We conducted an epigenome-wide association study on obesity-related traits. We used data from 2 prospective, population-based cohort studies: the Rotterdam Study (RS) (2006.2013) and the Atherosclerosis Risk in Communities (ARIC)Study (1990.1992).We used theRS(n = 1,450) as the discovery panel and the ARICStudy (n = 2,097) as the replication panel. Linear mixed-effect models were used to assess the cross-sectional associations between genome-wide DNA methylation in leukocytes and body mass index (BMI) and waist circumference (WC), adjusting for sex, age, smoking, leukocyte proportions, array number, and position on array. The latter 2 variables were modeled as random effects. Fourteen 5′-C-phosphate-G-3′ (CpG) sites were associated with BMI and 26 CpG sites with WC in the RS after Bonferroni correction (P < 1.07 × 10-7), of which 12 and 13 CpGs were replicated in the ARIC Study, respectively. The most significant novel CpGs were located on the Musashi RNA binding protein 2 gene (MSI2; cg21139312) and the leucyl-tRNA synthetase 2, mitochondrial gene (LARS2; cg18030453) and were associated with both BMI and WC. CpGs at BRDT, PSMD1, IFI44L, MAP1A, and MAP3K5 were associated with BMI. CpGs at LGALS3BP, MAP2K3, DHCR24, CPSF4L, andTMEM49 were associated with WC.We report novel associations between methylation at MSI2 and LARS2 and obesity-related traits. These results provide further insight into mechanisms underlying obesity-related traits, which can enable identification of new biomarkers in obesity-related chronic diseases.
Bibliographical noteFunding Information:
Netherlands (Kim V. E. Braun, Trudy Voortman, Oscar H. Franco); Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota (Ellen W. Demerath); Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota (Weihua Guan); Human Genetics Center, School of Public Health, University of Texas Health Sciences Center at Houston, Houston, Texas (Myriam Fornage); Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas (Myriam Fornage); Department of Internal Medicine, Erasmus University Medical Center (Erasmus MC), Rotterdam, the Netherlands (Joyce B. J. van Meurs, Andre G. Uitterlinden); Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts (Albert Hofman); and Department of Epidemiology, Imperial College London, London, United Kingdom (Abbas Dehghan). K.D. and K.V.E.B. contributed equally to this article. The Rotterdam Study is funded by Erasmus University Medical Center (Erasmus MC) and Erasmus University Rotterdam; the Netherlands Organization for Health Research and Development; the Research Institute for Diseases in the Elderly; the Netherlands Ministry of Education, Culture and Science; the Netherlands Ministry of Health, Welfare and Sport; the European Commission (Directorate-General XII); and the Municipality of Rotterdam. The ARIC Study is funded by the US National Heart, Lung, and Blood Institute. Generation and management of the Infinium Human Methylation 450K BeadChip array data for the Rotterdam Study was conducted by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC; funding was provided by Erasmus MC and the Netherlands Organization for Scientific Research (project 184021007). The data were made available as part of Rainbow Project 3 of the Biobanking and Biomolecular Resources Research Infrastructure–Netherlands. We thank Michael Verbiest, Mila Jhamai, Sarah Higgins, Marijn Verkerk, and Dr. Lisette Stolk for their help in creating the methylation database. We are grateful to the staff of and participants in the Rotterdam and ARIC studies and to all of the general practitioners and pharmacists involved. The funding organizations played no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; or the preparation, review, and approval of the manuscript. The Rotterdam Intergenerational Ageing Research Center (ErasmusAGE), a center for aging research across the life course, is supported by Nestlé Nutrition (Nestec Ltd., Lausanne, Switzerland) and Metagenics, Inc. (Aliso Viejo, California). Conflict of interest: none declared.
- Body mass index
- Cohort studies
- DNA methylation
- Epigenome-wide association studies
- Waist circumference