TY - JOUR
T1 - Exome chip association study excluded the involvement of rare coding variants with large effect sizes in the etiology of anorectal malformations
AU - van de Putte, Romy
AU - Wijers, Charlotte H. W.
AU - Reutter, Heiko
AU - Vermeulen, Sita H.
AU - Marcelis, Carlo L. M.
AU - Brosens, Erwin
AU - Broens, Paul M. A.
AU - Homberg, Markus
AU - Ludwig, Michael
AU - Jenetzky, Ekkehart
AU - Zwink, Nadine
AU - Sloots, Cornelius E. J.
AU - de Klein, Annelies
AU - Brooke, Alice S.
AU - Hofstra, Robert M. W.
AU - Holsink, Sophie A. C.
AU - van Der Zanden, Loes F. M.
AU - Galesloot, Tessel E.
AU - Tam, Paul Kwong-Hang
AU - Steehouwer, Marloes
AU - Acuna-Hidalgo, Rocio
AU - van de Vorst, Maartje
AU - Kiemeney, Lambertus A.
AU - Garcia-Barcelo, Maria-Merce
AU - de Blaauw, Ivo
AU - Brunner, Han G.
AU - Roeleveld, Nel
AU - van Rooij, Iris A. L. M.
PY - 2019/5/28
Y1 - 2019/5/28
N2 - IntroductionAnorectal 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.MethodsWe analyzed 568 Caucasian ARM patients and 1,860 population-based controls using the Illumina Human Exome 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.ResultsWhen 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.ConclusionOur results show that rare and low-frequency coding variants with large effect sizes, present on the exome chip do not contribute to ARM etiology.
AB - IntroductionAnorectal 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.MethodsWe analyzed 568 Caucasian ARM patients and 1,860 population-based controls using the Illumina Human Exome 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.ResultsWhen 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.ConclusionOur results show that rare and low-frequency coding variants with large effect sizes, present on the exome chip do not contribute to ARM etiology.
KW - BIRTH-DEFECTS
KW - CANDIDATE GENE
KW - RISK
KW - ANOMALIES
KW - EXCLUSION
KW - REGISTRY
KW - OBESITY
KW - FGF10
U2 - 10.1371/journal.pone.0217477
DO - 10.1371/journal.pone.0217477
M3 - Article
C2 - 31136621
VL - 14
JO - PLOS ONE
JF - PLOS ONE
SN - 1932-6203
IS - 5
M1 - 0217477
ER -