Pooled DNA resequencing of 68 myocardial infarction candidate genes in French canadians

Circ Cardiovasc Genet. 2012 Oct 1;5(5):547-54. doi: 10.1161/CIRCGENETICS.112.963165. Epub 2012 Aug 25.

Abstract

Background: Familial history is a strong risk factor for coronary artery disease (CAD), especially for early-onset myocardial infarction (MI). Several genes and chromosomal regions have been implicated in the genetic cause of coronary artery disease/MI, mostly through the discovery of familial mutations implicated in hyper-/hypocholesterolemia by linkage studies and single nucleotide polymorphisms by genome-wide association studies. Except for a few examples (eg, PCSK9), the role of low-frequency genetic variation (minor allele frequency [MAF]) ≈0.1%-5% on MI/coronary artery disease predisposition has not been extensively investigated.

Methods and results: We selected 68 candidate genes and sequenced their exons (394 kb) in 500 early-onset MI cases and 500 matched controls, all of French-Canadian ancestry, using solution-based capture in pools of nonindexed DNA samples. In these regions, we identified 1852 single nucleotide variants (695 novel) and captured 85% of the variants with MAF≥1% found by the 1000 Genomes Project in Europe-ancestry individuals. Using gene-based association testing, we prioritized for follow-up 29 low-frequency variants in 8 genes and attempted to genotype them for replication in 1594 MI cases and 2988 controls from 2 French-Canadian panels. Our pilot association analysis of low-frequency variants in 68 candidate genes did not identify genes with large effect on MI risk in French Canadians.

Conclusions: We have optimized a strategy, applicable to all complex diseases and traits, to discover efficiently and cost-effectively DNA sequence variants in large populations. Resequencing endeavors to find low-frequency variants implicated in common human diseases are likely to require very large sample size.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Canada
  • Cohort Studies
  • European Continental Ancestry Group / genetics*
  • Exons
  • Female
  • Gene Frequency
  • Genetic Linkage
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Myocardial Infarction / genetics*
  • Polymorphism, Single Nucleotide
  • Risk Factors
  • Sequence Analysis, DNA