Dianjianyi Sun1,2, Tao Zhang2,3, Shaoyong Su4, Guang Hao4, Tao Chen5, Quan-Zhen Li5, Lydia Bazzano2, Jiang He2, Xiaoling Wang4, Shengxu Li6, Wei Chen2. 1. From the Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China (D.S.). 2. Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA (D.S., T.Z., L.B., J.H., W.C.). 3. Department of Biostatistics, School of Public Health, Shandong University, Jinan, China (T.Z.). 4. Georgia Prevention Institute, Department of Population Health Sciences, Medical College of Georgia, Augusta University (S.S., G.H., X.W). 5. Microarray Core Facility, University of Texas Southwestern Medical Center, Dallas, TX (T.C., Z.L.). 6. Children's Minnesota Research Institute, Children's Hospitals and Clinics of Minnesota, Minneapolis (S.L.).
Abstract
RATIONALE: Previous EWASs (Epigenome-Wide Association Studies) suggest that obesity may be the cause, not a consequence, of changes in DNA methylation (DNAm). However, longitudinal observations are lacking. OBJECTIVE: To identify 5'-cytosine-phosphate-guanine-3' in DNA (CpG) sites associated with body mass index (BMI) and examine the temporal relationship between dynamic changes in DNAm and BMI in a longitudinal cohort. METHODS AND RESULTS: Race-specific EWASs were performed in 995 whites and 490 blacks from the Bogalusa Heart Study. Suggestive CpG sites were further replicated in 252 whites and 228 blacks from the Georgia Stress and Heart Study. Cross-lagged panel analysis was used to examine the temporal relationship between DNAm and BMI in 439 whites and 201 blacks who were examined twice 6.2 years apart. In discovery and replication samples, 349 CpG sites (266 novel) in whites and 36 (21 novel) in blacks were identified to be robustly associated with BMI, with 8 (1 novel) CpG sites overlapping between the 2 races. Cross-lagged panel analyses showed significant unidirectional paths (PFDR <0.05) from baseline BMI to follow-up DNAm at 18 CpG sites in whites and 7 in blacks; no CpG sites showed significant paths from DNAm at baseline to BMI at follow-up. Baseline BMI was associated with a DNAm score (calculated from DNAm levels at the associated CpG sites) at follow-up (P<0.001 both in blacks and in whites). CONCLUSIONS: The findings provide strong evidence that obesity is the cause, not a consequence, of changes in DNAm over time.
RATIONALE: Previous EWASs (Epigenome-Wide Association Studies) suggest that obesity may be the cause, not a consequence, of changes in DNA methylation (DNAm). However, longitudinal observations are lacking. OBJECTIVE: To identify 5'-cytosine-phosphate-guanine-3' in DNA (CpG) sites associated with body mass index (BMI) and examine the temporal relationship between dynamic changes in DNAm and BMI in a longitudinal cohort. METHODS AND RESULTS: Race-specific EWASs were performed in 995 whites and 490 blacks from the Bogalusa Heart Study. Suggestive CpG sites were further replicated in 252 whites and 228 blacks from the Georgia Stress and Heart Study. Cross-lagged panel analysis was used to examine the temporal relationship between DNAm and BMI in 439 whites and 201 blacks who were examined twice 6.2 years apart. In discovery and replication samples, 349 CpG sites (266 novel) in whites and 36 (21 novel) in blacks were identified to be robustly associated with BMI, with 8 (1 novel) CpG sites overlapping between the 2 races. Cross-lagged panel analyses showed significant unidirectional paths (PFDR <0.05) from baseline BMI to follow-up DNAm at 18 CpG sites in whites and 7 in blacks; no CpG sites showed significant paths from DNAm at baseline to BMI at follow-up. Baseline BMI was associated with a DNAm score (calculated from DNAm levels at the associated CpG sites) at follow-up (P<0.001 both in blacks and in whites). CONCLUSIONS: The findings provide strong evidence that obesity is the cause, not a consequence, of changes in DNAm over time.
Entities:
Keywords:
DNA methylation; body mass index; causality; epigenomics; longitudinal studies; obesity; race factors
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