An Epigenome-Wide Association Study of Obesity-Related Traits

• Published in: American journal of epidemiology Vol. 187; no. 8; pp. 1662 - 1669
• Main Authors: Dhana, Klodian, Braun, Kim V E, Nano, Jana, Voortman, Trudy, Demerath, Ellen W, Guan, Weihua, Fornage, Myriam, van Meurs, Joyce B J, Uitterlinden, Andre G, Hofman, Albert, Franco, Oscar H, Dehghan, Abbas
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.08.2018; Oxford Publishing Limited (England)
• Subjects: Amino Acyl-tRNA Synthetases - genetics; Arrays; Arteriosclerosis; Atherosclerosis; Biomarkers; Biomarkers - analysis; Body mass index; Body size; Chronic illnesses; Cohort analysis; CpG islands; CpG Islands - genetics; Deoxyribonucleic acid; DNA; DNA Methylation; Epigenomics - methods; Female; Genome-Wide Association Study; Genomes; Humans; Leucine-tRNA ligase; Leukocytes; Male; Middle Aged; Mitochondria; Netherlands - epidemiology; Obesity; Obesity - genetics; Original Contributions; Phenotype; Population studies; Prospective Studies; Random variables; Ribonucleic acid; RNA; RNA-binding protein; RNA-Binding Proteins - genetics; Smoking; tRNA; United States - epidemiology; United States; Netherlands; cohort studies; DNA methylation; epigenome-wide association studies; waist circumference; body mass index; obesity
• ISSN: 0002-9262; 1476-6256; 1476-6256
• DOI: 10.1093/aje/kwy025

Abstract 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 the RS (n = 1,450) as the discovery panel and the ARIC Study (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, and TMEM49 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.