1. GWAS Hits and Functional Implications Peter Castaldi February 1, 2013

2. Published Genome-Wide Associations through 07/2012 Published GWA at p≤5X10 -8 for 18 trait categories NHGRI GWA Catalog www.genome.gov/GWAStudies www.ebi.ac.uk/fgpt/gwas/ GWAS Has Identified Many Novel, Robust Genetic Associations with Common Diseases

3. The Majority of GWAS Hits have Weak Effects Hindorff PNAS 2009

4. GWAS Hits often Impact Gene Expression Hindorff PNAS 2009

6. Genetic Disease Causing Mechanisms Nonsynonymous mutation leading to altered, dysfunctional protein cystic fibrosis, sickle cell, alpha-1 antitrypsin Mutation in regulatory active site affecting transcription disruption of transcription factor binding sites microRNA binding sites

7. One Functional Story – HHIP and COPD

8. The GWAS Hit Near HHIP is Associated with Lower HHIP Expression

9. The HHIP GWAS region acts as an enhancer 500bp region in GWAS hit area, attached to HHIP and a luciferase reporter affects expression levels

10. Summary GWAS-identified signals for common disease are enriched in genomic regions associated with transcriptional regulation (in addition to non- synonymous SNPs). GWAS methods can identify key regions, but because of LD they often cannot identify the specific causal variant Functional follow-up of GWAS hits is often needed to identify the biological mechanism