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Cross-reactive probes on Illumina DNA methylation arrays: A large study on ALS shows that a cautionary approach is warranted in interpreting epigenome-wide association studies

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Cross-reactive probes on Illumina DNA methylation arrays : A large study on ALS shows that a cautionary approach is warranted in interpreting epigenome-wide association studies. / Hop, Paul J.; Zwamborn, Ramona A.J.; Hannon, Eilis J. et al.

In: NAR Genomics and Bioinformatics, Vol. 2, No. 4, lqaa105, 01.12.2020.

Research output: Contribution to journalArticlepeer-review

Harvard

Hop, PJ, Zwamborn, RAJ, Hannon, EJ, Dekker, AM, van Eijk, KR, Walker, EM, Iacoangeli, A, Jones, AR, Shatunov, A, Khleifat, AA, Opie-Martin, S, Shaw, CE, Morrison, KE, Shaw, PJ, McLaughlin, RL, Hardiman, O, Al-Chalabi, A, van Den Berg, LH, Mill, J & Veldink, JH 2020, 'Cross-reactive probes on Illumina DNA methylation arrays: A large study on ALS shows that a cautionary approach is warranted in interpreting epigenome-wide association studies', NAR Genomics and Bioinformatics, vol. 2, no. 4, lqaa105. https://doi.org/10.1093/nargab/lqaa105

APA

Hop, P. J., Zwamborn, R. A. J., Hannon, E. J., Dekker, A. M., van Eijk, K. R., Walker, E. M., Iacoangeli, A., Jones, A. R., Shatunov, A., Khleifat, A. A., Opie-Martin, S., Shaw, C. E., Morrison, K. E., Shaw, P. J., McLaughlin, R. L., Hardiman, O., Al-Chalabi, A., van Den Berg, L. H., Mill, J., & Veldink, J. H. (2020). Cross-reactive probes on Illumina DNA methylation arrays: A large study on ALS shows that a cautionary approach is warranted in interpreting epigenome-wide association studies. NAR Genomics and Bioinformatics, 2(4), [lqaa105]. https://doi.org/10.1093/nargab/lqaa105

Vancouver

Hop PJ, Zwamborn RAJ, Hannon EJ, Dekker AM, van Eijk KR, Walker EM et al. Cross-reactive probes on Illumina DNA methylation arrays: A large study on ALS shows that a cautionary approach is warranted in interpreting epigenome-wide association studies. NAR Genomics and Bioinformatics. 2020 Dec 1;2(4). lqaa105. https://doi.org/10.1093/nargab/lqaa105

Author

Hop, Paul J. ; Zwamborn, Ramona A.J. ; Hannon, Eilis J. et al. / Cross-reactive probes on Illumina DNA methylation arrays : A large study on ALS shows that a cautionary approach is warranted in interpreting epigenome-wide association studies. In: NAR Genomics and Bioinformatics. 2020 ; Vol. 2, No. 4.

Bibtex Download

@article{cf6611a189444bf9a7a036a526b1d023,
title = "Cross-reactive probes on Illumina DNA methylation arrays: A large study on ALS shows that a cautionary approach is warranted in interpreting epigenome-wide association studies",
abstract = "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.",
author = "Hop, {Paul J.} and Zwamborn, {Ramona A.J.} and Hannon, {Eilis J.} and Dekker, {Annelot M.} and {van Eijk}, {Kristel R.} and Walker, {Emma M.} and Alfredo Iacoangeli and Jones, {Ashley R.} and Aleksey Shatunov and Khleifat, {Ahmad Al} and Sarah Opie-Martin and Shaw, {Christopher E.} and Morrison, {Karen E.} and Shaw, {Pamela J.} and McLaughlin, {Russell L.} and Orla Hardiman and Ammar Al-Chalabi and {van Den Berg}, {Leonard H.} and Jonathan Mill and Veldink, {Jan H.}",
note = "Publisher Copyright: {\textcopyright} The Author(s) 2020. Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics.",
year = "2020",
month = dec,
day = "1",
doi = "10.1093/nargab/lqaa105",
language = "English",
volume = "2",
journal = "NAR Genomics and Bioinformatics",
issn = "2631-9268",
publisher = "Oxford University Press",
number = "4",

}

RIS (suitable for import to EndNote) Download

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

VL - 2

JO - NAR Genomics and Bioinformatics

JF - NAR Genomics and Bioinformatics

SN - 2631-9268

IS - 4

M1 - lqaa105

ER -

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