Details

Autor(en) / Beteiligte

• Shiwa, Yuh
• Hachiya, Tsuyoshi
• Furukawa, Ryohei
• Ohmomo, Hideki
• Ono, Kanako
• Kudo, Hisaaki
• Hata, Jun
• Hozawa, Atsushi
• Iwasaki, Motoki
• Matsuda, Koichi
• Minegishi, Naoko
• Satoh, Mamoru
• Tanno, Kozo
• Yamaji, Taiki
• Wakai, Kenji
• Hitomi, Jiro
• Kiyohara, Yutaka
• Kubo, Michiaki
• Tanaka, Hideo
• Tsugane, Shoichiro
• Yamamoto, Masayuki
• Sobue, Kenji
• Shimizu, Atsushi
• Koestler, Devin C.

Titel

Adjustment of Cell-Type Composition Minimizes Systematic Bias in Blood DNA Methylation Profiles Derived by DNA Collection Protocols

Ist Teil von

• PloS one, 2016-01, Vol.11 (1), p.e0147519-e0147519

Ort / Verlag

United States: Public Library of Science

Erscheinungsjahr

2016

Quelle

MEDLINE

Beschreibungen/Notizen

• Differences in DNA collection protocols may be a potential confounder in epigenome-wide association studies (EWAS) using a large number of blood specimens from multiple biobanks and/or cohorts. Here we show that pre-analytical procedures involved in DNA collection can induce systematic bias in the DNA methylation profiles of blood cells that can be adjusted by cell-type composition variables. In Experiment 1, whole blood from 16 volunteers was collected to examine the effect of a 24 h storage period at 4°C on DNA methylation profiles as measured using the Infinium HumanMethylation450 BeadChip array. Our statistical analysis showed that the P-value distribution of more than 450,000 CpG sites was similar to the theoretical distribution (in quantile-quantile plot, λ = 1.03) when comparing two control replicates, which was remarkably deviated from the theoretical distribution (λ = 1.50) when comparing control and storage conditions. We then considered cell-type composition as a possible cause of the observed bias in DNA methylation profiles and found that the bias associated with the cold storage condition was largely decreased (λ adjusted = 1.14) by taking into account a cell-type composition variable. As such, we compared four respective sample collection protocols used in large-scale Japanese biobanks or cohorts as well as two control replicates. Systematic biases in DNA methylation profiles were observed between control and three of four protocols without adjustment of cell-type composition (λ = 1.12-1.45) and no remarkable biases were seen after adjusting for cell-type composition in all four protocols (λ adjusted = 1.00-1.17). These results revealed important implications for comparing DNA methylation profiles between blood specimens from different sources and may lead to discovery of disease-associated DNA methylation markers and the development of DNA methylation profile-based predictive risk models.