Recommendations for the design and analysis of epigenome-wide association studies.
Epigenome-wide association studies (EWAS) hold promise for the detection of new regulatory mechanisms that may be susceptible to modification by environmental and lifestyle factors affecting susceptibility to disease. Epigenome-wide screening methods cover an increasing number of CpG sites, but the complexity of the data poses a challenge to separating robust signals from noise. Appropriate study design, a detailed a priori analysis plan and validation of results are essential to minimize the danger of false positive results and contribute to a unified approach. Epigenome-wide mapping studies in homogenous cell populations will inform our understanding of normal variation in the methylome that is not associated with disease or aging. Here we review concepts for conducting a stringent and powerful EWAS, including the choice of analyzed tissue, sources of variability and systematic biases, outline analytical solutions to EWAS-specific problems and highlight caveats in interpretation of data generated from samples with cellular heterogeneity.
1] Obstetrics and Gynecology Epidemiology Center, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.
Karin B
KB
Michels
Alexandra M
AM
Binder
Sarah
S
Dedeurwaerder
Charles B
CB
Epstein
John M
JM
Greally
Ivo
I
Gut
E Andres
EA
Houseman
Benedetta
B
Izzi
Karl T
KT
Kelsey
Alexander
A
Meissner
Aleksandar
A
Milosavljevic
Kimberly D
KD
Siegmund
Christoph
C
Bock
Rafael A
RA
Irizarry
D000818:Animals; D018899:CpG Islands; D019175:DNA Methylation; D003627:Data Interpretation, Statistical; D044127:Epigenesis, Genetic; D055106:Genome-Wide Association Study / Q000379:methods* / Q000706:statistics & numerical data; D006801:Humans; D012107:Research Design; D017422:Sequence Analysis, DNA