Send to

Choose Destination
Invest Ophthalmol Vis Sci. 2017 Aug 1;58(10):4027-4038. doi: 10.1167/iovs.17-21734.

Joint Analysis of Nuclear and Mitochondrial Variants in Age-Related Macular Degeneration Identifies Novel Loci TRPM1 and ABHD2/RLBP1.

Author information

John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, United States.
Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States.
Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States.
Centre for Eye Research Australia, Department of Surgery (Ophthalmology) University of Melbourne, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia.
Department of Ophthalmology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, United States.



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.


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 HumanCoreExome array. After imputation using MINIMAC and the 1000 Genomes Project Phase I reference panel, pairwise linkage disequilibrium pruning, and quality control, 3.9 million nSNPs were analyzed for interaction with mtSNPs chosen based on association in this dataset or publications: A4917G, T5004C, G12771A, and C16069T.


Novel locus TRPM1 was identified with genome-wide significant joint effects (P < 5.0 × 10-8) of two intronic TRPM1 nSNPs and AMD-associated nonsynonymous MT-ND2 mtSNP A4917G. Stratified analysis by mt allele identified an association only in 4917A (major allele) carriers (P = 4.4 × 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 × 10-8 to 4.9 × 10-8) and nominally statistically significant interaction effects with MT-ND5 synonymous mtSNP G12771A. 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).


These results show that joint tests of main effects and gene-gene interaction reveal associations at some novel loci that were missed when considering main effects alone.

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Silverchair Information Systems Icon for PubMed Central
Loading ...
Support Center