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10/07/08 Journal Club Simone Sanna-Cherchi OUTLINE Basis of Admixture Mapping as strategy do identify disease-associated genes Papers Implications of MYH9 association to FSGS and nondiabetic ESRD in African Americans LINKAGE DISEQUILIBIRUM • The probability of 2 independent events cooccurring is the product of the individual probabilities • LD is defined as the non-random association of alleles at different loci on the same chromosome/haplotype LINKAGE DISEQUILIBIRUM Allele 1 Allele 1 Marker A Marker B Genotype at Marker A allows prediction of genotype at marker B WHAT CAUSES LD • • • • Mutation Admixture Selection Random genetic drift WHAT CAUSES LD • • • • Mutation Admixture Selection Random genetic drift DECAY OF LD WITH TIME Simple Decay of LD with time 1 theta=0.01 theta=0.05 theta=0.10 0.9 0.8 0.7 D' 0.6 0.5 0.4 0.3 0.2 0.1 0 0 20 40 60 Number of Generations 80 100 AVERAGE EXTENT OF LD Half-life of LD: Distance at which average D’ drops below 0.5: – – – – US: 60kb; Nigerians: 5kb (Reich et al.) Sardinia, Finns, US, UK: ~50kb (Eaves et al.) British ancestry: ~50kb (Abecasis et al.) Sardinian subisolate: 1-4 Mb (Zavattari et al.) GENE MAPPING VIA GWAS: IMPLICATIONS At least 300,000 markers for GWAS in Caucasians (1 SNP every 10kb) At least 1 million markers for GWAS in Africans (1 SNP every 3kb) Statistical issues: multiple test adjustments require large data sets to identify variants with small effect Limitations to less common diseases in which sample sizes are in the order of hundreds of patients (ex FSGS) ADMIXTURE MAPPING HYPOTHESIS • Disease allele has different frequencies in source populations • For cases, disease allele site will be enriched for one ancestry African Americans: Admixture MS Prostate Cancer ADMIXTURE MAPPING: MALD Chromosomal admixture segments Smith, Nat Rev Genet 2005 EXPERIMENTALLY distinguish African and European ancestry West WestAfrican AfricanFrequency Frequency 100% 100% The most informative ~1% of SNPs provide powerful information about ancestry 80% 80% 60% 60% 40% 40% Advantages: 20% 20% 0% 0% 0% 0% -Cases only 20% 20% 40% 40% 60% 60% 80% 80% European American Frequency European American Frequency 100% 100% -Less than 2000 SNPs for GWAS POWER OF MALD ANALYSIS Patterson, Am J Hum Genet 2004 MAPPING BY SEGMENT ANCESTRY Patterson, Am J Hum Genet 2004 LINKAGE DISEQUILIBRIUM RESOLUTION DISEASES SUITABLE FOR MALD HYPOTHESES AND STUDY DESIGN Cumulative lifetime risk for ESRD is 2.1% in European Americans (EA) and 7.5% in African Americans (AA) AA have higher risk for several forms of nephropathy: diabetic, hypertensive, lupus nephritis, FSGS (4-fold risk) and HIVAN (18- to 50fold risk) MALD: 1,272 SNPs across the genome in 190 AA FSGS and 222 matched controls Fine Mapping and identification of MYH9 Extension of association to MYH9 in 241 AA FSGS and 611 controls Replication in 125 EA FSGS and 221 controls Extension to 525 AA ESRD (241 hypertensive, 284 diabetic) and 192 controls SUBJECTS MALD RESULTS MYH9 FINE MAPPING 20 MYH9 SNPs: - Pronounced difference in allelic differences btw African Yorubans and Europeans - Possible functional significance - Strong LD with previously typed SNPs associated to FSGS even after correction for local ancestry 12 SNPs in 4 neighboring genes as control GENOTYPIC ASSOCIATION SUGGESTS A RECESSIVE MODEL ASSOCIATION WITH IDIOPATHIC FSGS, HIVAN AND ESRD HAPLOTYPE ASSOCIATION CONCLUSIONS MALD is a increasingly efficient method to discover genes for complex traits in admixed populations MALD require less genotyping (200-500 times less markers compared to GWAS), thus reducing costs and, most importantly, increasing power (less correction for multiple testing) and simplifying computation Amenable for traits with pronounced differences in risk in the parental populations and for which large sample sizes are difficult to recruit Most of the difference in risk of developing FSGS in African Americans compared to European Americans is due to variants in MYH9 Variants at MYH9 account for the higher risk of non-diabetic ESRD in African Americans, especially ESRD due to hypertensive nephrosclerosis 1,354 SNPs for MALD All ESRD 1,372 cases / 806 controls DM 703 cases / 806 controls Non-DM 669 cases / 806 controls HTN 347 cases / 806 controls FSGS 87 cases / 806 controls GN 126 cases / 806 controls HIV 69 cases / 806 controls Grey=DM ESRD Black=non-DM ESRD Grey= controls Black= non-DM ESRD MALD RESULTS MYH9: nonmuscle myosin heavy chain, class II, isoform A 110 kb, 41 exons, highly conserved among mammals and very similar to other nonmuscle myosin isoforms Abundantly expressed in kidney, liver, platelets Involved in different cellular functions, including cell polarity, architecture and trafficking Rare mutations in MYH9 cause several autosomal dominant conditions, such as May-Hegglin anomaly, Fechtner, Epstein and Sebastian syndromes, featuring macrothrombocytopenia with variable association of sensorineural deafness, cataract, neutrophil Dohle-like bodies and glomerular disease (Alport-like) MYH9 KO mice show embryonic lethality, while heterozygous are normal except low penetrance hearing loss MYH9: nonmuscle myosin heavy chain, class II, isoform A In the kidney is expressed in the glomerulus (podocytes), peritubular capillaries and tubules It takes part of the actin cytoskeleton, regulating contractility and cell integrity One patients carrying a MYH9 mutation in whom kidney biopsy was performed at early kidney involvement showed focal podocyte foot process effacement and loss of slit diaphragm at the EM Since Mendelian forms of FSGS are caused by mutations in genes encoding for proteins of the actin cytoskeleton (ACTN4, CD2AP and others) it is tempting to speculate that more common variants in MYH9 can predispose to podocyte damage and FSGS and HTN ADMIXTURE MAPPING MARKERS • Theoretically: – • Much less markers sufficient Practically: 1. 2. Develop marker set for admixture mapping: Look for high frequency differences or Use many markers, ignore non-informative