{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/121193"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/121193","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"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","abstract":"Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2025-08-01","abstract_html":"Submission published under a 24 month embargo labeled &#x27;Closed Access&#x27;, the embargo will last until 2025-08-01","abstract_has_math":false,"creators":["Kadayifci, Fatma Zehra"],"institution":"University of Illinois at Urbana-Champaign","degree_name":"Ph.D.","degree_level":"Dissertation","degree_discipline":"Food Science & Human Nutrition","degree_department":null,"school":null,"contributors":["Pan, Yuan-Xiang","Teran-Garcia, Margarita","Donovan, Sharon M","Rodriquez Zas , Sandra L"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2023,"date_issued":"2023-08","date_published":"2023-08","updated_at":"2026-07-22T22:24:57Z","subjects":["Gwas","Dna Methylation","Childhood Obesity","Child Growth Trajectories"],"languages":["en","eng"],"rights":["Copyright 2023 Fatma Zehra Kadayifci"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/2142/121193","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Pan, Yuan-Xiang","Teran-Garcia, Margarita","Donovan, Sharon M","Rodriquez Zas , Sandra L"]},{"key":"dc:creator","label":"Author","values":["Kadayifci, Fatma Zehra"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2023-08","2023-05-26"]},{"key":"dc:type","label":"Dc Type","values":["text"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Food Science & Human Nutrition"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Ph.D."]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["University of Illinois at Urbana-Champaign"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Gwas","Dna Methylation","Childhood Obesity","Child Growth Trajectories"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en","eng"]},{"key":"dc:rights","label":"Dc Rights","values":["Copyright 2023 Fatma Zehra Kadayifci"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://hdl.handle.net/2142/121193"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2025-08-01","The student, Fatma Kadayifci, accepted the attached license on 2023-05-19 at 11:12.","The student, Fatma Kadayifci, submitted this Dissertation for approval on 2023-05-19 at 11:28.","This Dissertation was approved for publication on 2023-05-26 at 10:28.","DSpace SAF Submission Ingestion Package generated from Vireo submission #19382 on 2023-12-04 at 17:30:04","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<p<10-4). Additionally, enrichment analysis revealed potential signaling pathways associated with weight status. Some of the top significant pathways included the phospholipase D signaling pathway, apelin signaling pathway, oxytocin signaling pathway, endocrine resistance, cAMP signaling pathway, cGMP-PKG-signaling pathway, type II diabetes mellitus, Wnt signaling pathway, MAPK signaling pathway. Calcium signaling-associated pathways such as cAMP and Wnt signaling were apparent in the dataset. Ultimately, DMR and enrichment analysis suggest a potential association between DNA methylation, growth trajectories, and weight status in early-age children. This study revealed a minor but several significant associations between DNA methylation regions and weight status and growth trajectories that may potentially contribute to the obesity during childhood. Study 3 Comparing GWAS and genome-wide DNA methylation studies in childhood obesity can provide valuable insights into the genetic and epigenetic mechanisms contributing to this complex disorder’s development. Herein, the analysis was conducted between GWAS and genome-wide DNA methylation arrays to compare the overlapping samples (n=81) at 4-5 years of age for joint association studies. First, individual associations were performed. For GWAS, SNPs and WFHZ were tested using the ANOVA test, and for genome-wide DNA methylation, correlation analysis was conducted between methylation modifications (CpG signals) and WFHZ. Both data was filtered to include only the SNPs or CpGs that pass the p-value<0.05 threshold. Next, filtered GWAS and methylation data were merged based on position and the overlapping positions were identified in a new data frame. The early joint analysis revealed multiple correlations between SNPs and CpG sites based on their respective chromosome positions, along with further matching GWAS-SNP and CpG-SNP sites. The study identified eight specific locations of SNP-CpG sites, and six gene loci (KCND3, SLAMF1, TSBP1-AS1, PPP1R2P1, RIN2 and PDE9A) linked to changes in WFHZ at age 4-5 years. These links were established based on the matching of chromosome and position information. Moreover, nine sites-seven gene loci (HEG1, TMCO3, GTF2IRD1, SORCS2, EPN3, KMT2C and DNAH7) were correlated between GWAS-SNP and CpG-SNP joint association with changes in WFHZ at 4-5 years old. Although these findings represent an early stage of joint analysis, they offer valuable insight into the potential molecular mechanisms contributing to childhood obesity. In conclusion, precision medicine approaches targeting specific genetic variants and epigenetic changes may be a promising avenue for preventing and treating childhood obesity. These studies underscore the importance of a comprehensive approach that integrates genetic and epigenetic data to gain a more complete understanding of the molecular mechanisms underlying childhood obesity."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["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"]}]}],"canonical_facts":{"dc:contributor":["Pan, Yuan-Xiang","Teran-Garcia, Margarita","Donovan, Sharon M","Rodriquez Zas , Sandra L"],"dc:creator":["Kadayifci, Fatma Zehra"],"dc:date":["2023-08","2023-05-26"],"dc:description":["Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2025-08-01","The student, Fatma Kadayifci, accepted the attached license on 2023-05-19 at 11:12.","The student, Fatma Kadayifci, submitted this Dissertation for approval on 2023-05-19 at 11:28.","This Dissertation was approved for publication on 2023-05-26 at 10:28.","DSpace SAF Submission Ingestion Package generated from Vireo submission #19382 on 2023-12-04 at 17:30:04","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<p<10-4). Additionally, enrichment analysis revealed potential signaling pathways associated with weight status. Some of the top significant pathways included the phospholipase D signaling pathway, apelin signaling pathway, oxytocin signaling pathway, endocrine resistance, cAMP signaling pathway, cGMP-PKG-signaling pathway, type II diabetes mellitus, Wnt signaling pathway, MAPK signaling pathway. Calcium signaling-associated pathways such as cAMP and Wnt signaling were apparent in the dataset. Ultimately, DMR and enrichment analysis suggest a potential association between DNA methylation, growth trajectories, and weight status in early-age children. This study revealed a minor but several significant associations between DNA methylation regions and weight status and growth trajectories that may potentially contribute to the obesity during childhood. Study 3 Comparing GWAS and genome-wide DNA methylation studies in childhood obesity can provide valuable insights into the genetic and epigenetic mechanisms contributing to this complex disorder’s development. Herein, the analysis was conducted between GWAS and genome-wide DNA methylation arrays to compare the overlapping samples (n=81) at 4-5 years of age for joint association studies. First, individual associations were performed. For GWAS, SNPs and WFHZ were tested using the ANOVA test, and for genome-wide DNA methylation, correlation analysis was conducted between methylation modifications (CpG signals) and WFHZ. Both data was filtered to include only the SNPs or CpGs that pass the p-value<0.05 threshold. Next, filtered GWAS and methylation data were merged based on position and the overlapping positions were identified in a new data frame. The early joint analysis revealed multiple correlations between SNPs and CpG sites based on their respective chromosome positions, along with further matching GWAS-SNP and CpG-SNP sites. The study identified eight specific locations of SNP-CpG sites, and six gene loci (KCND3, SLAMF1, TSBP1-AS1, PPP1R2P1, RIN2 and PDE9A) linked to changes in WFHZ at age 4-5 years. These links were established based on the matching of chromosome and position information. Moreover, nine sites-seven gene loci (HEG1, TMCO3, GTF2IRD1, SORCS2, EPN3, KMT2C and DNAH7) were correlated between GWAS-SNP and CpG-SNP joint association with changes in WFHZ at 4-5 years old. Although these findings represent an early stage of joint analysis, they offer valuable insight into the potential molecular mechanisms contributing to childhood obesity. In conclusion, precision medicine approaches targeting specific genetic variants and epigenetic changes may be a promising avenue for preventing and treating childhood obesity. These studies underscore the importance of a comprehensive approach that integrates genetic and epigenetic data to gain a more complete understanding of the molecular mechanisms underlying childhood obesity."],"dc:format":["application/pdf"],"dc:identifier":["https://hdl.handle.net/2142/121193"],"dc:language":["en","eng"],"dc:rights":["Copyright 2023 Fatma Zehra Kadayifci"],"dc:subject":["Gwas","Dna Methylation","Childhood Obesity","Child Growth Trajectories"],"dc: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"],"dc:type":["text"],"thesis:degree_discipline":["Food Science & Human Nutrition"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Ph.D."],"thesis:institution_name":["University of Illinois at Urbana-Champaign"]},"updated_at":"2026-07-22T22:24:57Z"}