Genetic contributions to obesity and related complex traits in the Cebu Longitudinal Health and Nutrition Survey Public Deposited

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  • March 20, 2019
Creator
  • Croteau-Chonka, Damien
    • Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
Abstract
  • Obesity represents a major world health problem across socio-economic strata. Characterizing known candidate genes and identifying novel genes contributing to obesity and other related heritable risk factors may aid our understanding of its complex etiology and provide new treatment targets. Based in the Philippines, a country experiencing a rapid obesogenic transition, the Cebu Longitudinal Health and Nutrition Survey (CLHNS) is a useful population cohort in which to study the genetics of obesity. For more than 20 years since 1983, researchers have followed a cohort of Filipino mothers and their offspring from the metropolitan area of Cebu, collecting a wide variety of anthropometric, environmental, and dietary phenotypes. In 2005, blood samples were collected from all the participants, allowing the measurement of multiple plasma biomarkers, the extraction of genomic DNA, and the genetic analysis of complex traits. In this dissertation, I describe my genetic studies of three categories of obesity-related complex traits in the CLHNS: body size (body mass index (BMI), weight, and waist circumference), metabolic (adiponectin), and physiological (age of menarche). I first performed a genome-wide association (GWA) study of body size traits in Filipinos to determine the contribution of common genetic variants to those traits. I replicated three well-known BMI loci (BDNF, MC4R, and FTO) and further observed evidence of longitudinal changes in the effects of those genes. Next, I sought to establish the putative causal variant(s) underlying a haplotype at the ADIPOQ gene identified in a previous CLHNS GWA study to be strongly associated with lower circulating plasma adiponectin level. I identified a population-specific missense variant (R221S) that affected the original measurement of the phenotype and explained the observed GWA signal. Next, to identify novel biology underlying the etiology of central adiposity, I performed a meta-analysis of GWA studies of waist circumference (WC) in European individuals from the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Findings from this large-scale study may suggest other candidate loci for future genetic study in the CLHNS. I observed evidence of novel associations specific to WC and not other related anthropometric traits, such as BMI, height, and waist-hip ratio. These signals included the genes NLRP3, which is part of the obesity-related inflammasome complex, and IRS1, which is previously associated with body fat percentage and an adverse metabolic profile. Finally, to explore the relationships between several obesity genes and age of menarche, I performed replication and mediation analyses in female offspring from the CLHNS. I observed that the menarche signal at LIN28B previously reported in Europeans replicated in Filipinos. While this association appeared not to be mediated by childhood BMI, the results for several obesity genes were inconclusive. Together, these studies further our understanding of the genetic architecture of several obesity traits, and suggest many promising biological candidates for further genetic and molecular study.
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  • In Copyright
Advisor
  • Mohlke, Karen
Degree
  • Doctor of Philosophy
Graduation year
  • 2012
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