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

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

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

4. Indirect association (linkage disequilibrium) 22121 22 12 22212 10111110 1 2 1211 MDS PCA Reference haplotypes (HapMap) Observed genotypes Imputed genotypes Direct test of single SNP effect Imputation of ungenotyped SNPs 1) Increase coverage 2) Facilitate meta-analysis across platforms 3) Quality control (drop SNP/re-impute) Empirical assessment of ancestry 1) Detect outliers, substructure 2) Clusters or continuous indices 3) Batch effects, relatedness, sample swaps, contamination, etc Analytic tools to perform, validate and enhance basic single SNP WGAS, e.g.:

5. Age-related macular degeneration

6. Progress in type 2 diabetes and Crohn’s disease KCNJ11 PPARG 2000 2001 2002 2003 2004 2005 2006 2007 2008 TCF2 WSF1 CDKN2B/A IGF2BP2 CDKAL1 HHEX SLC30A8 TCF7L2 NOD2 5q31 5p13 10q21 3p21 PTPN2 IRGM IL12B NKX2-3 T2D - confirmed associated loci Crohn’s - confirmed associated loci TNFSF15IL23R ATG16L1 JAZF1 CDC123 ADAMTS9 THADA NOTCH2 TSPAN8 PTPN22 ITLN1 1q24 1q32 CDKAL1 MHC 6q21 CCR6 7p12 8q24 JAK2 10p11 11q13 12q12 13q14 ORMDL3 STAT3 19p13 21q21 ICOSLG Slide courtesy of Mark Daly

7. 5 x 10 -8 CACNA1C Ankryin-G (ANK3) Bipolar WGAS of 10,648 samples SampleCasesControlsP-value STEP7.4%5.8%0.0013 WTCCC7.6%5.9%0.0008 EXT7.3%4.7%0.0002 Total7.5%5.6%9.1×10 -9 SampleCaseControlsP-value STEP35.7%32.4%0.0015 WTCCC35.7%31.5%0.0003 EXT35.3%33.7%0.0108 Total35.6%32.4%7×10 -8 X >1.7 million genotyped and (high confidence) imputed SNPs Ferreira et al (Nature Genetics, 2008)

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

9. Altshuler, Daly & Lander (2008) Science Manolio, Brooks & Collins (2008) JCI Further reading on association mapping and interpretation of GWAS findings 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/)http://pngu.mgh.harvard.edu/purcell/plink/