An investigation into the genetic determinants of adult height

© 2012 Dr. Anna Elizabeth DuncanMany common diseases are complex, with multiple genetic loci and environmental factors influencing disease outcome. However, the genetic component may be difficult to determine. Therefore, there is much interest in the study of population variations in adult height as a model complex trait, to assist in understanding the genetic complexity of complex traits and to identify methods capable of discovering genes involved in trait outcome. Height is a model complex trait as it is highly heritable, easily and accurately measured, relatively stable over time, and many studies routinely include it in data collection meaning height data are readily available. By studying height, the benefits are three-fold; we gain an understanding of the genetic architecture of a complex trait and how this may assist in studying other complex traits and diseases, we can identify genes involved in height determination and possibly illuminate the various biological processes involved, and, by increasing our understanding of height determination, we may be able to better comprehend the diseases where height is a risk factor. Recently, a number of technological developments have changed the way that complex traits are investigated, leading to the identification of large numbers of complex trait-associated loci. However, the vast majority of the functional variants responsible for either these linkage or association signals have not been identified. This thesis presents work based on investigating three research questions that were proposed to aid in identifying genetic determinants of height, to both investigate the biological basis of growth as well as methods for studying complex traits: 1) can a gene responsible for a linkage signal be found via candidate gene association mapping (FLNB)?, 2) once an association signal has been established via genome-wide association studies (GWASs), can fine-mapping assist in further defining that association, leading towards the ultimate goal of identifying potential causal variants (ZBTB38)?, and 3) can a carefully selected region (using a candidate gene approach) be found to be associated with height variations given the lack of GWAS evidence in support (chromosome 11p15.5)? In general, a candidate gene approach using family-based and unrelated samples was utilised to investigate these questions. To enable replication of positive findings, three independent studies of European ancestry were used. With FLNB, convincing evidence of population stratification (e.g. rs6445945, p = 5.1 × 10-3) was detected using family-based analyses, which suggests that associations previously reported are likely to be false positives. Therefore, in the absence of evidence of association of height with FLNB, the results demonstrate the inherent difficulties of solely using linkage to map candidate genes for a complex trait. With the previously GWAS-identified ZBTB38, multiple variants were associated with height variation, with no population stratification detected via family-based analyses. Intriguing evidence of a possible functional variant was identified via in silico analyses (rs7632381, height p(meta) = 2.7 × 10-8, effect size per each additional minor allele 0.85 cm (SE 0.15 cm)). Previous work suggested that ZBTB38 interacts with the imprinted chromosome 11p15.5 region. Variants within this region were found to be associated with height in two independent samples (e.g. rs3741209, located in intron one of IGF2, p(meta) = 2.1 × 10-3, effect size per each additional minor allele 0.48 cm (SE 0.16 cm)), indicating that a candidate gene approach can be successful. Parent-of-origin effects were also observed for a subset of variants via family-based analyses, with implications for future studies in other imprinted regions and our understanding of the genetic architecture of height. Although the “big picture” offered by GWASs has greatly increased our understanding of how multi-faceted height determination is, this current research highlights that there are also benefits of a “boutique” approach that can contribute to understanding the genetic architecture of height