Abstract
Throughout the human genome millions of places exist where humans differ gentically. The aim of this PhD thesis was to systematically assess this genetic variation and its biological consequences in a genome-wide way, through the utilization of DNA oligonucleotide arrays that assess hundres of thousands of single nucleotide polymorphisms (SNPs).
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We describe a new statistical method that can detects very small copy number variations (CNVs). When applying this method to Illumina HumanHap550 oligonucleotide arrays that assay over 550,000 SNPs, approximately 99 deletions per individual were identified. We assessed the molecular biological consequences of genetic variation on gene expression through a combined genetical-genomics approach in 110 unrelated coeliac disease individuals. This study resulted in the identification of over 1,000 common genetic variants that affect gene expression. These include SNPs that affect the expression of IL18RAP and CCR2 and which were recently shown to be associated with coeliac disease. Additionally we identified several genes, in which certain genetic variants switch between different splice variants. We describe a novel method that uses a reconstructed functional human gene network to prioritize positional candidate genes within susceptibility loci, that either have been detected through linkage or (genome-wide) association studies. We describe a new method to study diseases for which the genetic basis is still mostly unclear, but for which there is evidence that patients often have deletions or duplications. We hypothesized that these mutations are likely to affect the function of the genes within these deletions or duplications. Since multiple genes usually map within these loci, it can be assumed that multiple biological processes are affected. We tested this hypothesis in previously identified susceptibility loci in autism. We determined which clinical symptoms could be caused by mutations within these genes for each loci per gene. We then assessed whether certain symptoms could be caused by mutations in more loci than expected. Various symptoms known to co-occur with autism were identified, such as craniofacial abnormalities and epilepsy. As such, these findings substantiate our hypothesis. A genome-wide association study was conducted in coeliac disease. By developing a new statistical method to assign genotypes to these samples, we were able to identify a new susceptibility locus that contains IL2 and IL21. These interleukins play an important role in the immune response which is characteristic for untreated celiac disease patients. Another genome-wide association study identified a new susceptibility locus in amyotrophic lateral sclerosis that contains DPP6, a gene that affects the biological activity of neuropeptides. These findings indicate that genome-wide approaches can help to gain insight in both fundamental aspects of the human genome and its effect on complex diseases.
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