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).