Genome and epigenome wide association analysis identify new risk loci and reveals the role of ion channels in the development of childhood obesity Strong Kids 2 cohort

Kadayifci, Fatma Zehra

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https://hdl.handle.net/2142/121193 Copy

Description

Title

Genome and epigenome wide association analysis identify new risk loci and reveals the role of ion channels in the development of childhood obesity Strong Kids 2 cohort

Author(s)

Kadayifci, Fatma Zehra

Issue Date

2023-05-26

Director of Research (if dissertation) or Advisor (if thesis)

Pan, Yuan-Xiang

Doctoral Committee Chair(s)

Teran-Garcia, Margarita

Committee Member(s)

• Donovan, Sharon M
• Rodriquez Zas , Sandra L

Department of Study

Food Science & Human Nutrition

Discipline

Food Science & Human Nutrition

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

GWAS, DNA methylation, childhood obesity, child growth trajectories

Abstract

Childhood obesity is a global public health concern. The condition's complex nature involves multiple etiologies, including genetic and environmental factors. While lifestyle choices are vital contributors to obesity, recent research highlights the importance of genetics and epigenetics in the disease's progression. Understanding the interplay between genetic, epigenetic, and weight status can provide valuable insight into the development and management of childhood obesity. Children’s weight status is crucial as having overweight and obesity in childhood can track into adulthood and increase the risk of numerous health problems. However, more studies are needed to investigate the complex mechanisms and develop effective prevention and treatment strategies. We hypothesize that specific genes and pathways increase the risk of childhood obesity, with alterations in genetic regions called single nucleotide polymorphisms (SNPs) correlating with changes in growth trajectories and weight-for-length/height z scores (WFLZ). Furthermore, studying methylation regions may reveal underlying epigenetic mechanisms involved in the development of childhood obesity. Study 1 Research indicates that genetics can play a role in the development of obesity among adults, but our understanding of its link to childhood obesity is still limited. Herein, genome-wide association study (GWAS) and weight status were investigated in children from birth to 4 years of old to test the hypothesis that genetic variations and molecular pathways, specifically in ion channel genes, contribute to the genetic susceptibility to childhood obesity by associating with changes on weight status and growth trajectories. WFLZ was calculated from height and weight measures and three growth trajectories were determined in the first two years in Strong Kids 2 cohort, and demographically matched children in each trajectory (low high raising [n=32], mid stable [n=80] and low slow raising [n=32]) were selected for analysis. Associations between genetic regions (SNPs) and phenotypes were tested using ANOVA (f-one way) test and Chi-square test. A total of 60 SNPs were suggestively (p< 10-5) associated with WFLZ scores at least at a one-time point from birth to 4 y-of-age. Twenty-eight of these SNPs -18 gene loci- were identified as coding region alleles above the suggestive significance threshold (p<10-5) associated with WFLZ scores. Three of the suggestively significant coding region genes (MATN1, MYLK, PITPNM3), which also appeared across multiple time points, were predicted to be associated with calcium ion activity and/or regulation and signaling. In addition, nine SNPs in the coding region were above the suggestive threshold (p<10-5) associated with the differences in growth trajectories. Post-GWAS, SNP-based analyses were used for functional and pathway enrichment analysis. Enrichment analysis was most significant around 12 and 18 months. Various signaling pathways, such as calcium signaling, cGMP signaling, and hippo signaling, were associated with a change in both WFLZ scores and growth trajectories. These findings demonstrate several candidate SNPs suggestively associated with changes in WFLZ and growth trajectories. Enrichment analysis indicates that genetic variation may provide crucial insights into the underlying mechanisms of obesity in children; however, genetic influence on obesity may differ according to age. Study 2 Epigenetic modifications impact gene expression and may contribute to the development and progression of obesity. However, our understanding of the relative contributions during childhood still needs to be completed. Here, genome-wide DNA methylation analysis and weight status were investigated in children at 4 or 5 years of age. Weight for height z scores (WFHZ) were calculated, and three growth trajectories described in Study 1 were used to select children. Differentially-methylated gene analysis was conducted using ChAMP pipeline between growth trajectories. Further, correlation analysis was conducted between methylation modifications (CpG signals) and WFHZ. A total of 19 differentially-methylated regions (DMRs) were significant (FDR <0.05) in comparison of growth trajectories. In the data set, significant DMR gene-S100A13 (hypomethylated) and MT1E (hypermethylated) were the two gene-regions associated with ion regulation metabolism as part of its function in the metabolism. The data on differentially methylated probes and individual CpG signals were below the recommended significant p-value (9.42x 10-8). Thus, the CpG signal search was extended to the suggestive threshold (10-8

Graduation Semester

2023-08

Type of Resource

Thesis

Copyright and License Information

Copyright 2023 Fatma Zehra Kadayifci

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