Replication and Finemapping of Quantitative Trait Loci Influencing

Replication and Finemapping of Quantitative Trait Loci Influencing QT interval duration in the Jackson Heart Study Sara Tribune Mentor: Christopher Newton-Cheh Broad Institute of MIT and Harvard Summer Research Program in Genomics Jackson Heart Study Undergraduate Training Center Massachusetts General Hospital Framingham Heart Study Tougaloo College

Sudden cardiac death n 300, 000 deaths/yr US n Risk factors inadequate 2

Prolonged QT intervals n Increased risk of Sudden Cardiac Death n Long QT Syndrome and Short QT Syndrome n Drug-induced arrhythmias

QT-Interval is Heritable n Framingham Heart Study (FHS) n n European descent (ED) n 35% heritable Jackson Heart Study (JHS) n African descent (AD) n 40 -41% heritable . Newton-Cheh et al. Heart Rhythm 2, 277 -284 (2005).

Finemapping of the NOS 1 AP Associations in African Americans from JHS 1 st Step þ Selection of SNPs 2 nd Step þ Genotyped SNPs Final Step þ Determine locus-specific ancestry þ Final data analysis

African Variants Show Less Correlation Using Hapmap data and Haploview CEU Data n Correlation of SNPS in CEU (ED) and YRI (AD) data set n Red=Strong Correlation n White=No Correlation YRI Data

Study Design: SNP Selection SNPs correlated to previously associated SNPs in CEU (European data) CEU Data

Study Design Tagger software selected SNPs with r 2 ≥ 0. 8 in YRI (West African data). rs 2074238 rs 4657140 rs 6696160 rs 1415262 rs 885148 rs 7548169 rs 16847548 rs 7550692 rs 2225845 rs 6696160 rs 1415262 rs 885148 YRI Data rs 12071519 rs 10800303 rs 4657140 0. 919 rs 12076589 rs 945706 rs 6696160 0. 966 rs 945707 rs 6672881 rs 4657140 1. 0 rs 7525891 rs 12085258 rs 3922867 rs 4657140 0. 882 rs 4422984 rs 4278353 rs 4256791 rs 1572498 rs 10494366 1. 0 rs 1415260 rs 4657140 0. 863 rs 1415259 rs 10494366 1. 0

Genotyping

Locus-Specific Ancestry Increases Locus-specific Statistical Power ancestry African Descent European Descent { } NOS 1 AP Locus { } Afr-Afr Afr-Eur Eur-Eur 67. 24 % 29. 52 % 3. 24 %

Whether the association between QT interval duration and the other QTGEN variants exists in African descent individuals is unknown.

Progress þ Study Design þ Selection of SNPs þ Selection and formation of assay pools þ Genotyped SNPs þ Interim analysis q Final data analysis (August 15)

Acknowledgments Broad Institute Christopher Newton-Cheh Paul Cullen Gabriel Crawford Candace Guiducci David Reich Nick Patterson Arti Tandon Shawna Young Bruce Birren Jackson Heart Study Herman Taylor James Wilson Meggie Akylbekova Sarah Buxbaum Funding support Jackson Heart Study Undergraduate Training Center (Tribune) Broad Summer Research Program in Genomics (Tribune) NIH, Doris Duke, Burroughs Wellcome Fund (Newton-Cheh)

Thank you

Electrocardiograms http: //www. mercksource. com/pp/us/cns_hl_adam. jspz. Qzpgz. Ezz. Szppdocsz. Szusz. Szcnsz. Szcontentz. Szadamz. Szimagepagesz. Sz 8772 z. Pzhtm

Why is it not accurate assume that an association exists between QT interval duration and a SNP in AD individuals if an association is found in ED individuals?

The structure of haplotype blocks in Distribution of NOS 1 AP haplotypes the human genome. Courtesy of Pardis Sabeti Gabriel, S. B. et al. The Structure of Haplotype Blocks in the Human Genome. Science 296, 2225 -2229 (2002).