Epigenome-wide association study (EWAS) of BMI, BMI change and waist circumference in African American adults identifies multiple replicated loci.
Obesity is an important component of the pathophysiology of chronic diseases. Identifying epigenetic modifications associated with elevated adiposity, including DNA methylation variation, may point to genomic pathways that are dysregulated in numerous conditions. The Illumina 450K Bead Chip array was used to assay DNA methylation in leukocyte DNA obtained from 2097 African American adults in the Atherosclerosis Risk in Communities (ARIC) study. Mixed-effects regression models were used to test the association of methylation beta value with concurrent body mass index (BMI) and waist circumference (WC), and BMI change, adjusting for batch effects and potential confounders. Replication using whole-blood DNA from 2377 White adults in the Framingham Heart Study and CD4+ T cell DNA from 991 Whites in the Genetics of Lipid Lowering Drugs and Diet Network Study was followed by testing using adipose tissue DNA from 648 women in the Multiple Tissue Human Expression Resource cohort. Seventy-six BMI-related probes, 164 WC-related probes and 8 BMI change-related probes passed the threshold for significance in ARIC (P < 1 × 10(-7); Bonferroni), including probes in the recently reported HIF3A, CPT1A and ABCG1 regions. Replication using blood DNA was achieved for 37 BMI probes and 1 additional WC probe. Sixteen of these also replicated in adipose tissue, including 15 novel methylation findings near genes involved in lipid metabolism, immune response/cytokine signaling and other diverse pathways, including LGALS3BP, KDM2B, PBX1 and BBS2, among others. Adiposity traits are associated with DNA methylation at numerous CpG sites that replicate across studies despite variation in tissue type, ethnicity and analytic approaches.
Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN 55454, USA, ewd@umn.edu.
Ellen W
EW
Demerath
Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN 55454, USA.
Weihua
W
Guan
Human Genetics Center, School of Public Health, University of Texas Health Sciences Center at Houston, Houston, TX 77030, USA.
Megan L
ML
Grove
Department of Epidemiology and.
Stella
S
Aslibekyan
Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20824, USA, Framingham Heart Study, Framingham, MA 01702, USA, Department of Cardiology, Boston Children's Hospital, Boston, MA 02215, USA.
Michael
M
Mendelson
Department of Statistics, North Carolina State University, Raleigh, NC 27695, USA.
Yi-Hui
YH
Zhou
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK, Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Åsa K
ÅK
Hedman
Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
Johanna K
JK
Sandling
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
Li-An
LA
Li
Department of Epidemiology and.
Marguerite R
MR
Irvin
Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Degui
D
Zhi
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK, Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah 21589, Saudi Arabia.
Panos
P
Deloukas
Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20824, USA, Framingham Heart Study, Framingham, MA 01702, USA, Departments of Epidemiology and Biostatistics, School of Public Health, Harvard University, Boston, MA 02115, USA.
Liming
L
Liang
Framingham Heart Study, Framingham, MA 01702, USA, Department of Biostatistics, Boston University, Boston, MA 02118, USA.
Chunyu
C
Liu
Human Genetics Center, School of Public Health, University of Texas Health Sciences Center at Houston, Houston, TX 77030, USA.
Jan
J
Bressler
Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK.
Tim D
TD
Spector
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
Kari
K
North
Department of Genetics, Department of Biostatistics and Department of Computer Science, University of North Carolina, Chapel Hill, NC 27599, USA.
Yun
Y
Li
Hudson Alpha Institute for Biotechnology, Huntsville, AL 34806, USA.
Devin M
DM
Absher
Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20824, USA, Framingham Heart Study, Framingham, MA 01702, USA.
Daniel
D
Levy
Department of Epidemiology and.
Donna K
DK
Arnett
Human Genetics Center, School of Public Health, University of Texas Health Sciences Center at Houston, Houston, TX 77030, USA, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
Myriam
M
Fornage
Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN 55454, USA.
James S
JS
Pankow
Human Genetics Center, School of Public Health, University of Texas Health Sciences Center at Houston, Houston, TX 77030, USA, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
Eric
E
Boerwinkle
D001741:Black or African American / Q000235:genetics; D000368:Aged; D050197:Atherosclerosis / Q000235:genetics* / Q000473:pathology; D015992:Body Mass Index; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics; D008875:Middle Aged; D009765:Obesity / Q000235:genetics* / Q000473:pathology; D055105:Waist Circumference / Q000235:genetics; D044465:White People / Q000235:genetics