Speaker: Dr Sinan Shi, Lecturer in Genomic Medicine, University of Manchester
Title: Genome-wide investigation of nuclear modifiers underlying incomplete penetrance in Leber’s hereditary optic neuropathy (LHON)
Abstract: Leber’s hereditary optic neuropathy is thought to be caused by three mitochondria mutations, with a clinical prevalence of approximately 1 in 27,000. Carriage of a primary pathogenic variant is far more common than disease – roughly 1 in 500. Penetrance also varies markedly between families carrying the same homoplasmic variant, from as low as 1% to over 70%. The primary mtDNA mutation is therefore necessary but not sufficient, and a nuclear modifier of penetrance has long been proposed. We assembled genotype and sequence data from LHON pedigrees recruited in Italy and the United Kingdom, together with carriers identified in UK Biobank, to test this hypothesis at genome-wide scale. Case–carrier association analysis in this setting is inherently underpowered, since unaffected carriers are the limiting group and the total ascertainable cohort is small; our analytical strategy was designed around that constraint. We performed genome-wide association analysis under complementary designs, including inverse-variance meta-analysis of the two pedigree collections analysed separately, mega-analysis of pooled individual-level data, and time-to-onset modelling of age at conversion and prioritised loci on the basis of screening thresholds, variant- and peak-level quality control, and coherence across designs. We complemented this with gene-based rare-variant burden testing in exome-sequenced carriers, and with genome-wide multipoint linkage analysis across the pedigree collection under model-free and parametric specifications. Finally, we evaluated published polygenic scores against penetrance and age at onset. Beyond the candidates themselves, the study illustrates what can be recovered from an underpowered cohort by aggregation and complementary study designs, and where that recovery reaches its limit.
