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Article: Exome chip association study excluded the involvement of rare coding variants with large effect sizes in the etiology of anorectal malformations

TitleExome chip association study excluded the involvement of rare coding variants with large effect sizes in the etiology of anorectal malformations
Authors
Issue Date2019
PublisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.action
Citation
PLoS One, 2019, v. 14 n. 5, article no. e0217477 How to Cite?
AbstractIntroduction: 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. Methods: 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. Results: 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. Conclusion: 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.
Persistent Identifierhttp://hdl.handle.net/10722/272356
ISSN
2017 Impact Factor: 2.766
2015 SCImago Journal Rankings: 1.395
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorvan de Putte, R-
dc.contributor.authorWijers, CHW-
dc.contributor.authorReutter, H-
dc.contributor.authorVermeulen, SH-
dc.contributor.authorMarcelis, CLM-
dc.contributor.authorBrosens, E-
dc.contributor.authorBroens, PMA-
dc.contributor.authorHomberg, M-
dc.contributor.authorLudwig, M-
dc.contributor.authorJenetzky, E-
dc.contributor.authorZwink, N-
dc.contributor.authorSloots, CEJ-
dc.contributor.authorde Klein, A-
dc.contributor.authorBrooks, AS-
dc.contributor.authorHofstra, RMW-
dc.contributor.authorHolsink, SAC-
dc.contributor.authorvan der Zanden, LFM-
dc.contributor.authorGalesloot, TE-
dc.contributor.authorTam, PKH-
dc.contributor.authorSteehouwer, M-
dc.contributor.authorAcuna-Hidalgo, R-
dc.contributor.authorvan de Vorst, M-
dc.contributor.authorKiemeney, LA-
dc.contributor.authorGarcia-Barcelo, MM-
dc.contributor.authorde Blaauw, I-
dc.contributor.authorBrunner, H-
dc.contributor.authorRoeleveld, N-
dc.contributor.authorvan Rooij, IALM-
dc.date.accessioned2019-07-20T10:40:42Z-
dc.date.available2019-07-20T10:40:42Z-
dc.date.issued2019-
dc.identifier.citationPLoS One, 2019, v. 14 n. 5, article no. e0217477-
dc.identifier.issn1932-6203-
dc.identifier.urihttp://hdl.handle.net/10722/272356-
dc.description.abstractIntroduction: 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. Methods: 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. Results: 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. Conclusion: 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.-
dc.languageeng-
dc.publisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.action-
dc.relation.ispartofPLoS One-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleExome chip association study excluded the involvement of rare coding variants with large effect sizes in the etiology of anorectal malformations-
dc.typeArticle-
dc.identifier.emailTam, PKH: paultam@hku.hk-
dc.identifier.emailGarcia-Barcelo, MM: mmgarcia@hku.hk-
dc.identifier.authorityTam, PKH=rp00060-
dc.identifier.authorityGarcia-Barcelo, MM=rp00445-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1371/journal.pone.0217477-
dc.identifier.pmid31136621-
dc.identifier.pmcidPMC6538182-
dc.identifier.scopuseid_2-s2.0-85066432643-
dc.identifier.hkuros299510-
dc.identifier.volume14-
dc.identifier.issue5-
dc.identifier.spagearticle no. e0217477-
dc.identifier.epagearticle no. e0217477-
dc.identifier.isiWOS:000469224300043-
dc.publisher.placeUnited States-

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