Biology subjects

Paternoster, L.

Publications and source records attributed to Paternoster, L..

6 recordsLinked to original sources

bioRxiv2018

Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors

Birth weight (BW) variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. These associations have been proposed to reflect the lifelong consequences of an adverse intrauterine environment. In earlier work, we demonstrated that much of the negative correlation between BW and adult cardio-metabolic traits could instead be attributable to shared genetic effects. However, that work and other previous studies did not systematically distinguish the direct effects of an individuals own genotype on BW and subsequent disease risk from indirect effects of their mothers correlated genotype, mediated by the intrauterine environment. Here, we describe expanded genome-wide association analyses of own BW (n=321,223) and offspring BW (n=230,069 mothers), which identified 278 independent association signals influencing BW (214 novel). We used structural equation modelling to decompose the contributions of direct fetal and indirect maternal genetic influences on BW, implicating fetal- and maternal-specific mechanisms. We used Mendelian randomization to explore the causal relationships between factors influencing BW through fetal or maternal routes, for example, glycemic traits and blood pressure. Direct fetal genotype effects dominate the shared genetic contribution to the association between lower BW and higher type 2 diabetes risk, whereas the relationship between lower BW and higher later blood pressure (BP) is driven by a combination of indirect maternal and direct fetal genetic effects: indirect effects of maternal BP-raising genotypes act to reduce offspring BW, but only direct fetal genotype effects (once inherited) increase the offsprings later BP. Instrumental variable analysis using maternal BW-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring BP. In successfully separating fetal from maternal genetic effects, this work represents an important advance in genetic studies of perinatal outcomes, and shows that the association between lower BW and higher adult BP is attributable to genetic effects, and not to intrauterine programming.

genetics↗

bioRxiv2018

Common genetic variants and health outcomes appear geographically structured in the UK Biobank sample: Old concerns returning and their implications.

Introductory paragraphThe inclusion of genetic data in large studies has enabled the discovery of genetic contributions to complex traits and their application in applied analyses including those using genetic risk scores (GRS) for the prediction of phenotypic variance. If genotypes show structure by location and coincident structure exists for the trait of interest, analyses can be biased. Having illustrated structure in an apparently homogeneous collection, we aimed to a) test for geographical stratification of genotypes in UK Biobank and b) assess whether stratification might induce bias in genetic association analysis.\n\nWe found that single genetic variants are associated with birth location within UK Biobank and that geographic structure in genetic data could not be accounted for using routine adjustment for study centre and principal components (PCs) derived from genotype data. We found that GRS for complex traits do appear geographically structured and analysis using GRS can yield biased associations. We discuss the likely origins of these observations and potential implications for analysis within large-scale population based genetic studies.

genetics↗

bioRxiv2018

Evidence of a common causal relationship between body mass index and inflammatory skin disease: a Mendelian Randomization study

ObjectivePsoriasis and eczema are common inflammatory skin diseases that have been reported to be associated with obesity. However, causality has not yet been established. We aimed to investigate the possible causal relationship between body mass index (BMI) and psoriasis or eczema.\n\nMethodsFollowing a review of published epidemiological evidence of the association between obesity and either psoriasis or eczema, Mendelian Randomization (MR) was used to test for a causal relationship between BMI and these inflammatory skin conditions. We used a genetic instrument comprising 97 single nucleotide polymorphisms (SNPs) associated with BMI. One-sample MR was conducted using individual-level data (401,508 individuals) from the UK Biobank and the Nord-Trondelag Health Study (HUNT), Norway. Two-sample MR was performed with summary-level data (731,021 individuals) from published BMI, psoriasis and eczema GWAS. The one-sample and two-sample MR estimates were meta-analysed using a fixed effect model. To explore the reverse causal direction, MR analysis with genetic instruments comprising variants from recent genome-wide analyses for psoriasis and eczema were used to test if inflammatory skin disease has a causal effect on BMI.\n\nResultsPublished observational data show an association of greater BMI with both psoriasis and eczema case status. The observational associations were confirmed in UK Biobank and HUNT datasets. MR analyses provide evidence that higher BMI causally increases the odds of psoriasis (by 53% per 5 units higher BMI; OR= 1.09 (1.06 to 1.12) per 1 kg/m2; P=4.67x10-9) and eczema (by 8% per 5 units higher BMI; OR=1.02 (1.00 to 1.03) per 1 kg/m2; P=0.09). When investigating causality in the opposite direction, MR estimates provide little evidence for an effect of either psoriasis or eczema influencing BMI.\n\nConclusionOur study, using genetic variants as instrumental variables for BMI, shows that higher BMI leads to a higher risk of inflammatory skin disease. The causal relationship was stronger for psoriasis than eczema. Therapies and life-style interventions aimed at controlling BMI or targeting the mechanisms linking obesity with skin inflammation may offer an opportunity for the prevention or treatment of these common skin diseases.

genetics↗

bioRxiv2017

Multiethnic Meta-analysis Identifies New Loci for Pulmonary Function

Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N=60,552), African (N=8,429), Asian (N=9,959), and Hispanic/Latino (N=11,775) ethnicities. We identified over 50 novel loci at genome-wide significance in ancestry-specific and/or multiethnic meta-analyses. Recent fine mapping methods incorporating functional annotation, gene expression, and/or differences in linkage disequilibrium between ethnicities identified potential causal variants and genes at known and newly identified loci. Sixteen of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12.

genetics↗

bioRxiv2017

Genetic Epidemiology And Mendelian Randomization For Informing Disease Therapeutics: Conceptual And Methodological Challenges

The past decade has been proclaimed as a hugely successful era of gene discovery through the high yields of many genome-wide association studies (GWAS). However, much of the perceived benefit of such discoveries lies in the promise that the identification of genes that influence disease would directly translate into the identification of potential therapeutic targets (1-4), but this has yet to be realised at a level reflecting expectation. One reason for this, we suggest, is that GWAS to date have generally not focused on phenotypes that directly relate to the progression of disease, and thus speak to disease treatment.

genetics↗

bioRxiv2017

Maternal and fetal genetic contribution to gestational weight gain

BackgroundClinical recommendations to limit gestational weight gain (GWG) imply high GWG is causally related to adverse outcomes in mother or offspring, but GWG is the sum of several inter-related complex phenotypes (maternal fat deposition and vascular expansion, placenta, amniotic fluid and fetal growth). Understanding the genetic contribution to GWG could help clarify the potential effect of its different components on maternal and offspring health. Here we explore the genetic contribution to total, early and late GWG.\n\nParticipants and MethodsA genome-wide association study was used to identify maternal and fetal variants contributing to GWG in up to 10,543 mothers and up to 16,317 offspring of European origin, with replication in 10,660 mothers and 7,561 offspring. Additional analyses determined the proportion of variability in GWG from maternal and fetal common genetic variants and the overlap of established genome-wide significant variants for phenotypes relevant to GWG (e.g. maternal BMI and glucose, birthweight).\n\nResultsWe found that approximately 20% of the variability in GWG was tagged by common maternal genetic variants, and that the fetal genome made a surprisingly minor contribution to explaining variation in GWG. We were unable to identify any genetic variants that reached genome-wide levels of significance (P<5x10-8) and replicated. Some established maternal variants associated with increased BMI, fasting glucose and type 2 diabetes were associated with lower early, and higher later GWG. Maternal variants related to higher systolic blood pressure were related to lower late GWG. Established maternal and fetal birthweight variants were largely unrelated to GWG.\n\nConclusionWe found a modest contribution of maternal common variants to GWG and some overlap of maternal BMI, glucose and type 2 diabetes variants with GWG. These findings suggest that associations between GWG and later offspring/maternal outcomes may be due to the relationship of maternal BMI and diabetes with GWG.

genetics↗