Common variants increase risk for congenital diaphragmatic hernia within the context of de novo variants.

IF 8.1 1区 生物学 Q1 GENETICS & HEREDITY American journal of human genetics Pub Date : 2024-09-24 DOI:10.1016/j.ajhg.2024.08.024
Lu Qiao,Carrie L Welch,Rebecca Hernan,Julia Wynn,Usha S Krishnan,Jill M Zalieckas,Terry Buchmiller,Julie Khlevner,Aliva De,Christiana Farkouh-Karoleski,Amy J Wagner,Andreas Heydweiller,Andreas C Mueller,Annelies de Klein,Brad W Warner,Carlo Maj,Dai Chung,David J McCulley,David Schindel,Douglas Potoka,Elizabeth Fialkowski,Felicitas Schulz,Florian Kipfmuller,Foong-Yen Lim,Frank Magielsen,George B Mychaliska,Gudrun Aspelund,Heiko Martin Reutter,Howard Needelman,J Marco Schnater,Jason C Fisher,Kenneth Azarow,Mahmoud Elfiky,Markus M Nöthen,Melissa E Danko,Mindy Li,Przemyslaw Kosiński,Rene M H Wijnen,Robert A Cusick,Samuel Z Soffer,Suzan C M Cochius-Den Otter,Thomas Schaible,Timothy Crombleholme,Vincent P Duron,Patricia K Donahoe,Xin Sun,Frances A High,Charlotte Bendixen,Erwin Brosens,Yufeng Shen,Wendy K Chung
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Abstract

Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly often accompanied by other structural anomalies and/or neurobehavioral manifestations. Rare de novo protein-coding variants and copy-number variations contribute to CDH in the population. However, most individuals with CDH remain genetically undiagnosed. Here, we perform integrated de novo and common-variant analyses using 1,469 CDH individuals, including 1,064 child-parent trios and 6,133 ancestry-matched, unaffected controls for the genome-wide association study. We identify candidate CDH variants in 15 genes, including eight novel genes, through deleterious de novo variants. We further identify two genomic loci contributing to CDH risk through common variants with similar effect sizes among Europeans and Latinx. Both loci are in putative transcriptional regulatory regions of developmental patterning genes. Estimated heritability in common variants is ∼19%. Strikingly, there is no significant difference in estimated polygenic risk scores between isolated and complex CDH or between individuals harboring deleterious de novo variants and individuals without these variants. The data support a polygenic model as part of the CDH genetic architecture.
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在新变异的背景下,常见变异会增加先天性膈疝的风险。
先天性膈疝(CDH)是一种严重的先天性畸形,通常伴有其他结构异常和/或神经行为表现。在人群中,罕见的蛋白质编码变异和拷贝数变异是导致 CDH 的原因之一。然而,大多数 CDH 患者在遗传学上仍未确诊。在此,我们利用 1,469 名 CDH 患者(包括 1,064 名儿童-父母三人组和 6,133 名与祖先匹配的未受影响的全基因组关联研究对照)进行了从头变异和常见变异的综合分析。我们通过有害的从头变异发现了 15 个基因中的 CDH 候选变异,其中包括 8 个新基因。我们进一步确定了两个基因组位点,这两个位点通过在欧洲人和拉美人中具有相似效应大小的常见变异导致 CDH 风险。这两个基因位点都位于发育模式基因的假定转录调控区。常见变异的遗传率估计为 19%。令人震惊的是,在孤立型 CDH 和复杂型 CDH 之间,或在携带有害新生变异的个体和不携带这些变异的个体之间,估计的多基因风险评分没有显著差异。这些数据支持将多基因模型作为 CDH 遗传结构的一部分。
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来源期刊
CiteScore
14.70
自引率
4.10%
发文量
185
审稿时长
1 months
期刊介绍: The American Journal of Human Genetics (AJHG) is a monthly journal published by Cell Press, chosen by The American Society of Human Genetics (ASHG) as its premier publication starting from January 2008. AJHG represents Cell Press's first society-owned journal, and both ASHG and Cell Press anticipate significant synergies between AJHG content and that of other Cell Press titles.
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