Miriam Kesselmeier1, Carolin Pütter2, Anna-Lena Volckmar3, Hansjörg Baurecht4, Harald Grallert5,6, Thomas Illig5,7,8, Khadeeja Ismail9, Miina Ollikainen9, Yasmina Silén9, Anna Keski-Rahkonen9, Cynthia M Bulik10,11, David A Collier12,13, Eleftheria Zeggini14, Johannes Hebebrand3, André Scherag1, Anke Hinney3. 1. a Clinical Epidemiology, Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital , Jena , Germany. 2. b Institute for Medical Informatics, Biometry and Epidemiology, University of Duisburg-Essen , Essen , Germany. 3. c Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy , University Hospital Essen, University of Duisburg-Essen , Essen , Germany. 4. d Department of Dermatology, Allergology, and Venereology , University Hospital Schleswig-Holstein , Campus Kiel, Kiel , Germany. 5. e Research Unit of Molecular Epidemiology , Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health , Neuherberg , Germany. 6. f German Center for Diabetes Research , Neuherberg , Germany. 7. g Hannover Unified Biobank , Hannover Medical School , Hannover , Germany. 8. h Institute of Human Genetics , Hannover Medical School , Hannover , Germany. 9. i Department of Public Health , University of Helsinki , Helsinki , Finland. 10. j Department of Psychiatry , University of North Carolina at Chapel Hill , Chapel Hill , NC , USA. 11. k Department of Nutrition , The University of North Carolina at Chapel Hill , Chapel Hill , NC , USA. 12. l Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London , London , UK. 13. m Eli Lilly and Company, Erl Wood Manor , Windlesham , UK. 14. n Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus , Hinxton , Cambridge , UK.
Abstract
OBJECTIVES: Patients with anorexia nervosa (AN) are ideally suited to identify differentially methylated genes in response to starvation. METHODS: We examined high-throughput DNA methylation derived from whole blood of 47 females with AN, 47 lean females without AN and 100 population-based females to compare AN with both controls. To account for different cell type compositions, we applied two reference-free methods (FastLMM-EWASher, RefFreeEWAS) and searched for consensus CpG sites identified by both methods. We used a validation sample of five monozygotic AN-discordant twin pairs. RESULTS: Fifty-one consensus sites were identified in AN vs. lean and 81 in AN vs. population-based comparisons. These sites have not been reported in AN methylation analyses, but for the latter comparison 54/81 sites showed directionally consistent differential methylation effects in the AN-discordant twins. For a single nucleotide polymorphism rs923768 in CSGALNACT1 a nearby site was nominally associated with AN. At the gene level, we confirmed hypermethylated sites at TNXB. We found support for a locus at NR1H3 in the AN vs. lean control comparison, but the methylation direction was opposite to the one previously reported. CONCLUSIONS: We confirm genes like TNXB previously described to comprise differentially methylated sites, and highlight further sites that might be specifically involved in AN starvation processes.
OBJECTIVES:Patients with anorexia nervosa (AN) are ideally suited to identify differentially methylated genes in response to starvation. METHODS: We examined high-throughput DNA methylation derived from whole blood of 47 females with AN, 47 lean females without AN and 100 population-based females to compare AN with both controls. To account for different cell type compositions, we applied two reference-free methods (FastLMM-EWASher, RefFreeEWAS) and searched for consensus CpG sites identified by both methods. We used a validation sample of five monozygotic AN-discordant twin pairs. RESULTS: Fifty-one consensus sites were identified in AN vs. lean and 81 in AN vs. population-based comparisons. These sites have not been reported in AN methylation analyses, but for the latter comparison 54/81 sites showed directionally consistent differential methylation effects in the AN-discordant twins. For a single nucleotide polymorphism rs923768 in CSGALNACT1 a nearby site was nominally associated with AN. At the gene level, we confirmed hypermethylated sites at TNXB. We found support for a locus at NR1H3 in the AN vs. lean control comparison, but the methylation direction was opposite to the one previously reported. CONCLUSIONS: We confirm genes like TNXB previously described to comprise differentially methylated sites, and highlight further sites that might be specifically involved in AN starvation processes.
Entities:
Keywords:
Anorexia nervosa; DNA methylation; eating disorder; epigenome-wide association study; starvation
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