Biology subjects

Lyons, M. J.

Publications and source records attributed to Lyons, M. J..

3 recordsLinked to original sources

bioRxiv2018

Genetic risk for coronary heart disease alters the influence of Alzheimer’s genetic risk on mild cognitive impairment

BACKGROUNDAlzheimers disease (AD) is under considerable genetic influence. However, known susceptibility loci only explain a modest proportion of variance in disease outcomes. This small proportion could occur if the etiology of AD is heterogeneous. We previously found that an AD polygenic risk score (PRS) was significantly associated with mild cognitive impairment (MCI), an early stage of AD. Poor cardiovascular health is also associated with increased risk for AD and has been found to interact with AD pathology. Conditions such as coronary artery disease (CAD) are also heritable, and may contribute to heterogeneity if there are interactions of genetic risk for these conditions as there is phenotypically. However, case-control designs based on prevalent cases of a disease with relatively high case-fatality rate such as CAD may be biased toward individuals who have long post-event survival times and may therefore also identify loci with protective effects.\n\nMETHODSWe compared interactions between an AD-PRS and two CAD-PRSs, one based on a GWAS of incident cases and one on prevalent cases, on MCI status in 1,209 individuals.\n\nRESULTSAs expected, the incidence-based CAD-PRS interacts with the AD-PRS to further increase MCI risk. Conversely, higher prevalence-based CAD-PRSs reduced the effect of AD genetic risk on MCI status.\n\nCONCLUSIONSThese results demonstrate: i) the utility of including multiple PRSs and their interaction effects; ii) how genetic risk for one disease may modify the impact of genetic risk for another; and iii) the importance of considering ascertainment procedures of GWAS being used for genetic risk prediction.

genomics↗

bioRxiv2018

Thrombocytopenia Microcephaly Syndrome - a novel phenotype associated with ACTB mutations

Introductory paragraphUntil recently missense germ-line mutations in ACTB, encoding the ubiquitously expressed {beta}-cytoplasmic actin (CYA), were exclusively associated with Baraitser-Winter Cerebrofrontofacial syndrome (BWCFF), a complex developmental disorder1,2. Here, we report six patients with previously undescribed heterozygous variants clustered in the 3-coding region of ACTB. These patients present with clinical features different from BWCFF, including thrombocytopenia, microcephaly, and mild developmental disability. Patient derived cells are morphologically and functionally distinct from controls. Assessment of cytoskeletal constituents identified a discrete filament population altered in these cells, which comprises force generating and transmitting actin binding proteins (ABP) known to be associated with thrombocytopenia3-8. In silico modelling and molecular dynamics (MD)-simulations support altered interactions between these ABP and mutant {beta}-CYA. Our results describe a new clinical syndrome associated with ACTB mutations with a distinct genotype-phenotype correlation, identify a cytoskeletal protein interaction network crucial for thrombopoiesis, and provide support for the hypomorphic nature of these actinopathy mutations.

genetics↗

bioRxiv2017

Brain structure mediates the association between height and cognitive ability

Height and general cognitive ability (GCA) are positively associated, but the underlying mechanisms of this relationship are unclear. We used a sample of 515 middle-aged male twins with structural magnetic resonance imaging data to study if the association between height and cognitive ability is mediated by cortical size. We used genetically, ontogenetically and phylogenetically distinct cortical metrics of cortical surface area (SA) and cortical thickness (CT). Our results indicate that the well-replicated height-GCA association is accounted for by individual differences in total cortical SA (highly heritable metric related to global brain size), and not mean CT, and that the genetic association between SA and GCA underlies the phenotypic height-GCA relationship.

neuroscience↗