Appraising the causal relevance of DNA methylation for risk of lung cancer
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
Appraising the causal relevance of DNA methylation for risk of lung cancer. / Battram, Thomas; Richmond, Rebecca C.; Baglietto, Laura; Haycock, Philip C.; Perduca, Vittorio; Bojesen, Stig E.; Gaunt, Tom R.; Hemani, Gibran; Guida, Florence; Carreras-Torres, Robert; Hung, Rayjean; Amos, Christopher I.; Freeman, Joshua R.; Sandanger, Torkjel M.; Nøst, Therese H.; Nordestgaard, Børge G.; Teschendorff, Andrew E.; Polidoro, Silvia; Vineis, Paolo; Severi, Gianluca; Hodge, Allison M.; Giles, Graham G.; Grankvist, Kjell; Johansson, Mikael B.; Johansson, Mattias; Davey Smith, George; Relton, Caroline L.
In: International Journal of Epidemiology, Vol. 48, No. 5, 2019, p. 1493-1504.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Appraising the causal relevance of DNA methylation for risk of lung cancer
AU - Battram, Thomas
AU - Richmond, Rebecca C.
AU - Baglietto, Laura
AU - Haycock, Philip C.
AU - Perduca, Vittorio
AU - Bojesen, Stig E.
AU - Gaunt, Tom R.
AU - Hemani, Gibran
AU - Guida, Florence
AU - Carreras-Torres, Robert
AU - Hung, Rayjean
AU - Amos, Christopher I.
AU - Freeman, Joshua R.
AU - Sandanger, Torkjel M.
AU - Nøst, Therese H.
AU - Nordestgaard, Børge G.
AU - Teschendorff, Andrew E.
AU - Polidoro, Silvia
AU - Vineis, Paolo
AU - Severi, Gianluca
AU - Hodge, Allison M.
AU - Giles, Graham G.
AU - Grankvist, Kjell
AU - Johansson, Mikael B.
AU - Johansson, Mattias
AU - Davey Smith, George
AU - Relton, Caroline L.
PY - 2019
Y1 - 2019
N2 - Background: DNA methylation changes in peripheral blood have recently been identified in relation to lung cancer risk. Some of these changes have been suggested to mediate part of the effect of smoking on lung cancer. However, limitations with conventional mediation analyses mean that the causal nature of these methylation changes has yet to be fully elucidated. Methods: We first performed a meta-analysis of four epigenome-wide association studies (EWAS) of lung cancer (918 cases, 918 controls). Next, we conducted a two-sample Mendelian randomization analysis, using genetic instruments for methylation at CpG sites identified in the EWAS meta-analysis, and 29 863 cases and 55 586 controls from the TRICL-ILCCO lung cancer consortium, to appraise the possible causal role of methylation at these sites on lung cancer. Results: Sixteen CpG sites were identified from the EWAS meta-analysis [false discovery rate (FDR) < 0.05], for 14 of which we could identify genetic instruments. Mendelian randomization provided little evidence that DNA methylation in peripheral blood at the 14 CpG sites plays a causal role in lung cancer development (FDR > 0.05), including for cg05575921-AHRR where methylation is strongly associated with both smoke exposure and lung cancer risk. Conclusions: The results contrast with previous observational and mediation analysis, which have made strong claims regarding the causal role of DNA methylation. Thus, previous suggestions of a mediating role of methylation at sites identified in peripheral blood, such as cg05575921-AHRR, could be unfounded. However, this study does not preclude the possibility that differential DNA methylation at other sites is causally involved in lung cancer development, especially within lung tissue.
AB - Background: DNA methylation changes in peripheral blood have recently been identified in relation to lung cancer risk. Some of these changes have been suggested to mediate part of the effect of smoking on lung cancer. However, limitations with conventional mediation analyses mean that the causal nature of these methylation changes has yet to be fully elucidated. Methods: We first performed a meta-analysis of four epigenome-wide association studies (EWAS) of lung cancer (918 cases, 918 controls). Next, we conducted a two-sample Mendelian randomization analysis, using genetic instruments for methylation at CpG sites identified in the EWAS meta-analysis, and 29 863 cases and 55 586 controls from the TRICL-ILCCO lung cancer consortium, to appraise the possible causal role of methylation at these sites on lung cancer. Results: Sixteen CpG sites were identified from the EWAS meta-analysis [false discovery rate (FDR) < 0.05], for 14 of which we could identify genetic instruments. Mendelian randomization provided little evidence that DNA methylation in peripheral blood at the 14 CpG sites plays a causal role in lung cancer development (FDR > 0.05), including for cg05575921-AHRR where methylation is strongly associated with both smoke exposure and lung cancer risk. Conclusions: The results contrast with previous observational and mediation analysis, which have made strong claims regarding the causal role of DNA methylation. Thus, previous suggestions of a mediating role of methylation at sites identified in peripheral blood, such as cg05575921-AHRR, could be unfounded. However, this study does not preclude the possibility that differential DNA methylation at other sites is causally involved in lung cancer development, especially within lung tissue.
KW - ALSPAC
KW - ARIES
KW - DNA methylation
KW - Lung cancer
KW - Mendelian randomization
U2 - 10.1093/ije/dyz190
DO - 10.1093/ije/dyz190
M3 - Journal article
C2 - 31549173
AN - SCOPUS:85075089105
VL - 48
SP - 1493
EP - 1504
JO - International Journal of Epidemiology
JF - International Journal of Epidemiology
SN - 0300-5771
IS - 5
ER -
ID: 241366552