Genome-wide analysis of mitochondrial single nucleotide polymorphism (mtSNP)-nuclear SNP interaction in age-related macular degeneration (AMD). P. J. Persad1, M. D. Courtenay1, G. Wang1, P. W. Gay1, W. Cade1, A. Agarwal3, S. G. Schwartz2, J. L. Kovach2, M. A. Brantley3, R. J. Sardell1, J. N. Cooke Bailey4, J. L. Haines4, M. A. Pericak-Vance1, W. K. Scott1 1) Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL; 2) Bascom Palmer Eye Institute, Naples, FL, University of Miami Miller School of Medicine, Miami, FL; 3) Vanderbilt University, Nashville, TN; 4) Department of Epidemiology & Biostatistics, Case Western Reserve University, Cleveland, OH.

   AMD has 19 identified genetic risk factors, and variations in CFH are among the strongest. Deletion of related genes CFHR1 and CFHR3 is inversely associated with AMD. Mitochondrial (mt) dysfunction contributes to retinal pigment epithelium degeneration, which characterizes AMD. Prior studies suggested that mt haplogroup H was inversely associated with AMD and was associated with increased CFH expression (Kenney et al., 2013). Since this implied that mt variants might alter effects of nuclear SNPs (nSNPs), we examined joint effects of mtSNPs and nSNPs in a genome-wide interaction analysis of 668,238 SNPs on the Affymetrix 6.0 GWAS chip (Naj et al., 2013). In total, 1,419 people with smoking history were included: 894 AMD cases with varying grades of AMD and 525 controls. A two-degree of freedom joint test of gene-gene interaction was conducted using PLINK. A model including the nSNP (coded additively), the mtSNP (coded 0,1), and the nSNP-mtSNP interaction term was compared to a second model excluding the nSNP and interaction terms. Both models were adjusted for age, sex, and smoking. Interaction was assessed for 26 mtSNPs and all nSNPs. Analyses stratified by mt allele for statistically significant interactions utilized logistic regression models containing the nSNP, age, smoking, and sex. Joint effects of mtSNP rs3928306 in the 16S rRNA gene and nSNPs rs13375236, rs6428369, and rs2336503 in the CFH region achieved genome-wide statistical significance (p<5.00x10-8) with nominally statistically significant (p<0.01) interaction effects. Analyses stratified by rs3928306 allele revealed genome-wide significant association in rs3928306-G carriers for the three nSNPs, which were in complete linkage disequilibrium (LD) [OR=0.31, 95% CI: (0.22-0.44), p=2.91x10-11]; there was no association in the rs3928306-A carriers [OR= 0.87, CI: (0.47-1.61); p=0.66]. The three nSNPs were in moderate LD (r2=0.52) with rs7542235 (HapMap phase II data), a tag SNP for the CFHR1-CFHR3 deletion (Raychaudhuri et al., 2010). Thus, the mtSNP rs3928306 may modify the association of the CFHR1-CFHR3 deletion with AMD. This deletions protective effect is not present in rs3928306-A carriers but is found in rs3928306-G carriers. These results demonstrate the importance of considering the joint effects of mtSNPs and nSNPs in AMD.

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