Improving Genetic Prediction by Leveraging Genetic Correlations Among Human Diseases and Traits

Genomic prediction has the potential to contribute to precision medicine. However, to date, the utility of such predictors is limited due to low accuracy for most traits. Here theory and simulation study are used to demonstrate that widespread pleiotropy among phenotypes can be utilised to improve genomic risk prediction. We show how a genetic predictor can be created as a weighted index that combines published genome-wide association study (GWAS) summary statistics across many different traits. We apply this framework to predict risk of schizophrenia and bipolar disorder in the Psychiatric Genomics consortium data, finding substantial heterogeneity in prediction accuracy increases across cohorts. For six additional phenotypes in the UK Biobank data, we find increases in prediction accuracy ranging from 0.7 for height to 47 for type 2 diabetes, when using a multi-trait predictor that combines published summary statistics from multiple traits, as compared to a predictor based only on one trait. © 2018 The Author(s)

Age at first birth in women is genetically associated with increased risk of schizophrenia

Prof. Paunio on PGC:n jäsenPrevious studies have shown an increased risk for mental health problems in children born to both younger and older parents compared to children of average-aged parents. We previously used a novel design to reveal a latent mechanism of genetic association between schizophrenia and age at first birth in women (AFB). Here, we use independent data from the UK Biobank (N = 38,892) to replicate the finding of an association between predicted genetic risk of schizophrenia and AFB in women, and to estimate the genetic correlation between schizophrenia and AFB in women stratified into younger and older groups. We find evidence for an association between predicted genetic risk of schizophrenia and AFB in women (P-value = 1.12E-05), and we show genetic heterogeneity between younger and older AFB groups (P-value = 3.45E-03). The genetic correlation between schizophrenia and AFB in the younger AFB group is -0.16 (SE = 0.04) while that between schizophrenia and AFB in the older AFB group is 0.14 (SE = 0.08). Our results suggest that early, and perhaps also late, age at first birth in women is associated with increased genetic risk for schizophrenia in the UK Biobank sample. These findings contribute new insights into factors contributing to the complex bio-social risk architecture underpinning the association between parental age and offspring mental health.Peer reviewe

Reference analysis on the use of engineered barriers for isolation of spent nuclear fuel in granite and basalt

This report evaluates the effectiveness of engineered barriers in delaying or reducing the rate of release of radionuclides from spent fuel in geologic respositories in granite and basalt. It was assumed that the major exposure pathway from the respository to humans would be the ground-water system overlying or underlying a site. Hence, this report focuses on ground-water pathways. A geosphere transport model, GETOUT, and the biosphere transport/dose models, ALLDOS and PABLM, were integrated and used to calculate the potential radiological dose that might be received by humans at various times after repository closure

Analysis on the use of engineered barriers for geologic isolation of spent fuel in a reference salt site repository

A perspective on the potential durability and effectiveness requirements for the waste form, container and other engineered barriers for geologic disposal of spent nuclear fuel has been developed. This perspective is based on calculated potential doses to individuals who may be exposed to radioactivity released from a repository via a groundwater transport pathway. These potential dose commitments were calculated with an integrated geosphere transport and bioshpere transport model. A sensitivity analysis was accomplished by varying four important system parameters, namely the waste radionuclide release rate from the repository, the delay prior to groundwater contact with the waste (leach initiation), aquifer flow velocity and flow path length. The nuclide retarding capacity of the geologic media, a major determinant of the isolation effectiveness, was not varied as a parameter but was held constant for a particular reference site. This analysis is limited to looking only at engineered barriers whose net effect is either to delay groundwater contact with the waste form or to limit the rate of release of radionuclides into the groundwater once contact has occurred. The analysis considers only leach incident scenarios, including a water well intrusion into the groundwater near a repository, but does not consider other human intrusion events or catastrophic events. The analysis has so far been applied to a reference salt site repository system and conclusions are presented.Basically, in nearly all cases, the regional geology is the most effective barrier to release of radionuclides to the biosphere; however, for long-lived isotopes of carbon, technetium and iodine, which were poorly sorbed on the geologic media, the geology is not very effective once a leach incident is initiated