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.
Division of Statistical Genomics
GEMS Course M21-621
Computational Statistical Genetics
March 24, 2010
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
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.
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
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
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
(An Example of African American)
Ancestry from Africans
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
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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.