TY - JOUR
T1 - Cross-reactive probes on Illumina DNA methylation arrays
T2 - A large study on ALS shows that a cautionary approach is warranted in interpreting epigenome-wide association studies
AU - Hop, Paul J.
AU - Zwamborn, Ramona A.J.
AU - Hannon, Eilis J.
AU - Dekker, Annelot M.
AU - van Eijk, Kristel R.
AU - Walker, Emma M.
AU - Iacoangeli, Alfredo
AU - Jones, Ashley R.
AU - Shatunov, Aleksey
AU - Khleifat, Ahmad Al
AU - Opie-Martin, Sarah
AU - Shaw, Christopher E.
AU - Morrison, Karen E.
AU - Shaw, Pamela J.
AU - McLaughlin, Russell L.
AU - Hardiman, Orla
AU - Al-Chalabi, Ammar
AU - van Den Berg, Leonard H.
AU - Mill, Jonathan
AU - Veldink, Jan H.
N1 - Publisher Copyright:
© The Author(s) 2020. Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics.
PY - 2020/12/1
Y1 - 2020/12/1
N2 - Illumina DNA methylation arrays are a widely used tool for performing genome-wide DNA methylation analyses. However, measurements obtained from these arrays may be affected by technical artefacts that result in spurious associations if left unchecked. Cross-reactivity represents one of the major challenges, meaning that probes may map to multiple regions in the genome. Although several studies have reported on this issue, few studies have empirically examined the impact of cross-reactivity in an epigenome-wide association study (EWAS). In this paper, we report on cross-reactivity issues that we discovered in a large EWAS on the presence of the C9orf72 repeat expansion in ALS patients. Specifically, we found that that the majority of the significant probes inadvertently cross-hybridized to the C9orf72 locus. Importantly, these probes were not flagged as cross-reactive in previous studies, leading to novel insights into the extent to which cross-reactivity can impact EWAS. Our findings are particularly relevant for epigenetic studies into diseases associated with repeat expansions and other types of structural variation. More generally however, considering that most spurious associations were not excluded based on pre-defined sets of cross-reactive probes, we believe that the presented data-driven flag and consider approach is relevant for any type of EWAS.
AB - Illumina DNA methylation arrays are a widely used tool for performing genome-wide DNA methylation analyses. However, measurements obtained from these arrays may be affected by technical artefacts that result in spurious associations if left unchecked. Cross-reactivity represents one of the major challenges, meaning that probes may map to multiple regions in the genome. Although several studies have reported on this issue, few studies have empirically examined the impact of cross-reactivity in an epigenome-wide association study (EWAS). In this paper, we report on cross-reactivity issues that we discovered in a large EWAS on the presence of the C9orf72 repeat expansion in ALS patients. Specifically, we found that that the majority of the significant probes inadvertently cross-hybridized to the C9orf72 locus. Importantly, these probes were not flagged as cross-reactive in previous studies, leading to novel insights into the extent to which cross-reactivity can impact EWAS. Our findings are particularly relevant for epigenetic studies into diseases associated with repeat expansions and other types of structural variation. More generally however, considering that most spurious associations were not excluded based on pre-defined sets of cross-reactive probes, we believe that the presented data-driven flag and consider approach is relevant for any type of EWAS.
UR - http://www.scopus.com/inward/record.url?scp=85115256196&partnerID=8YFLogxK
U2 - 10.1093/nargab/lqaa105
DO - 10.1093/nargab/lqaa105
M3 - Article
AN - SCOPUS:85115256196
SN - 2631-9268
VL - 2
JO - NAR Genomics and Bioinformatics
JF - NAR Genomics and Bioinformatics
IS - 4
M1 - lqaa105
ER -