PloS one · 2019
Exome chip association study excluded the involvement of rare coding variants with large effect sizes in the etiology of anorectal malformations.
Клиническое исследованиеСтатьяМногоцентровое исследованиеПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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van de Putte Romy, Wijers Charlotte H W, Reutter Heiko, Vermeulen Sita H, Marcelis Carlo L M, Brosens Erwin, Broens Paul M A, Homberg Markus, Ludwig Michael, Jenetzky Ekkehart, Zwink Nadine, Sloots Cornelius E J, de Klein Annelies, Brooks Alice S, Hofstra Robert M W, Holsink Sophie A C, van der Zanden Loes F M, Galesloot Tessel E, Tam Paul Kwong-Hang, Steehouwer Marloes, Acuna-Hidalgo Rocio, Vorst Maartje van de, Kiemeney Lambertus A, Garcia-Barceló Maria-Mercè, de Blaauw Ivo, Brunner Han G, Roeleveld Nel, van Rooij Iris A L M
Аннотация
INTRODUCTION: 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.
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.