Bailey, Jessica N. Cooke

ABSTRACT/SUMMARY Purpose Common LOXL1 protein-altering variants are significant genetic risk factors for exfoliation syndrome (XFS) and the related secondary glaucoma (XFG). A rare LOXL1 missense allele was associated with protective effects in a Japanese cohort, suggesting that other rare alleles may also exhibit protective effects. The goal of this study is to assess the contributions of rare LOXL1 variants to XFS/XFG risk in cases and controls from the United States (US). Methods LOXL1 rare variants (minor allele frequency (MAF) < 1%) were identified from Human exome BeadArray (Illumina) data for 1118 XFS/XFG cases and 3661 controls (Mass Eye and Ear (MEE) cohort) and from exome sequence data for 284 cases and 37,499 controls in All of Us (AoU) The distribution of rare variants, haplotypes, and diplotypes was examined using Fisher exact test. Results Four rare LOXL1 missense alleles, more common in controls, were identified in MEE, P= 7.6E-4), and 456 variants identified in AoU were found only in controls (P=0.045). The rare protective alleles were preferentially located (P= 5.8E-45) in a LOXL1 intrinsic disordered region (IDR) potentially involved in LOXL1 aggregation. Haplotypes that included the rare or minor variants were more common in controls compared to cases in both MEE (Odds Ratio (OR)= 0.21 (95% Confidence interval (CI): 0.19-0.24), P=1.7E-173) and AoU (OR=0.28 (95% CI: 0.23-0.34), P=4.4E-41), and heterozygous diplotypes were also significantly associated with reduced risk overall in both MEE (OR= 0.45 (95% CI: 0.52-0.39), P= 1.7E-89) and AoU (OR=0.26 (95% CI: 0.18-0.33, P=7.6E-28). Diplotypes comprised of only homozygous genotypes were associated with increased disease risk in both MEE and AoU (OR= 4.16 (95% CI: 3.60-4.76), P= 4.2E-89 and 5.26 (95% CI: 4.12-6.73), P=1.87E-42, respectively) and excess homozygosity and decreased heterozygosity was correlated with disease risk for common LOXL1 variants across multi-ethnic populations (P=1.0E-6). Conclusions Using exome array and exome sequence data from XFS/XFG cases and controls from the United States, we identified rare protective LOXL1 missense variants and show that the distribution of the corresponding haplotypes and diplotypes was associated with lower risk of XFS/XFG. Diplotype results also demonstrated that LOXL1 allelic heterozygosity was inversely associated, while homozygosity was associated with increased disease risk. These results suggest that LOXL1 MAF variation among populations, with corresponding variation in genotype heterozygosity and homozygosity, determines the XFS/XFG association.

Abstract Objective: Several attributes of female reproductive history, including age at natural menopause (ANM), have been related to primary open-angle glaucoma (POAG). We assembled 18 previously reported common genetic variants that predict ANM to determine their association with ANM or POAG. Methods: Using data from the Nurses’ Health Study (7,143 women), we validated the ANM weighted genetic risk score in relation to self-reported ANM. Subsequently, to assess the relation with POAG, we used data from 2,160 female POAG cases and 29,110 controls in the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database (NEIGHBORHOOD), which consists of 8 datasets with imputed genotypes to 5.6+ million markers. Associations with POAG were assessed in each dataset, and site-specific results were meta-analyzed using the inverse weighted variance method. Results: The genetic risk score was associated with self-reported ANM (P = 2.2 × 10–77) and predicted 4.8% of the variance in ANM. The ANM genetic risk score was not associated with POAG (Odds Ratio (OR) = 1.002; 95% Confidence Interval (CI): 0.998, 1.007; P = 0.28). No single genetic variant in the panel achieved nominal association with POAG (P ≥0.20). Compared to the middle 80 percent, there was also no association with the lowest 10th percentile or highest 90th percentile of genetic risk score with POAG (OR = 0.75; 95% CI: 0.47, 1.21; P = 0.23 and OR = 1.10; 95% CI: 0.72, 1.69; P = 0.65, respectively). Conclusions: A genetic risk score predicting 4.8% of ANM variation was not related to POAG; thus, genetic determinants of ANM are unlikely to explain the previously reported association between the two phenotypes.

AbstractIntroductionAfrican‐American (AA) individuals have a higher risk for late‐onset Alzheimer's disease (LOAD) than Americans of primarily European ancestry (EA). Recently, the largest genome‐wide association study in AAs to date confirmed that six of the Alzheimer's disease (AD)‐related genetic variants originally discovered in EA cohorts are also risk variants in AA; however, the risk attributable to many of the loci (e.g., APOE, ABCA7) differed substantially from previous studies in EA. There likely are risk variants of higher frequency in AAs that have not been discovered.MethodsWe performed a comprehensive analysis of genetically determined local and global ancestry in AAs with regard to LOAD status.ResultsCompared to controls, LOAD cases showed higher levels of African ancestry, both globally and at several LOAD relevant loci, which explained risk for AD beyond global differences.DiscussionExploratory post hoc analyses highlight regions with greatest differences in ancestry as potential candidate regions for future genetic analyses.