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Whole genome association studies

Whole genome association studies. Introduction and practical Boulder, March 2009. 100K+ SNPs, CNVs →. W hole G enome A ssociation S tudy. ← ~1000s individuals. Associating phenotypic and genotypic variation. Scz. Scz. …. ?. Control. Control. …. ….

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Whole genome association studies

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  1. Whole genome association studies Introduction and practical Boulder, March 2009

  2. 100K+ SNPs, CNVs → Whole Genome Association Study ← ~1000s individuals

  3. Associating phenotypic and genotypic variation Scz Scz … ? Control Control … …

  4. Direct test of single SNP effect Indirect association (linkage disequilibrium) Analytic tools to perform, validate and enhance basic single SNP WGAS, e.g.: Empirical assessment of ancestry 1) Detect outliers, substructure 2) Clusters or continuous indices 3) Batch effects, relatedness, sample swaps, contamination, etc 2 2 2 2 2 1 2 2 2 1 2 1 1 2 1 1 2 1 1 1 0 1 1 1 1 1 0 2 MDS PCA Reference haplotypes (HapMap) Imputation of ungenotyped SNPs 1) Increase coverage 2) Facilitate meta-analysis across platforms 3) Quality control (drop SNP/re-impute) Observed genotypes Imputed genotypes

  5. Age-related macular degeneration

  6. Progress in type 2 diabetes and Crohn’s disease TCF2 WSF1 CDKN2B/A IGF2BP2 CDKAL1 HHEX SLC30A8 JAZF1 CDC123 ADAMTS9 THADA NOTCH2 TSPAN8 T2D - confirmed associated loci KCNJ11 PPARG TCF7L2 2000 2001 2002 2003 2004 2005 2006 2007 2008 NOD2 5q31 TNFSF15 IL23R ATG16L1 5p13 10q21 3p21 PTPN2 IRGM IL12B NKX2-3 PTPN22 ITLN1 1q24 1q32 CDKAL1 MHC 6q21 CCR6 7p12 8q24 JAK2 10p11 11q13 12q12 13q14 ORMDL3 STAT3 19p13 21q21 ICOSLG Crohn’s - confirmed associated loci Slide courtesy of Mark Daly

  7. Bipolar WGAS of 10,648 samples >1.7 million genotyped and (high confidence) imputed SNPs 5 x 10-8 X Ankryin-G (ANK3) CACNA1C Sample Cases Controls P-value STEP 7.4% 5.8% 0.0013 WTCCC 7.6% 5.9% 0.0008 EXT 7.3% 4.7% 0.0002 Total 7.5% 5.6% 9.1×10-9 Sample Case Controls P-value STEP 35.7% 32.4% 0.0015 WTCCC 35.7% 31.5% 0.0003 EXT 35.3% 33.7% 0.0108 Total 35.6% 32.4% 7×10-8 Ferreira et al (Nature Genetics, 2008)

  8. Interactions dominant, recessive Joint tests of aggregate effect, genes, pathways Variants <1% frequency Structural variants Subtypes, endophenotypes Main focus of many association studies: additive effects of single common SNPs on disease

  9. Further reading on association mapping and interpretation of GWAS findings Altshuler, Daly & Lander (2008) Science Manolio, Brooks & Collins (2008) JCI Maher (2008) Nature

  10. Practical session • Data are in ~pshaun/prac2/ • Software required: PLINK and Haploview • PDF with instructions is ~pshaun/instruct.pdf • Work through until section “Empirical assessment of population stratification” • Use PLINK website for help (http://pngu.mgh.harvard.edu/purcell/plink/)

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