (IA) can be used as a genetic background covariate for population structure control

Phenotype= a + b * Genotype + c * IA + Error

Locus-specific Ancestry (LSA) can be directly used to detect association (admixture mapping)

Phenotype=a + b * LSA

individual ancestry ia estimation using mle

Individual Ancestry (IA) Estimation using MLE

  • G: Observed genotypes of admixed and ancestral populations
  • Q: Allelic frequencies in ancestral populations
  • P : Individual Ancestry to be estimated
  • Goal: obtain P that maximizes Pr(G|P,Q)
  • Assign prior values for Q (randomly or estimated from ancestral population genotype data) & P (randomly)
  • Compute P(i) by solving
  • Compute Q(i) by solving
  • Iterate Steps 1 and 2 until convergence.
  • Tang et al. Genetic Epidemiology, 2005(28): 289–301
locus specific ancestry estimation using mcmc

ObservedG:genotypes of admixed and ancestral populations

  • UnknownZ :admixed individuals’ locus specific ancestries from ancestral populations
  • Problem: How to estimateZ ?
  • Maximum Likelihood Estimate(MLE):
  • How to obtain aZthat maximizes Pr(G|Z) ?
  • Zis a huge space of parameters, in which search is difficult for likelihood method.
  • Bayesian and Markov Chain Monte Carlo (MCMC) methods
  • Assume ancestral population numberK
  • Define prior distribution Pr(Z) underK
  • Use MCMC to sample from posterior distribution Pr(Z|G) = Pr(Z)∙ Pr(G|Z)
  • Average over large number of MCMC samples to obtain estimate ofZ
  • Falush et al. Genetics, 2003(164):1567–1587

Locus-specific Ancestry Estimationusing MCMC

slide10

Distribution of Locus-specific Ancestries from Africans

(An Example of African American)

Ancestry from Africans

Maker Position

software

Software

STRUCTUREFalush D, Stephens M, Pritchard JK (2003) Inference of population structure using multilocus genotype data: linked loci and correlated allele frequencies. Genetics 164:1567–1587.

ADMIXMAPHoggart CJ, Parra EJ, Shriver MD, Bonilla C, Kittles RA, Clayton DG, McKeigue PM (2003) Control of confounding of genetic associations in stratified populations. Am J Hum Genet 72:1492–1504.

ANCESTRYMAPPatterson N, Hattangadi N, Lane B, Lohmueller KE, Hafler DA, Oksenberg JR, Hauser SL, Smith MW, O’Brien SJ, Altshuler D, Daly MJ, Reich D (2004) Methods for high-density admixture mapping of disease genes. Am J Hum Genet 74:979–1000

references

References

D.C.Rife. Populations of hybrid origin as source material for the detection of linkage. Am.J.Hum.Genet. 1954, (6):26-33

R.Chakraborty et al. Adimixture as a tool for finding linked genes and detecting that difference from allelic association between loci. Proc.Natl.Acad.Sci. 1988,Vol.85:9119-9123

N. Risch. Mapping genes for complex disease using association studies with recently admixed populations. Am.J.Hum.Genet.Suppl. 1992, 51:13

P.M.McKeigue. Prospects for admixture mapping of complex traits. Am.J.Hum.Genet. 2005, Vol.76:1-7

X.Zhu et al. Admixture mapping for hypertention loci with genome-scan markers. Nature Genetics. 2005,Vol.37(2): 177-181

Q Zhang et al. Genome-wide admixture mapping for coronary artery calcification in African Americans: the NHLBI Family Heart Study. Genet Epidemiol. 2008 Apr;32(3):264-72.