A perspective on epistasis: limits of models displaying no main effect

Area of Science:

• Human Genetics
• Statistical Genetics
• Genomic Association Studies

Background:

• The human genome draft sequence and SNP genotyping advance genome-wide association studies (GWAS).
• There's a push to replace traditional linkage studies with association-based approaches.
• Purely epistatic genetic models pose a challenge for current association methods.

Purpose of the Study:

• To investigate the efficacy of linkage studies for purely epistatic genetic models.
• To define the genetic determination and recurrence risks for multi-locus epistatic models.
• To explore extensions of association methods for complex genetic architectures.

Main Methods:

• Analysis of two-, three-, and four-locus purely epistatic models.
• Quantification of genetic determination and recurrence risks.
• Examination of allele sharing patterns in affected sib pairs.
• Development of extended multilocus association methods, including a conditional TDT.

Main Results:

• Purely epistatic models lack additive or dominance variation, rendering single-locus association tests powerless.
• These models exhibit increased allele sharing between affected siblings.
• Linkage analysis can successfully identify genomic regions containing susceptibility loci for epistatic traits.

Conclusions:

• Linkage studies remain valuable for detecting disease genes underlying purely epistatic models.
• Genome scans for linkage can complement association studies in complex genetic trait discovery.
• Modified association methods may improve power for detecting epistatic effects.