Abstract
PURPOSE. Presently; 52 independent nuclear single nucleotide polymorphisms (nSNPs) have been associated with age-related macular degeneration (AMD) but their effects do not explain all its variance. Genetic interactions between the nuclear and mitochondrial (mt) genome may unearth additional genetic loci previously unassociated with AMD risk. METHODS. joint effects of nSNPs and selected mtSNPs ...
Abstract
PURPOSE. Presently; 52 independent nuclear single nucleotide polymorphisms (nSNPs) have been associated with age-related macular degeneration (AMD) but their effects do not explain all its variance. Genetic interactions between the nuclear and mitochondrial (mt) genome may unearth additional genetic loci previously unassociated with AMD risk. METHODS. joint effects of nSNPs and selected mtSNPs were analyzed by two degree of freedom. (2df.) joint tests of association in the International AMD Genomics Consortium (IAMDGC) dataset (17,832 controls and 16,144 advanced AMD cases of European ancestry). Subjects were genotyped on the Illumina HtunanCoreExome array. After imputation using MINIMAC and the 1000 Genomes Project Phase I reference panel, pairwise linkage disequilibrium pruning, and quality control, 3.9 million nS.NPs were analyzed for interaction with. mtSNPs chosen based on association in this dataset or publications: A49170, T5004C, 012771A, and C16069T. RESULTS. Novel locus TRPM1 was identified with genome-wide significant joint effects (P < 5.0 X 10(-8)) of two intronic TRPM1 nSNPs and AMD-associated nonsynonymous MT-ND2 mtSNP A49170. Stratified analysis by mt allele identified an association only in 4917A (major allele) carriers (P = 4.4 X 10(-9), odds ratio [OR] = 0.90, 95% confidence interval [CI] = 0.87-0.93). Intronic and intergenic ABHD2/RLBP1 nSNPs demonstrated genome-wide significant joint effects (2df joint test P values from 1.8 X 10(-8) to 4.9 X 10(-8)) and nominally statistically significant interaction effects with,MT-ND5, synonymous mtSNP 012771A. Although. a positive association was detected in. both strata, the association. was stronger in. 12771A subjects (P = 0.0020, OR 2.17, 95% CI 1.34-3.60). CONCLUSIONS. These results show that joint tests of main effects and gene-gene interaction
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