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Sara Tribune Mentor: Christopher Newton-Cheh

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

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Sara Tribune Mentor: Christopher Newton-Cheh

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  1. 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

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

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

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

  5. 1st Step Selection of SNPs 2nd Step Genotyped SNPs Final Step Determine locus-specific ancestry Final data analysis Finemapping of the NOS1AP Associations in African Americans from JHS

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

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

  8. rs2074238 rs4657140 rs6696160 rs1415262 rs885148 rs7548169 rs16847548 rs7550692 rs2225845 rs6696160 rs1415262 rs885148 YRI Data Study Design Tagger software selected SNPs with r2 ≥0.8 in YRI (West African data).

  9. Genotyping

  10. Locus-Specific Ancestry Increases Statistical Power Locus-specific ancestry African Descent European Descent { } NOS1AP Locus { } NOS1AP Locus { } Afr-Afr 67.24 % Afr-Eur 29.52 % Eur-Eur 3.24 %

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

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

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

  14. Thank you

  15. Electrocardiograms http://www.mercksource.com/pp/us/cns/cns_hl_adam .jspzQzpgzEzzSzppdocszSzuszSzcnszSzcontentzSzadamzSzimagepageszSz8772zPzhtm

  16. 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?

  17. The structure of haplotype blocks in the human genome. Distribution of NOS1AP haplotypes Gabriel, S. B. et al. The Structure of Haplotype Blocks in the Human Genome. Science 296, 2225-2229 (2002). Courtesyof Pardis Sabeti

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