Synthetic associations in the context of genome-wide association scan signals.
- Authors
- Orozco, Gisela; Barrett, Jeffrey C; Zeggini, Eleftheria
- Year
- 2010
- Journal
- Human molecular genetics
- PMID
- 20805105
- DOI
- 10.1093/hmg/ddq368
- PMCID
- PMC2953742
Genome-wide association studies (GWAS) have successfully identified a large number of genetic variants associated with complex traits, but these only explain a small proportion of the total heritability. It has been recently proposed that rare variants can create 'synthetic association' signals in GWAS, by occurring more often in association with one of the alleles of a common tag single nucleotide polymorphism. While the ultimate evaluation of this hypothesis will require the completion of large-scale sequencing studies, it is informative to place it in the broader context of what is known about the genetic architecture of complex disease. In this review, we draw from empirical and theoretical data to summarize evidence showing that synthetic associations do not underlie many reported GWAS associations.
Simplified view of genetic variation at the NOD2 locus, a well-documented example of a synthetic association. The left-hand side shows a genealogical tree representing six SNPs in this region after discarding rare recombinant events. The right-hand side shows the resulting haplotypes and their population frequencies (48), with coloured circles representing common GWAS SNPs, and starbursts representing previously identified low-frequency coding variants responsible for association between NOD2 and CD. While none of the GWAS SNPs is strongly correlated with any individual causal allele, the three coding variants create a synthetic association because they cluster by chance on the side of the tree marked by the green GWAS SNP (rs2076756).
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| 20 | FUNDING | G.O. is funded by the European Union (Marie Curie IEF Fellowship PIEF-GA-2009-235662). E.Z. and… |
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