Table 1.
Genome-wide significant epistatic pairs identified in the ARIC cohort and their replication in the NFBC199 cohort.*
Figure 1.
Differences in the numbers of SNP pairs with Pint<5.0E-08 and local interaction pairs (Pint<1.0E-05) detected in each trait between ARIC and NFBC1966.
Figure 2.
A cartoon model illustrating a haplotype tagging a recessive causal variant can generate an apparent statistical interaction between two unlinked SNPs each with limited marginal effects.
(I) A recessive causative variant (black star) is associated with only the ab SNP haplotype, assuming Hardy-Weinberg Equilibrium, i.e. an equal allele frequency of 0.5 for each SNP so there is no LD between the two SNPs and an equal frequency of 0.25 for each of the four possible haplotypes, and the causal variant with an effect size of 1. (II) Only individuals homozygous for this haplotype (ab/ab) are genetically differentiated generating apparent epistasis (averaged trait value and joint genotype frequency in the bracket in each cell). (III) Marginal effects associated with the individual SNPs are limited with only one in four individuals of the aa or bb SNP genotype being affected with a trait value of 2 so the averaged trait value of the genotype is 0.5 (SNP genotype frequency in brackets), thus the individual SNPs may not be detected by a conventional GWAS. (IV) This resembles the interaction between rs17119975 and rs10892020 in TRI (Table 1) where neither SNP had important marginal effects and their interaction signal was mainly because of the differentiated phenotype associated with the double homozygous aabb genotype.
Figure 3.
Proportions of local interactions in different LD ranges.
Figure 4.
Local interactions (Pint<1.0E-05) within the 11q23.3 region associated with TRI in ARIC and supporting ENCODE regulatory evidence.
(A) black oval: the top marginal SNP rs964184 within the region; each line representing an interaction between two SNPs at the start and end locations where red and blue lines represent interactions prior to and post conditional tests respectively; red and blue ovals: the marginal SNP rs6589567 prior to and post conditional test respectively; y axis: association P values in the −log10 scale; x axis: genomic location in base pair; arrow bar showing transcription direction and location of the gene (italic) below the bar. (B) a snapshot from UCSC genome browser showing clustered ENCODE regulatory elements aligning to the 5′ ends of BUD13 and ZNF259 respectively.
Table 2.
Local interactions captured additional genome-wide significant loci identified in GWAS of the eight traits in ARIC and/or NFBC1966.*