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

Abstract

PurposePresently, 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.MethodsJoint 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.ResultsNovel 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).ConclusionsThese 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.

Mitochondrial diseases caused by mtDNA mutations: a mini-review

“…A similar effect was observed when mtDNA mutation m.12771G>A (gene MT-ND5 ) was combined with polymorphisms of nuclear DNA rs4932478, rs4932480, rs11459118, rs875390, rs875391, rs2351006, rs144871045 and rs2070780 (loci ABHD2 / RLBP1 , chromosome 15). 104 In the research work by Meng et al, 105 it was shown that the combination of the nuclear modifier allele A10S in the TRMU gene with mitochondrial genome mutation m.1555A>G ( MT-RNR1 gene) increased the risk of deafness.…”

Genetic polymorphisms of transient receptor potential melastatin 1 correlate with voriconazole‐related visual adverse events

“…It was found to participate in generating depolarising light response and to functionally regulate melanocyte pigmentation 22,23 . TRPM1 genetic polymorphisms had been implicated in human diseases, including CSNB1, age‐related macular degeneration, albuminuria and mental disorder like schizophrenia and autism 13,24‐28 . Notably, production of anti‐TRPM1 autoantibodies resulted in melanoma‐associated retinopathy (MAR), an autoimmune syndrome presented with photophobia, photopsia and enhanced perception, which were similar to those described in VVAE 29,30 .…”

Investigating the modulation of genetic effects on late AMD by age and sex: Lessons learned and two additional loci

“…While 27 of the 29 loci overlap with regions that were identified in the previous screen for AMD (using the identical data set) [ 13 ], two additional AMD loci were identified in this study by accounting for age differences. One hit is located in a novel AMD region on chromosome 18 (rs9973159, P Agejoint = 3.91 x 10 −8 ) and one in a region on chromosome 15 that was recently identified for AMD in a joint analysis of nuclear and mitochondrial variants [ 20 ] (rs2070780, P Agejoint = 3.19 x 10 −8 , Figs 2 and 3 , Table 2 , S3 Table ). A search for independent second signals at the two loci by conditioning on the two lead variants did not reveal any independent second signals (P Agejoin;cond ≥ 5 x 10 −8 ).…”

“…Secondly, by accounting for potentially differential genetic effects between age groups, we identified two AMD loci that were undetected in a previous main effect screen using the identical dataset [ 13 ]. These two additional AMD loci point to a novel AMD GWAS region on chromosome 15 and one region on chromosome 18 that was recently identified as AMD risk locus in a joint analysis of nuclear and mitochondrial variants [ 20 ]. Thirdly, we found no differences in the genetic effects for late AMD between men and women despite considerable power in our study design.…”

“…This is in line with the observation that the cumulative genetic risk for late AMD calculated for 13 genetic variants was higher in younger than in older individuals [ 14 ]. For the RLBP1 locus, the stronger effect on AMD in the younger is linked to the observed modification of the effect of this variant to AMD disease development (or a highly correlated variant, rs11459118, r 2 = 0.85) given the genotypes of a mitochondrial variant [ 20 ]. One might speculate that a genetically modified mitochondrial function triggers the effect of the nuclear variant in the younger, but may not cause a similar damage in the older due to a well-known decline of mitochondrial function at higher age [ 31 ].…”