title: Accounting for a quantitative trait locus for plasma triglyceride levels: utilization of variants in multiple genes.
abstract: BACKGROUND
  For decades, research efforts have tried to uncover the underlying genetic basis of human susceptibility to a variety of diseases. Linkage studies have resulted in highly replicated findings and helped identify quantitative trait loci (QTL) for many complex traits; however identification of specific alleles accounting for linkage remains elusive. The purpose of this study was to determine whether with a sufficient number of variants a linkage signal can be fully explained.
  
  
  METHODS
  We used comprehensive fine-mapping using a dense set of single nucleotide polymorphisms (SNPs) across the entire quantitative trait locus (QTL) on human chromosome 7q36 linked to plasma triglyceride levels. Analyses included measured genotype and combined linkage association analyses.
  
  
  RESULTS
  Screening this linkage region, we found an over representation of nominally significant associations in five genes (MLL3, DPP6, PAXIP1, HTR5A, INSIG1). However, no single genetic variant was sufficient to account for the linkage. On the other hand, multiple variants capturing the variation in these five genes did account for the linkage at this locus. Permutation analyses suggested that this reduction in LOD score was unlikely to have occurred by chance (p = 0.008).
  
  
  CONCLUSIONS
  With recent findings, it has become clear that most complex traits are influenced by a large number of genetic variants each contributing only a small percentage to the overall phenotype. We found that with a sufficient number of variants, the linkage can be fully explained. The results from this analysis suggest that perhaps the failure to identify causal variants for linkage peaks may be due to multiple variants under the linkage peak with small individual effect, rather than a single variant of large effect.
authors.affiliation: Divisions of Human Genetics and Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America. Lisa.martin@cchmc.org
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Martin
authors.forename: Ahmed H
authors.initials: AH
authors.lastname: Kissebah
authors.forename: Michael
authors.initials: M
authors.lastname: Olivier
mesh_terms: D000328:Adult; D015331:Cohort Studies; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D009765:Obesity / Q000097:blood / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D017422:Sequence Analysis, DNA; D014280:Triglycerides / Q000097:blood*
chemical_list: D014280:Triglycerides