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Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort
Abbas Dehghan1, Joshua C Bis2, Charles C White3
1Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
Insights
Genome-wide association studies identified a new locus near QKI associated with coronary heart disease (CHD) risk. The 9p21 locus influences myocardial infarction (MI) risk and survival post-MI.
Area of Science:
- Genetics
- Cardiovascular Disease Epidemiology
Background:
- Limited genome-wide association studies (GWAS) data exists for incident coronary heart disease (CHD).
- The association of previously identified genetic variants with prospective CHD risk remains unclear.
Purpose of the Study:
- To conduct a two-stage GWAS for incident myocardial infarction (MI) and CHD.
- To investigate whether known GWAS single nucleotide polymorphisms (SNPs) associate with mortality risk after MI.
Main Methods:
- A two-stage GWAS was performed on 64,297 individuals, including 3898 MI and 5465 CHD cases.
- SNPs surpassing a 5×10-6 threshold in Stage I proceeded to Stage II for discovery.
- Prognostic analysis examined associations between known GWAS SNPs and mortality in MI survivors.
Main Results:
- Fifteen loci met the Stage I significance threshold; 8 for MI and 8 for CHD, with one overlapping locus not previously reported.
- Four SNPs near QKI showed nominal association with MI, with one (rs6941513) reaching genome-wide significance (p = 6.2×10-9) after combining stages.
- The 9p21 locus SNP (rs1333049) showed modest association with MI risk (HR=1.09) and marginal association with CHD risk (HR=1.06).
- In MI survivors, the rs1333049 risk allele was linked to decreased subsequent mortality (HR=0.90).
Conclusions:
- The QKI locus is a novel predictor for incident CHD in prospective studies.
- The 9p21 locus's dual role in MI risk and post-MI survival underscores the importance of study design in genetic research for complex diseases.
Background:
Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting.
Methods:
We performed a two-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5×10-6 in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with total mortality in individuals who experienced MI during follow-up.
Results:
In Stage I 15 loci passed the threshold of 5×10-6; 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value<8.8×10-3) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2×10-9). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2×10-3).
Conclusions:
QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders.
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