Date of Award

January 2021

Document Type

Thesis

Degree Name

Master of Public Health (MPH)

Department

School of Public Health

First Advisor

Yasmmyn D. Salinas

Abstract

Genetic data suggest that obesity and inflammation shared a portion of their genetic architectures. Meanwhile, epidemiologic data suggest a causal link between obesity and inflammation. Therefore, we hypothesized that there are variants in the human genome that display pleiotropy for obesity and inflammation and that the effects of at least some of those variants could be mediated by obesity-related pathways. To test these hypotheses, we conducted univariate genome-wide association analyses of obesity-related traits (BMI and WHRadjBMI) and inflammation (CRP) in the UK Biobank (n= 291,396 Caucasian subjects), searched for overlapping signals, fine-mapped the regions to identify putative causal SNPs, and decomposed the total genetic effects of the SNPs using causal mediation analyses, with an adjustment of confounding of the obesity-inflammation relationship. We identified 16 SNPs (rs79113395, rs58048722, rs199956414, rs12203592, rs2049870, rs2721966, rs10086741, rs179444, rs3808478, rs6265, rs7926362, rs4922793, rs4755725, rs12577464, rs8047395 and rs11075987), residing in 8 distinct genetic loci, that display pleiotropy for CRP and BMI and 1 SNP (rs429358) that displays pleiotropy for CRP and WHRadjBMI. Among these SNPs, 4 (rs58048722, rs199956414, rs4755725, rs12577464) affected CRP only through obesity-related pathways. All other SNPs had both direct effects on CRP and indirect effects through obesity-related pathways. We found insufficient evidence that the indirect effects of SNPs on CRP through our obesity measures were moderated by sex, despite of sex differences in the phenotypic relationship between these two traits. These identified SNPs lays the foundation for mechanistically understanding the pathogenesis of obesity- and inflammation-associated diseases and may serve as targets for therapies that simultaneously treat these conditions.

Comments

This thesis is restricted to Yale network users only. It will be made publicly available on 06/01/2023

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