Hansen, A. F. | bioRxiv Science

bioRxiv2021

Within-sibship GWAS improve estimates of direct genetic effects

Estimates from genome-wide association studies (GWAS) represent a combination of the effect of inherited genetic variation (direct effects), demography (population stratification, assortative mating) and genetic nurture from relatives (indirect genetic effects). GWAS using family-based designs can control for demography and indirect genetic effects, but large-scale family datasets have been lacking. We combined data on 159,701 siblings from 17 cohorts to generate population (between-family) and within-sibship (within-family) estimates of genome-wide genetic associations for 25 phenotypes. We demonstrate that existing GWAS associations for height, educational attainment, smoking, depressive symptoms, age at first birth and cognitive ability overestimate direct effects. We show that estimates of SNP-heritability, genetic correlations and Mendelian randomization involving these phenotypes substantially differ when calculated using within-sibship estimates. For example, genetic correlations between educational attainment and height largely disappear. In contrast, analyses of most clinical phenotypes (e.g. LDL-cholesterol) were generally consistent between population and within-sibship models. We also report compelling evidence of polygenic adaptation on taller human height using within-sibship data. Large-scale family datasets provide new opportunities to quantify direct effects of genetic variation on human traits and diseases.

genetics↗

bioRxiv2018

Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins

Deficiency in the cytosolic DNA sensor RNA Polymerase III was recently described in children with severe varicella zoster infection in the CNS or lungs. Here we describe a pair of monozygotic female twins, who both experienced severe recurrent CNS vasculitis caused by VZV reactivation. The clinical presentation and findings included recurrent episodes of headache, dizziness, and neurological deficits, cerebrospinal fluid with pleocytosis and intrathecal VZV antibody production, and magnetic resonance scan of the brain showing ischaemic lesions. We performed whole exome sequencing and identified a rare mutation in the Pol III subunit POLR3F. The identified R50W POLR3F mutation is predicted to be damaging by bioinformatics and when tested in functional assays, patient PBMCs exhibited impaired antiviral and inflammatory responses to the PoL III agonist Poly(dA:dT) as well as increased viral replication in patient cells compared to controls. Altogether, these cases add genetic and immunological evidence to the novel association between defects in sensing of AT-rich DNA present in the VZV genome and increased susceptibility to severe manifestations of VZV infection in the CNS in humans.\n\nAbbreviations

immunology↗