Replication and Finemapping of Quantitative Trait Loci Influencing
QT interval duration in the Jackson Heart Study
Sara TribuneMentor: Christopher Newton-Cheh
Broad Institute of MIT and Harvard Summer Research Program in GenomicsJackson Heart Study Undergraduate Training Center
Massachusetts General HospitalFramingham Heart Study
Tougaloo College
2
Sudden cardiac death
300,000 deaths/yr US
Risk factors inadequate
Prolonged QT intervals
Increased risk of Sudden Cardiac Death Long QT Syndrome and Short QT Syndrome Drug-induced arrhythmias
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).
1st Step Selection of SNPs2nd Step Genotyped SNPs Final Step Determine locus-specific ancestry Final data analysis
Finemapping of the NOS1AP Associations in African Americans from JHS
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
SNPs correlated to previously associated SNPs in CEU (European data)
Study Design: SNP Selection
CEU Data
YRI Data
rs2074238rs4657140 rs6696160 rs1415262 rs885148 rs7548169 rs16847548 rs7550692 rs2225845
rs6696160 rs1415262 rs885148
Study Design
rs12071519rs12071519 rs10800303 rs4657140 0.919
rs12076589 rs945706 rs6696160 0.966
rs945707rs945707 rs6672881 rs4657140 1.0
rs7525891rs7525891
rs12085258rs12085258 rs3922867 rs4657140 0.882
rs4422984rs4422984
rs4278353rs4278353
rs4256791rs4256791 rs1572498 rs10494366 1.0
rs1415260 rs4657140 0.863
rs1415259 rs10494366 1.0
rs10494366 rs10494366 1.0
Tagger software selected SNPs with r2 ≥0.8 in YRI (West African data).
GenotypingGenotyping
African Descent
European Descent
Locus-specific Locus-specific ancestryancestry
{ } NOS1AP Locus { } NOS1AP Locus { }
Afr-Afr
67.24 %
Afr-Eur
29.52 %
Eur-Eur
3.24 %
Locus-Specific Ancestry Increases Locus-Specific Ancestry Increases Statistical PowerStatistical Power
Whether the association between QT interval duration and the other QTGEN variants exists in
African descent individuals is unknown.
Progress
Study Design Selection of SNPs Selection and formation of assay
pools Genotyped SNPs Interim analysis Final data analysis (August 15)
Acknowledgments
Broad InstituteChristopher Newton-ChehPaul CullenGabriel CrawfordCandace GuiducciDavid ReichNick PattersonArti TandonShawna YoungBruce Birren
Funding supportJackson Heart Study Undergraduate Training Center (Tribune)Broad Summer Research Program in Genomics (Tribune)NIH, Doris Duke, Burroughs Wellcome Fund (Newton-Cheh)
Jackson Heart StudyHerman Taylor James Wilson Meggie Akylbekova Sarah Buxbaum
Thank you
Electrocardiograms
http://www.mercksource.com/pp/us/cns/cns_hl_adam.jspzQzpgzEzzSzppdocszSzuszSzcnszSzcontentzSzadamzSzimagepageszSz8772zPzhtm
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?
Distribution of NOS1AP haplotypes The structure of haplotype blocks in the human genome.
Courtesy of Pardis SabetiGabriel, S. B. et al. The Structure of Haplotype Blocks in the Human Genome. Science 296, 2225-2229 (2002).