Journal Article

DKFZ-2019-01443

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Exome chip association study excluded the involvement of rare coding variants with large effect sizes in the etiology of anorectal malformations.

van de Putte, R. ; Wijers, C. H. W. ; Reutter, H. ; Vermeulen, S. H. ; Marcelis, C. L. M. ; Brosens, E. ; Broens, P. M. A. ; Homberg, M. ; Ludwig, M. ; Jenetzky, E.DKFZ* ; Zwink, N. ; Sloots, C. E. J. ; de Klein, A. ; Brooks, A. S. ; Hofstra, R. M. W. ; Holsink, S. A. C. ; van der Zanden, L. F. M. ; Galesloot, T. E. ; Tam, P. K. ; Steehouwer, M. ; Acuna-Hidalgo, R. ; Vorst, M. v. d. ; Kiemeney, L. A. ; Garcia-Barceló, M.-M. ; de Blaauw, I. ; Brunner, H. G. ; Roeleveld, N. ; van Rooij, I. A. L. M.

2019
PLOS San Francisco, California, US

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Please use a persistent id in citations: doi:10.1371/journal.pone.0217477

Abstract: Anorectal malformations (ARM) are rare congenital malformations, resulting from disturbed hindgut development. A genetic etiology has been suggested, but evidence for the involvement of specific genes is scarce. We evaluated the contribution of rare and low-frequency coding variants in ARM etiology, assuming a multifactorial model.We analyzed 568 Caucasian ARM patients and 1,860 population-based controls using the Illumina HumanExome Beadchip array, which contains >240,000 rare and low-frequency coding variants. GenomeStudio clustering and calling was followed by re-calling of 'no-calls' using zCall for patients and controls simultaneously. Single variant and gene-based analyses were performed to identify statistically significant associations, applying Bonferroni correction. Following an extra quality control step, candidate variants were selected for validation using Sanger sequencing.When we applied a MAF of ≥1.0%, no variants or genes showed statistically significant associations with ARM. Using a MAF cut-off at 0.4%, 13 variants initially reached statistical significance, but had to be discarded upon further inspection: ten variants represented calling errors of the software, while the minor alleles of the remaining three variants were not confirmed by Sanger sequencing.Our results show that rare and low-frequency coding variants with large effect sizes, present on the exome chip do not contribute to ARM etiology.

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Contributing Institute(s):

1. Klinische Epidemiologie und Alternsforschung (C070)

Research Program(s):

1. 313 - Cancer risk factors and prevention (POF3-313) (POF3-313)

Appears in the scientific report 2019

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