👤 Andrew T DeWan

Primary open-angle glaucoma is the most common form of glaucoma worldwide and one of the leading causes of irreversible blindness. Current therapies focus on intraocular pressure control despite substantial evidence on the importance of additional pathogenic mechanisms involved in neuronal repair and regeneration. Some of these mechanisms may be shared with and across other neurodegenerative disorders, such as Alzheimer's disease. Joint analyses that address this pathogenic overlap can be leveraged to identify suspected neurodegenerative and neuroprotective pathways. In this study, we derived gene-level summary statistics from available genome-wide association studies for primary open-angle glaucoma and Alzheimer's Disease and employed a multivariate analysis to identify genes with an effect on both neurodegenerative diseases. We assessed the influence of the prioritized genes using Mendelian randomization to obtain the effect of retina- and brain cortex-specific gene expression on primary open-angle glaucoma risk. We identified ten genes with evidence of a pleiotropic effect on primary open-angle glaucoma and Alzheimer's disease: TMCO1, ANXA11, ARHGAP27, PLEKHM1, CRHR1, KANSL1, LRRC37A, ARL17A, LRRC37A2, and CBY1. Additionally, gene expression in either the retina or brain cortex of TMCO1, ANXA11, ARHGAP27, PLEKHM1, KANSL1, LRRC37A, ARL17A, LRRC37A2, and CBY1 influenced POAG risk. These genes have known roles in neurodegeneration-associated pathways. Our analysis uncovered evidence of pleiotropy and gene expression as a mechanism impacting disease risk. Further investigation into these genes may yield valuable insights into their involvement in neurodegenerative pathways potentially informing new approaches for early detection, classification, and treatment strategies. Show less

Age-related (AR) hearing loss (HL) is the most prevalent sensorineural disorder in older adults. Here we demonstrate that rare-variants in well-established Mendelian HL genes play an important role in ARHL etiology. In all we identified 32 Mendelian HL genes which are associated with ARHL. We performed single and rare-variant aggregate association analyses using exome data obtained from white-Europeans with self-reported hearing phenotypes from the UK Biobank. Our analysis revealed previously unreported associations between ARHL and rare-variants in Mendelian non-syndromic and syndromic HL genes, including MYO15A, and WFS1. Additionally, rare-variant aggregate association analyses identified associations with Mendelian HL genes i.e., ACTG1, GRHL2, KCNQ4, MYO7A, PLS1, TMPRSS3, and TNRC6B. Four novel ARHL genes were also detected: FBXO2 and PALM3, implicated in HL in mice, TWF1, associated with HL in Dalmatian dogs, and TXNDC17. In-silico analyses provided further evidence of inner ear expression of these genes in both murine and human models, supporting their relevance to ARHL. Analysis of variants with minor allele frequency >0.005 revealed additional ARHL associations with known e.g., ILDR1 and novel i.e., ABHD12, COA8, KANSL1, SERAC1, and UBE3B Mendelian non-syndromic and syndromic HL genes as well as ARHL associations with genes that have not been previously reported to be involved in HL e.g., VCL. Rare-variants in Mendelian HL genes typically exhibited higher effect sizes for ARHL compared to those in other associated genes. In conclusion, this study highlights the critical role Mendelian non-syndromic and syndromic HL genes play in the etiology of ARHL. Show less

Our study examined whether common variants of obesity-associated genes FTO, MC4R, BDNF, and CREB1 moderated the effects of a lifestyle intervention on weight change among breast cancer survivors. 151 breast cancer survivors with a body mass index ≥ 25 kg/m Women in the intervention group achieved significantly greater weight loss than the usual care group (5.9% vs 0.4%, p < 0.001), regardless of genotype. Changes in weight and percent body fat did not differ significantly between carriers of the FTO rs9939609, MC4R rs6567160, BDNF rs11030104, and CREB1 rs17203016 risk alleles compared to non-carriers (p-interaction > 0.0125 for each single-nucleotide polymorphisms). Women who are genetically predisposed to obesity and recently diagnosed with breast cancer may achieve significant and clinically meaningful weight loss through healthy eating and exercise. NCT02863887 (Date of Registration: August 11, 2016); NCT02110641 (Date of Registration: April 10, 2014). Show less