Multi-Trait Genomic Risk Stratification for Type 2 Diabetes

Type 2 diabetes mellitus (T2DM) is continuously rising with more disease cases every year. T2DM is a chronic disease with many severe comorbidities and therefore remains a burden for the patient and the society. Disease prevention, early diagnosis, and stratified treatment are important elements in slowing down the increase in diabetes prevalence. T2DM has a substantial genetic component with an estimated heritability of 40–70%, and more than 500 genetic loci have been associated with T2DM. Because of the intrinsic genetic basis of T2DM, one tool for risk assessment is genome-wide genetic risk scores (GRS). Current GRS only account for a small proportion of the T2DM risk; thus, better methods are warranted for more accurate risk assessment. T2DM is correlated with several other diseases and complex traits, and incorporating this information by adjusting effect size of the included markers could improve risk prediction. The aim of this study was to develop multi-trait (MT)-GRS leveraging correlated information. We used phenotype and genotype information from the UK Biobank, and summary statistics from two independent T2DM studies. Marker effects for T2DM and seven correlated traits, namely, height, body mass index, pulse rate, diastolic and systolic blood pressure, smoking status, and information on current medication use, were estimated (i.e., by logistic and linear regression) within the UK Biobank. These summary statistics, together with the two independent training summary statistics, were incorporated into the MT-GRS prediction in different combinations. The prediction accuracy of the MT-GRS was improved by 12.5% compared to the single-trait GRS. Testing the MT-GRS strategy in two independent T2DM studies resulted in an elevated accuracy by 50–94%. Finally, combining the seven information traits with the two independent T2DM studies further increased the prediction accuracy by 34%. Across comparisons, body mass index and current medication use were the two traits that displayed the largest weights in construction of the MT-GRS. These results explicitly demonstrate the added benefit of leveraging correlated information when constructing genetic scores. In conclusion, constructing GRS not only based on the disease itself but incorporating genomic information from other correlated traits as well is strongly advisable for obtaining improved individual risk stratification

Exploring Approaches for Blended Learning in Life Sciences

Digital tools and platforms offer new solutions to design and conduct university teaching. This case illustrates how such digital solutions may be utilized in problem-based learning programmes within life science educations. Specifically, the case evaluated the use of live-streamed and recorded lectures, the incorporation of digital formative assessment in lectures, and the use of a digital platform to support experimental project work in a research laboratory. We find that digital solutions provide flexibility for both lecturers and students, advantageous options for collecting and sharing information, and for engaging students in their learning process. However, digital tools cannot replace all aspects of traditional in-person teaching, such as social interactions. Rather, when blended with in-person teaching, digital solutions have a large potential for supporting new forms of and approaches to both theoretical and experimental university teaching

Functional Validation of Candidate Genes Detected by Genomic Feature Models

Understanding the genetic underpinnings of complex traits requires knowledge of the genetic variants that contribute to phenotypic variability. Reliable statistical approaches are needed to obtain such knowledge. In genome-wide association studies, variants are tested for association with trait variability to pinpoint loci that contribute to the quantitative trait. Because stringent genome-wide significance thresholds are applied to control the false positive rate, many true causal variants can remain undetected. To ameliorate this problem, many alternative approaches have been developed, such as genomic feature models (GFM). The GFM approach tests for association of set of genomic markers, and predicts genomic values from genomic data utilizing prior biological knowledge. We investigated to what degree the findings from GFM have biological relevance. We used the Drosophila Genetic Reference Panel to investigate locomotor activity, and applied genomic feature prediction models to identify gene ontology (GO) categories predictive of this phenotype. Next, we applied the covariance association test to partition the genomic variance of the predictive GO terms to the genes within these terms. We then functionally assessed whether the identified candidate genes affected locomotor activity by reducing gene expression using RNA interference. In five of the seven candidate genes tested, reduced gene expression altered the phenotype. The ranking of genes within the predictive GO term was highly correlated with the magnitude of the phenotypic consequence of gene knockdown. This study provides evidence for five new candidate genes for locomotor activity, and provides support for the reliability of the GFM approach

Genotype and Trait Specific Responses to Rapamycin Intake in <i>Drosophila melanogaster</i>

Rapamycin is a powerful inhibitor of the TOR (Target of Rapamycin) pathway, which is an evolutionarily conserved protein kinase, that plays a central role in plants and animals. Rapamycin is used globally as an immunosuppressant and as an anti-aging medicine. Despite widespread use, treatment efficiency varies considerably across patients, and little is known about potential side effects. Here we seek to investigate the effects of rapamycin by using Drosophila melanogaster as model system. Six isogenic D. melanogaster lines were assessed for their fecundity, male longevity and male heat stress tolerance with or without rapamycin treatment. The results showed increased longevity and heat stress tolerance for male flies treated with rapamycin. Conversely, the fecundity of rapamycin-exposed individuals was lower than for flies from the non-treated group, suggesting unwanted side effects of the drug in D. melanogaster. We found strong evidence for genotype-by-treatment interactions suggesting that a ‘one size fits all’ approach when it comes to treatment with rapamycin is not recommendable. The beneficial responses to rapamycin exposure for stress tolerance and longevity are in agreement with previous findings, however, the unexpected effects on reproduction are worrying and need further investigation and question common believes that rapamycin constitutes a harmless drug