Using large-scale cohorts to identify genetic backgrounds of complex traits

Most cases of diseases with heritable components are not explained by single-gene variants following Mendelian inheritance. The majority of such heritable traits result from the combined contributions of many genes, environmental factors, and chance. These are called complex traits, and include phenotypes such as intelligence, neuropsychiatric disorders, and susceptibility to infection. In this thesis, I investigate how the genetic component of complex traits can be explained using rare and common variation. The first study investigated the genetic etiology of rare idiopathic intellectual disability and syndromic comorbidities in an extreme population isolate in Northern Finland affected by several genetic bottlenecks. Here, I found that there is a significant common variant component in ID, in addition to the rare variant burden expected by nature of the phenotype and study design. I then sought to improve our understanding of general differences in rare variant burden. I analyzed the phenotypes of rare disease-associated copy number variants (CNVs) among patients with epilepsy and comorbid features from several neurology specialist clinics in Europe and the US. Pathogenic CNVs were detected in 10.9% of cases and associated with non-neurological but not neurological phenotypes. The results indicate that in syndromic epilepsy, rare CNV impact associates with other organ systems instead of along neurological disease severity. Next, to investigate the impact rare pathogenic CNVs have on general quality of life in unaffected carriers, I analyzed the impact on general health and socioeconomic factors in two Finnish population cohorts. I found that in the unaffected population, there is an average socioeconomic impact of high-risk CNVs, although one that is less than the impact of polygenic risk scores (PRSs) for educational attainment and intelligence. Finally, to improve understanding of chronic and complicated infections of the upper respiratory tract, I performed a genome-wide association study (GWAS) of these diseases in the biobank-scale FinnGen study. I detected an underlying genetic structure impacting several heritable inflammatory traits of the upper respiratory tract, including their shared and distinct genetic signals. Several important results of the biology of these diseases were recognized, although the majority of the expected high heritability remains unexplained. In conclusion, the studies of this thesis highlight distinct features of both rare and common variation. Rare variant analysis studies the extent of phenotypic variation, with biology inferred from the extreme. For common variation, shared effects observed along the disease spectrum can be leveraged to highlight broad biological impact—as observed here in infectious and inflammatory upper respiratory diseases. These results challenge the single-gene hypothesis for complex traits and highlight a joint contribution of common and rare variation.