Novel Statistical Methods in Quantitative Genetics : Modeling Genetic Variance for Quantitative Trait Loci Mapping and Genomic Evaluation

This thesis develops and evaluates statistical methods for different types of genetic analyses, including quantitative trait loci (QTL) analysis, genome-wide association study (GWAS), and genomic evaluation. The main contribution of the thesis is to provide novel insights in modeling genetic variance, especially via random effects models. In variance component QTL analysis, a full likelihood model accounting for uncertainty in the identity-by-descent (IBD) matrix was developed. It was found to be able to correctly adjust the bias in genetic variance component estimation and gain power in QTL mapping in terms of precision.  Double hierarchical generalized linear models, and a non-iterative simplified version, were implemented and applied to fit data of an entire genome. These whole genome models were shown to have good performance in both QTL mapping and genomic prediction. A re-analysis of a publicly available GWAS data set identified significant loci in Arabidopsis that control phenotypic variance instead of mean, which validated the idea of variance-controlling genes.  The works in the thesis are accompanied by R packages available online, including a general statistical tool for fitting random effects models (hglm), an efficient generalized ridge regression for high-dimensional data (bigRR), a double-layer mixed model for genomic data analysis (iQTL), a stochastic IBD matrix calculator (MCIBD), a computational interface for QTL mapping (qtl.outbred), and a GWAS analysis tool for mapping variance-controlling loci (vGWAS).

Integration av webbaserat analysprogram och kartprogram : Integration of web based analysis-software andmap-software

I takt med att GIS (Grafiska InformationsSystem) blir allt vanligare och mer användarvänligt har WM-data sett att kunder skulle ha intresse i att kunna koppla information från sin verksamhet till en kartbild. Detta för att lättare kunna ta till sig informationen om hur den geografiskt finns utspridd över ett område för att t.ex. ordna effektivare tranporter. WM-data, som det här arbetet är utfört åt, avser att ta fram en prototyp som sedan kan visas upp för att påvisa för kunder och andra intressenter att detta är möjligt att genomföra genom att skapa en integration mellan redan befintliga system. I det här arbetet har prototypen tagits fram med skogsindustrin och dess lager som inriktning. Befintliga program som integrationen ska skapas mellan är båda webbaserade och körs i en webbläsare. Analysprogrammet som ska användas heter Insikt och är utvecklat av företaget Trimma, kartprogrammet heter GIMS som är WM-datas egna program. Det ska vara möjligt att i Insikt analysera data och skapa en rapport. Den ska sedan skickas till GIMS där informationen skrivs ut på kartan på den plats som respektive information hör till. Det ska även gå att välja ut ett eller flera områden i kartan och skicka till Insikt för att analysera information från enbart de utvalda områdena. En prototyp med önskad funktionalitet har under arbetets gång tagits fram, men för att ha en säljbar produkt är en del arbeta kvar. Prototypen har visats för ett antal intresserade som tyckte det var intressant och tror att det är något som skulle kunna användas flitigt inom många områden.

System Integration of PV/T Collectors in Solar Cooling Systems

The demand for cooling and air-conditioning of building is increasingly ever growing. This increase is mostly due to population and economic growth in developing countries, and also desire for a higher quality of thermal comfort. Increase in the use of conventional cooling systems results in larger carbon footprint and more greenhouse gases considering their higher electricity consumption, and it occasionally creates peaks in electricity demand from power supply grid. Solar energy as a renewable energy source is an alternative to drive the cooling machines since the cooling load is generally high when solar radiation is high. This thesis examines the performance of PV/T solar collector manufactured by Solarus company in a solar cooling system for an office building in Dubai, New Delhi, Los Angeles and Cape Town. The study is carried out by analyzing climate data and the requirements for thermal comfort in office buildings. Cooling systems strongly depend on weather conditions and local climate. Cooling load of buildings depend on many parameters such as ambient temperature, indoor comfort temperature, solar gain to the building and internal gains including; number of occupant and electrical devices. The simulations were carried out by selecting a suitable thermally driven chiller and modeling it with PV/T solar collector in Polysun software. Fractional primary energy saving and solar fraction were introduced as key figures of the project to evaluate the performance of cooling system. Several parametric studies and simulations were determined according to PV/T aperture area and hot water storage tank volume. The fractional primary energy saving analysis revealed that thermally driven chillers, particularly adsorption chillers are not suitable to be utilizing in small size of solar cooling systems in hot and tropic climates such as Dubai and New Delhi. Adsorption chillers require more thermal energy to meet the cooling load in hot and dry climates. The adsorption chillers operate in their full capacity and in higher coefficient of performance when they run in a moderate climate since they can properly reject the exhaust heat. The simulation results also indicated that PV/T solar collector have higher efficiency in warmer climates, however it requires a larger size of PV/T collectors to supply the thermally driven chillers for providing cooling in hot climates. Therefore using an electrical chiller as backup gives much better results in terms of primary energy savings, since PV/T electrical production also can be used for backup electrical chiller in a net metering mechanism.

Flyktingguide: En väg till integration? : Brukarutvärdering av projektet Flyktingguide i Falun

In this qualitative user evaluation participants in the project refugee guide, Falun, was interviewed about their experience of the project and how the project contributed to their integration into society and establishment on the labor market. The collection of empirical data has been made by six interviews. The results of the evaluation indicate that participants feel that they through the project had the opportunity to meet new people, practice the language and learn about each other's culture. The results also show that participants are satisfied with the project. Some participants expressed a desire to meet with several people at once while others don´t have that need. Furthermore, the interviews shows that establishment on labor market occurred through job placement and not through participation in the project. Integration proved to be a difficult concept to define, but the interviews show that the participants have a perception that it is about learning the Swedish language and culture.

Defining the role of common variation in the genomic and biological architecture of adult human height

Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.2014

Trans-ethnic fine mapping highlights kidney-function genes linked to salt sensitivity

We analyzed genome-wide association studies (GWASs), including data from 71,638 individuals from four ancestries, for estimated glomerular filtration rate (eGFR), a measure of kidney function used to define chronic kidney disease (CKD). We identified 20 loci attaining genome-wide-significant evidence of association (p < 5 × 10(-8)) with kidney function and highlighted that allelic effects on eGFR at lead SNPs are homogeneous across ancestries. We leveraged differences in the pattern of linkage disequilibrium between diverse populations to fine-map the 20 loci through construction of "credible sets" of variants driving eGFR association signals. Credible variants at the 20 eGFR loci were enriched for DNase I hypersensitivity sites (DHSs) in human kidney cells. DHS credible variants were expression quantitative trait loci for NFATC1 and RGS14 (at the SLC34A1 locus) in multiple tissues. Loss-of-function mutations in ancestral orthologs of both genes in Drosophila melanogaster were associated with altered sensitivity to salt stress. Renal mRNA expression of Nfatc1 and Rgs14 in a salt-sensitive mouse model was also reduced after exposure to a high-salt diet or induced CKD. Our study (1) demonstrates the utility of trans-ethnic fine mapping through integration of GWASs involving diverse populations with genomic annotation from relevant tissues to define molecular mechanisms by which association signals exert their effect and (2) suggests that salt sensitivity might be an important marker for biological processes that affect kidney function and CKD in humans.