Replication and Finemapping of Quantitative Trait Loci Influencing QT interval duration in the Jackson Heart Study

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

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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).
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Finemapping of the NOS1AP Associations in African
Americans from JHS

• 1st Step
• Selection of SNPs
• 2nd Step
• Genotyped SNPs
• Final Step
• Determine locus-specific ancestry
• Final data analysis

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African Variants Show Less Correlation

• Using Hapmap data and Haploview
• Correlation of SNPS in CEU (ED) and YRI (AD)
  data set
• RedStrong Correlation
• WhiteNo Correlation

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Study Design SNP Selection
SNPs correlated to previously associated SNPs in
CEU (European data)
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Study Design
Tagger software selected SNPs with r2 0.8 in
YRI (West African data).
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Genotyping
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Locus-Specific Ancestry Increases Statistical
Power
Afr-Afr 67.24
Afr-Eur 29.52
Eur-Eur 3.24
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• Whether the association between QT interval
  duration and the other QTGEN variants exists in
  African descent individuals is unknown.

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Progress

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

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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

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Electrocardiograms
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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?
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The structure of haplotype blocks in the human
genome.
Distribution of NOS1AP haplotypes

Courtesy of Pardis Sabeti
Gabriel, S. B. et al. The Structure of Haplotype
Blocks in the Human Genome. Science 296,
2225-2229 (2002).