Search

Pedigree analysis showed that a large proportion of Leber hereditary optic neuropathy (LHON) family members who carry a mitochondrial risk variant never lose vision. Mitochondrial haplotype appears to be a major factor influencing the risk of vision loss from LHON. Mitochondrial variants, including m.14484TC and m.11778GA, have been added to gene arrays, and thus many patients and research participants are tested for LHON mutations. Analysis of the UK Biobank and Australian cohort studies found more than 1 in 1,000 people in the general population carry either the m.14484TC or the m.11778GA LHON variant. None of the subset of carriers examined had visual acuity at 20/200 or worse, suggesting a very low penetrance of LHON. Haplogroup analysis of m.14484TC carriers showed a high rate of haplogroup U subclades, previously shown to have low penetrance in pedigrees. Penetrance calculations of the general population are lower than pedigree calculations, most likely because of modifier genetic factors. This Matters Arising Response paper addresses the Watson et al. (2022) Matters Arising paper, published concurrently in The American Journal of Human Genetics.

Alzheimer's disease (AD) is predicted to affect 132 million people by 2050. Targeting modifiable lifestyle risk factors that are associated with an increased risk of AD could prevent a large proportion of dementia cases, allowing people to reach the end of their life dementia free. However, evidence obtained from the observational studies does not take into account how risk factors are correlated with one another, and whether they causally contribute to increased AD risk. In this study, we determine whether the relationship between previously speculated AD risk factors and AD susceptibility is consistent with causality using large-scale genetic data. We focus on educational attainment (EA), intelligence and household income which have been previously shown to be causally associated with AD. Using GWAS-by-subtraction and Multivariable Mendelian Randomization we show that of these, only the cognitive component of EA (intelligence) is independently causally associated with AD. This work has ramifications for the modifiability of lifestyle risk factors for AD.

Background: Primary open-angle glaucoma (POAG) is an optic neuropathy characterized by progressive degeneration of the optic nerve that leads to irreversible visual impairment. Multiple epidemiological studies suggest an association between POAG and major neurodegenerative disorders (Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and Parkinson's disease). However, the nature of the overlap between neurodegenerative disorders, brain morphology and glaucoma remains inconclusive. Method: In this study, we performed a comprehensive assessment of the genetic and causal relationship between POAG and neurodegenerative disorders, leveraging genome-wide association data from studies of magnetic resonance imaging of the brain, POAG, and four major neurodegenerative disorders. Findings: This study found a genetic overlap and causal relationship between POAG and its related phenotypes (i.e., intraocular pressure and optic nerve morphology traits) and brain morphology in 19 regions. We also identified 11 loci with a significant local genetic correlation and a high probability of sharing the same causal variant between neurodegenerative disorders and POAG or its related phenotypes. Of interest, a region on chromosome 17 corresponding to MAPT, a well-known risk locus for Alzheimer's and Parkinson's disease, was shared between POAG, optic nerve degeneration traits, and Alzheimer's and Parkinson's diseases. Despite these local genetic overlaps, we did not identify strong evidence of a causal association between these neurodegenerative disorders and glaucoma. Interpretation: Our findings indicate a distinctive and likely independent neurodegenerative process for POAG involving several brain regions although several POAG or optic nerve degeneration risk loci are shared with neurodegenerative disorders, consistent with a pleiotropic effect rather than a causal relationship between these traits. Funding: PG was supported by an NHMRC Investigator Grant (# 1173390), SM by an NHMRC Senior Research Fellowship and an NHMRC Program Grant (APP1150144), DM by an NHMRC Fellowship, LP is funded by the NEI EY015473 and EY032559 grants, SS is supported by an NIH-Oxford Cambridge Fellowship and NIH T32 grant ( GM136577), APK is supported by a UK Research and Innovation Future Leaders Fellowship, an Alcon Research Institute Young Investigator Award and a Lister Institute for Preventive Medicine Award.

Background: Observational studies have suggested that individuals with pre-existing sleep apnoea (SA) have up to double the risk of developing glaucoma than individuals without SA. However, it is unclear if these associations are due to confounding or reverse causation. Disentangling causality from confounding is essential to further our understanding of both diseases. Mendelian randomisation (MR) techniques, which use genetic variants associated with a risk factor (e.g. SA) as instrumental variables (IVs), can be used to infer causality. MR methods can be less susceptible to confounders or reverse causation than observational studies. Methods: In this study, 34 IVs for SA were derived from a genome-wide association study (GWAS) of 25 008 SA cases, 313 372 controls. Two Sample MR analyses were performed to evaluate the relationship between genetically predicted SA and glaucoma susceptibility using summary data from a glaucoma GWAS meta-analysis (20 582 cases, 119 318 controls). We derived odds ratios (OR) for glaucoma arising from a doubling in the genetic odds of having SA. Finding: Using 34 SA SNPs as IVs, we found no strong evidence for an association between SA susceptibility and glaucoma (OR = 0.95, 95% confidence intervals = 0.77 - 1.13) based on the inverse variance weighted (IVW) MR estimator. Interpretation: We found little genetic evidence supporting a causal association between SA and glaucoma. Our results refute the possibility of a large effect (glaucoma OR > 1.5 per doubling of odds on SA) between SA and glaucoma. Funding Information: S.M. and D.A.M are supported by the Australian National Health and Medical Research Council (NHMRC) Fellowships. X.H. is supported by the University of Queensland Research Training Scholarship and QIMR Berghofer Medical Research Institute PhD Top Up Scholarship. We acknowledge funding from NHMRC grants 1123248, 1116360, 1150144, 1023911. A.I.C. is supported by a UQ Research Training Scholarship from The University of Queensland (UQ). M.E.R. acknowledges support from the NHMRC and Australian Research Council (ARC) through a Research Fellowship (GNT1102821). Declaration of Interests: There are no competing interest to disclose. Ethics Approval Statement: Both sources of GWAS summary statistics included here acquired appropriate ethical approval. No ethical approval was required for this study.