Shuxia Li1, Weijing Wang2, Dongfeng Zhang2, Weilong Li3, Jesper Lund4, Torben Kruse5, Jonas Mengel-From6, Kaare Christensen7, Qihua Tan8. 1. Epidemiology and Biostatistics, Department of Public Health, University of Southern Denmark, Odense, Denmark. Electronic address: sli@health.sdu.dk. 2. Qingdao University School of Public Health, Qingdao, China. 3. Epidemiology and Biostatistics, Department of Public Health, University of Southern Denmark, Odense, Denmark; Population Research Unit, Faculty of Social Sciences, University of Helsinki, Finland. Electronic address: weilong.li@helsinki.fi. 4. Epidemiology and Biostatistics, Department of Public Health, University of Southern Denmark, Odense, Denmark; Digital Health & Machine Learning Research Group, Hasso Plattner Institute for Digital Engineering, Potsdam, Germany. Electronic address: jlund@health.sdu.dk. 5. Unit of Human Genetics, Department of Clinical Research, University of Southern Denmark, Odense, Denmark. Electronic address: torben.kruse@rsyd.dk. 6. Epidemiology and Biostatistics, Department of Public Health, University of Southern Denmark, Odense, Denmark. Electronic address: jmengel-from@health.sdu.dk. 7. Epidemiology and Biostatistics, Department of Public Health, University of Southern Denmark, Odense, Denmark. Electronic address: kchristensen@health.sdu.dk. 8. Epidemiology and Biostatistics, Department of Public Health, University of Southern Denmark, Odense, Denmark; Unit of Human Genetics, Department of Clinical Research, University of Southern Denmark, Odense, Denmark. Electronic address: qtan@health.sdu.dk.
Abstract
BACKGROUND: Extensive epidemiological studies have established the association between exposure to early-life adversity and health status and diseases in adults. Epigenetic regulation is considered as a key mediator for this phenomenon but analysis on humans is sparse. The Great Chinese Famine lasting from 1958 to 1961 is a natural string of disasters offering a precious opportunity for elucidating the underlying epigenetic mechanism of the long-term effect of early adversity. METHODS: Using a high-throughput array platform for DNA methylome profiling, we conducted a case-control epigenome-wide association study on early-life exposure to Chinese famine in 79 adults born during 1959-1961 and compared to 105 unexposed subjects born 1963-1964. RESULTS: The single CpG site analysis of whole epigenome revealed a predominant pattern of decreased DNA methylation levels associated with fetal exposure to famine. Four CpG sites were detected with p < 1e-06 (linked to EHMT1, CNR1, UBXN7 and ESM1 genes), 16 CpGs detected with 1e-06 < p < 1e-05 and 157 CpGs with 1e-05 < p < 1e-04, with a predominant pattern of hypomethylation. Functional annotation to genes and their enriched biological pathways mainly involved neurodevelopment, neuropsychological disorders and metabolism. Multiple sites analysis detected two top-rank differentially methylated regions harboring RNF39 on chromosome 6 and PTPRN2 on chromosome 7, both showing epigenetic association with stress-related conditions. CONCLUSION: Early-life exposure to famine could mediate DNA methylation regulations that persist into adulthood with broad impacts in the activities of genes and biological pathways. Results from this study provide new clues to the epigenetic embedding of early-life adversity and its impacts on adult health.
BACKGROUND: Extensive epidemiological studies have established the association between exposure to early-life adversity and health status and diseases in adults. Epigenetic regulation is considered as a key mediator for this phenomenon but analysis on humans is sparse. The Great Chinese Famine lasting from 1958 to 1961 is a natural string of disasters offering a precious opportunity for elucidating the underlying epigenetic mechanism of the long-term effect of early adversity. METHODS: Using a high-throughput array platform for DNA methylome profiling, we conducted a case-control epigenome-wide association study on early-life exposure to Chinese famine in 79 adults born during 1959-1961 and compared to 105 unexposed subjects born 1963-1964. RESULTS: The single CpG site analysis of whole epigenome revealed a predominant pattern of decreased DNA methylation levels associated with fetal exposure to famine. Four CpG sites were detected with p < 1e-06 (linked to EHMT1, CNR1, UBXN7 and ESM1 genes), 16 CpGs detected with 1e-06 < p < 1e-05 and 157 CpGs with 1e-05 < p < 1e-04, with a predominant pattern of hypomethylation. Functional annotation to genes and their enriched biological pathways mainly involved neurodevelopment, neuropsychological disorders and metabolism. Multiple sites analysis detected two top-rank differentially methylated regions harboring RNF39 on chromosome 6 and PTPRN2 on chromosome 7, both showing epigenetic association with stress-related conditions. CONCLUSION: Early-life exposure to famine could mediate DNA methylation regulations that persist into adulthood with broad impacts in the activities of genes and biological pathways. Results from this study provide new clues to the epigenetic embedding of early-life adversity and its impacts on adult health.