African American disease gene discovery utilizing mapping by admixture linkage disequilibrium: progress and prospects

Michael W. Smith

Linkage disequilibrium resolution

Family studies20 cM

ALD3-7 cM

HAP map<0.1 cM

ALD around FY locus

MALD Map SNP Sources

Unique~450,000

AB ValidatedAB ValidatedSNPsSNPs

180,178180,178

Public DatabasePublic Database66,20466,204

Celera/ABCelera/ABResequencingResequencing

266,135266,135

MALD SNP map samplesGroup Population Sample sizeEuropean American Chicago 40

Baltimore 40African American Chicago 19

Pittsburgh 23Baltimore 45North Carolina 23

Africa Senegal 46Ghana 33Cameroon 20Botswana 21

Chinese Canton 40Amerindian Zapotec 29

MALD map loci assessed

3669 SNPs assayed

35 replicated SNPs

61 discrepancies 12,447 comparisons

WICGRWICGR18471847

LGDLGD18571857

Shannon Information ContentAfrican European TOTAL

Allele 1 (1-m)fA[a00]

mfE[a01]

(1-m)fA + mfE[a0*]

Allele 2 (1-m)(1-fA)[a10]

m(1-fE)[a11]

(1-m)(1-fA) + m(1-fE)[a1*]

TOTAL 1-m[a*0]

m[a*1]

1

iiii

iji j

ij

aaaa

aa

SIC

*2**2*

2

1

0

1

0

loglog

log

−−

=

∑∑= =

Same as “informativeness of assignment” (Rosenberg et al., 2003)

MALD Marker informativenessSingle Multi

Admixture in African Americans

Admixture linkage disequilibrium decay

MALD Marker Map, part 1

MALD Marker Map, part 2

SNPs for estimating individual ancestry

Comparison Average allele frequency difference

African/European 78%

African/Amerindian 85%

European/Amerindian 56%

European/East Asian 57%

100 Markers each spaced by at least 25cM

Structure Analysis

• Pritchard et al. 2001 and Falush et al 2003• Bayesian Approach of Modeling

– Number of populations– Admixture– Estimates contributions from each population

• Per sampled population• Per individual

MCMC Model

• Estimate ancestral origin along genome– Composite genotype of linked markers– Utilize parental allele frequencies– Estimate number of generations since admixture for

individuals– Estimate admixture fraction for individuals

• Evaluation– Locus genome statistic– Locus case-control

Mapping by segment ancestry

ALD around specific genes

Examples of chromosomal

admixturesegments

Power of MALD analysis

For 80% power

Samples needed to detect a gene

Pict AB 31003,000LocusMALDScreenOn one individual

MALD candidate diseasesCause of Death or Disease

(African/European)1 Relative Risk 95% CIHepatitis C Clearance2 0.19 (0.10,0.38)Melanoma 0.24 (0.09,0.66)HIV vertical transmission3 0.30 (0.10,0.90)

HIV progression5 1.41 (1.06,1.86)

Multiple sclerosis4 0.5

Suicide 0.64 (0.45,0.93)

Lung cancer 1.48 (1.30,1.67)Stroke 1.57 (1.27,1.94)

End-Stage Renal Disease6 1.87 (1.47,2.39)Intracranial hemorrhage 2.10 (1.44,3.06)Focal segmental glomerulosclerosis7 2.49 (1.05,5.95)

Prostate cancer 2.73 (2.13,3.52)Hypertensive heart disease 2.80 (2.03,3.86)Myeloma 3.14 (2.00,4.93)

1Daley Smith et al. 1998 except 2Thomas et al. 2000, 3Tess et al, 1998; 4Hogancamp, 1997; 5McGinniss et al, 2003; 6Klag et al. 1997 and 7Lopes et al., 2000

Acknowledgements

Jeffrey Kopp NIDDK)David Thomas (JHMI)Chloe Thio (JHMI)

(NCI/LGD)Holli HutchinsonMike MalaskyMary McNallyBailey KessingJoanne Clarke

Thanks to my lab too!

Yvette Berthier-SchaadTaras OleksykSadeep ShresthaAnn TrueloveKai Zhao Joanne Clarke