Edwina H Yeung1, Pauline Mendola2, Rajeshwari Sundaram3, Xuehuo Zeng4, Weihua Guan5, Michael Y Tsai6, Sonia L Robinson7, Judy E Stern8, Akhgar Ghassabian9, David Lawrence10, Thomas G O'Connor11, James Segars12, Robert E Gore-Langton13, Erin M Bell14. 1. Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland. Electronic address: edwina.yeung@nih.gov. 2. Epidemiology and Environmental Health, School of Public Health and Health Professions, University at Buffalo, Buffalo, New York. 3. Biostatistics and Bioinformatics Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland. 4. Glotech, Inc., Rockville, Maryland. 5. Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota. 6. Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota. 7. Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland. 8. Department of Obstetrics and Gynecology, Dartmouth-Hitchcock, Lebanon, New Hampshire. 9. Departments of Pediatrics, Population Health, and Environmental Medicine, New York University School of Medicine, New York, New York. 10. Department of Environmental Health Sciences, University at Albany School of Public Health, Albany, New York. 11. Departments of Psychiatry, Psychology, Neuroscience, Obstetrics and Gynecology, University of Rochester, Rochester, New York. 12. Howard W. and Georgeanna Seegar Jones Laboratory of Reproductive Sciences and Women's Health Research, Department of Obstetrics and Gynecology, Johns Hopkins Medical University, Baltimore, Maryland. 13. Emmes, Rockville, Maryland. 14. Department of Epidemiology and Biostatistics, University at Albany School of Public Health, Albany, New York.
Abstract
OBJECTIVE: To investigate whether deoxyribonucleic acid (DNA) methylation at birth and in childhood differ by conception using assisted reproductive technologies (ART) or ovulation induction compared with those in children conceived without fertility treatment. DESIGN: Upstate KIDS is a matched exposure cohort which oversampled on newborns conceived by treatment. SETTING: New York State (excluding New York City). PATIENT(S): This analysis included 855 newborns and 152 children at approximately 9 years of age. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): DNA methylation levels were measured using the Illumina EPIC platform. Single CpG and regional analyses at imprinting genes were conducted. RESULT(S): Compared to no fertility treatment, ART was associated with lower mean DNA methylation levels at birth in 11 CpGs (located in/near SYCE1, SPRN, KIAA2013, MYO1D, GET1/WRB-SH4BGR, IGF1R, SORD, NECAB3/ACTL10, and GET1) and higher mean methylation level in 1 CpG (KLK4; all false discovery rate P<.05). The strongest association (cg17676129) was located at SYCE1, which codes for a synaptonemal complex that plays a role in meiosis and therefore infertility. This CpG remained associated with newborn hypomethylation when the analysis was limited to those conceived with ICSI, but this may be because of underlying male infertility. In addition, nine regions in maternally imprinted genes (IGF1R, PPIEL, SVOPL GNAS, L3MBTL, BLCAP, HYMAI/PLAGL1, SNU13, and MEST) were observed to have decreased mean DNA methylation levels among newborns conceived by ART. In childhood, hypomethylation of the maternally imprinted gene, GNAS, persisted. No CpGs or regions were associated with ovulation induction. CONCLUSION(S): ART but not ovulation induction was associated with hypomethylation at birth, but only one difference at an imprinting region appeared to persist in childhood. Published by Elsevier Inc.
OBJECTIVE: To investigate whether deoxyribonucleic acid (DNA) methylation at birth and in childhood differ by conception using assisted reproductive technologies (ART) or ovulation induction compared with those in children conceived without fertility treatment. DESIGN: Upstate KIDS is a matched exposure cohort which oversampled on newborns conceived by treatment. SETTING: New York State (excluding New York City). PATIENT(S): This analysis included 855 newborns and 152 children at approximately 9 years of age. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): DNA methylation levels were measured using the Illumina EPIC platform. Single CpG and regional analyses at imprinting genes were conducted. RESULT(S): Compared to no fertility treatment, ART was associated with lower mean DNA methylation levels at birth in 11 CpGs (located in/near SYCE1, SPRN, KIAA2013, MYO1D, GET1/WRB-SH4BGR, IGF1R, SORD, NECAB3/ACTL10, and GET1) and higher mean methylation level in 1 CpG (KLK4; all false discovery rate P<.05). The strongest association (cg17676129) was located at SYCE1, which codes for a synaptonemal complex that plays a role in meiosis and therefore infertility. This CpG remained associated with newborn hypomethylation when the analysis was limited to those conceived with ICSI, but this may be because of underlying male infertility. In addition, nine regions in maternally imprinted genes (IGF1R, PPIEL, SVOPL GNAS, L3MBTL, BLCAP, HYMAI/PLAGL1, SNU13, and MEST) were observed to have decreased mean DNA methylation levels among newborns conceived by ART. In childhood, hypomethylation of the maternally imprinted gene, GNAS, persisted. No CpGs or regions were associated with ovulation induction. CONCLUSION(S): ART but not ovulation induction was associated with hypomethylation at birth, but only one difference at an imprinting region appeared to persist in childhood. Published by Elsevier Inc.
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