title: Pooled DNA resequencing of 68 myocardial infarction candidate genes in French canadians.
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.
  
  
  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.
authors.affiliation: Montreal Heart Institute, 5000 Rue Bélanger, Montreal, Québec, Canada.
authors.forename: Mélissa
authors.initials: M
authors.lastname: Beaudoin
authors.forename: Ken Sin
authors.initials: KS
authors.lastname: Lo
authors.forename: Amidou
authors.initials: A
authors.lastname: N'Diaye
authors.forename: Manuel A
authors.initials: MA
authors.lastname: Rivas
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Dubé
authors.forename: Nathalie
authors.initials: N
authors.lastname: Laplante
authors.forename: Michael S
authors.initials: MS
authors.lastname: Phillips
authors.forename: John D
authors.initials: JD
authors.lastname: Rioux
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Tardif
authors.forename: Guillaume
authors.initials: G
authors.lastname: Lettre
mesh_terms: D000328:Adult; D000368:Aged; D002170:Canada; D015331:Cohort Studies; D005091:Exons; D005260:Female; D005787:Gene Frequency; D008040:Genetic Linkage; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D044465:White People / Q000235:genetics*