Hemani et al. reply

Gibran Hemani, Konstantin Shakhbazov, Harm-Jan Westra, Tonu Esko, Anjali K. Henders, Allan F. McRae, Jian Yang, Greg Gibson, Nicholas G. Martin, Andres Metspalu, Lude Franke, Grant W. Montgomery (+2 others)
2014 Nature  
Hemani et al. We thank Wood et al. for their interesting observations but do not believe that their overall conclusions are consistent with the results presented. First, although we replicate our results in large, independent samples, they do not replicate 19/30 of our reported interactions ( Table 1 in [1]) in the InCHIANTI dataset (N=450) at a type-I error rate of 0.05/30=0.002, including none of our reported cis-trans interactions. Despite having insufficient data to draw conclusions on the
more » ... is-trans effects, Wood et al. claim that this alternative explanation implies that there remains 'no compelling evidence for widespread epistasis in humans'. Second, applying their method in our discovery and replication datasets [1] fails to abrogate the statistical evidence for epistasis. Specifically, the meta-analysis of these results shows that interaction effects remain for 24/26 epistasis pairs after correcting for effects of the IncSeq SNP (Table 1) . For the remaining two pairs (at CSTB and LAX1) we cannot rule out a haplotype effect such as postulated by Wood et al. and this may indeed be a more parsimonious explanation for these two pairs. Haplotype effects are known to be confounding factors in cis-cis interactions, as stated in Hemani et al. Third, Wood et al. ignore the possibility that the IncSeq SNP is either one of the epistatic causal loci, or in higher LD with the causal loci than the genotyped epistatic SNP and
doi:10.1038/nature13692 pmid:25279929 pmcid:PMC4404158 fatcat:4fp6sxuhzbflthwn76f4wbslrq