engleski

Genome-Wide Association Approach in Identifying Loci for Complex Diseases, an Example for Hashimoto’s Thyroiditis

Genome-wide association analysis (GWAS) is a powerful method for identifying the genetic background of complex traits. Without prior assumption of the gene candidacy underlying the investigated traits, GWAS tests a panel of strategically designed genetic markers that capture a substantial proportion of common genetic variation across the genome. Additional expansion of coverage of genetic variants is usually achieved by an imputation process, which is a statistically and computationally complex method that infers and fills in missing genotypes on the basis of reference panels, such as 1000 Genomes. Using this approach, the final number of analyzed genetic markers usually reaches several million covering the whole genome, making it a very efficient tool to identify the loci underlying the investigated trait. The case- control GWAS relies on the assumption that risk alleles predisposed to a specific disease are enriched in the group of patients, which makes them easy to detect through a direct comparison of allele frequencies between patients and healthy individuals. The disease in which we are interested is Hashimoto’s thyroiditis (HT), the most common autoimmune thyroid disease. HT is characterized by progressive destruction and reduced function of the thyroid gland that may lead to hypothyroidism. Although genetic and environmental factors are thought to play an important role in disease development, these factors are not certain. With the aim to systematically investigate genetic and environmental factors associated with HT, we formed a biobank of biological samples and genome- wide genotypes of 430 deeply phenotyped HT patients. Our immediate goal was to perform the first case-control GWAS using newly recruited HT patients and 439 existing controls. We treated binary disease status as a quantitative trait and applied a univariate linear mixed model adjusted for age, sex, population stratification, and relatedness. We identified the first genome-wide significant association of a variant inside the biologically plausible HT candidate gene, in addition to several suggested associations. Prioritized genetic variants are currently being validated in an independent replication cohort. To further help in elucidating environmental contribution to HT, our next aim is to extensively analyze collected medical, personal, lifestyle, and food-intake information. In conclusion, by implementing the newest concepts of study design and statistical analysis of genome-wide data, we aim to generate new knowledge of the genetic basis and underlying biological mechanisms of HT. Understanding the core biological pathways associated with the functioning of thyroid disorders will be the basis for improving treatment and developing new prevention, diagnostic, and therapeutic methods.

Hashimoto’s thyroiditis (HT)

nije evidentirano