Identification of genomic copy number variations associated with obesity-related phenotypes

Obesity is a chronic disease with increasing prevalence worldwide. Recent advances in human genetics have led to the discovery of genetic variations underlying obesity, including copy number variants (CNVs). The overall aim of this thesis was to explore the contribution of CNVs to human obesity by (i) producing high quality CNV catalogues from various SNP genotyping datasets; (ii) identifying specific CNVs previously reported to be associated with obesity-related phenotypes (two rare deletion variants in the 16p11.2 region, and multi-allelic CNVs in the amylase gene region on chromosome 1) in 5 study cohorts in order to perform replication studies and extend understanding of their phenotypic effects; and (iii) to identify rare, novel CNVs in morbid obesity. The CNVs were predicted and quality-checked based on the signal intensity data from the SNP genotyping data, which yielded CNVs with consistent characteristics across the study cohorts, and comparable with other studies. Salivary amylase (AMY1) CNVs were genotyped by a collaborator using Paralogue Ratio Tests (PRTs) in a small intensively-phenotyped cohort of overweight-to-obese individuals. Statistical analyses indicated no significant associations for AMY1 CNVs with body mass index, waist-to-hip ratio, body fats and starch intake, further increasing the evidence that AMY1 CNVs are not associated with obesity, as reported in previous studies. Both 16p11.2 deletion variants (~600-kb and ~200-kb) were confirmed as associated with BMI and WHR in the UK Biobank and Northern Finland Birth Cohort 1966 participants: 600-kb deletion carriers had 12-fold increased risk of obesity in the UK Biobank. Finally, 3 potentially causative CNVs were discovered in 3 different morbidly obese people from the Northern Finland general population; duplications in 17p13 and 22q11.2 regions and a 5p14.3 deletion. The 3 CNVs spanned regions involving brain function and implicated in obesity. The findings are consistent with previous studies, highlighting the role of rare CNVs in the aetiology of obesity.Open Acces