Diverse ancestry whole-genome sequencing association study identifies TBX5 and PTK7 as susceptibility genes for posterior urethral valves.
Diverse ancestry whole-genome sequencing association study identifies TBX5 and PTK7 as susceptibility genes for posterior urethral valves.
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DOI：
10.7554/elife.74777
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发表时间：
2022-09-20
期刊：
影响因子：
7.7
通讯作者：
Gale DP
中科院分区：
文献类型：
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作者：
Chan MMY;Sadeghi-Alavijeh O;Lopes FM;Hilger AC;Stanescu HC;Voinescu CD;Beaman GM;Newman WG;Zaniew M;Weber S;Ho YM;Connolly JO;Wood D;Maj C;Stuckey A;Kousathanas A;Genomics England Research Consortium;Kleta R;Woolf AS;Bockenhauer D;Levine AP;Gale DP
后尿道瓣膜（PUV）是儿童终末期肾病最常见的原因，但这种罕见疾病的遗传结构仍不清楚。我们对132例不相关的男性PUV病例和23,727例不同血统的对照进行了基于测序的全基因组关联研究（seqGWAS），确定了12 q24处常见变异的统计学显著关联。（p=7.8 × 10 - 12; OR 0.4）和6p21.1的罕见变异（p=2.0 × 10-8; OR 7.2），这些变异在395例病例和4151例对照的独立欧洲队列中重复。精细定位和功能基因组数据将这些位点分别定位到转录因子TBX 5和平面细胞极性基因PTK 7，其编码的蛋白质在人类胚胎发育的泌尿道中被检测到。我们还观察到与候选顺式调控元件交叉的罕见结构变异的富集，特别是预测影响染色质成环的倒位（p=3.1 × 10-5）。这些发现代表了PUV的第一个强大的遗传关联，为这种知之甚少的疾病的潜在生物学提供了新的见解，并展示了如何将不同的祖先seqGWAS用于罕见疾病的疾病位点发现。
Posterior urethral valves (PUV) are the commonest cause of end-stage renal disease in children, but the genetic architecture of this rare disorder remains unknown. We performed a sequencing-based genome-wide association study (seqGWAS) in 132 unrelated male PUV cases and 23,727 controls of diverse ancestry, identifying statistically significant associations with common variants at 12q24.21 (p=7.8 × 10−12; OR 0.4) and rare variants at 6p21.1 (p=2.0 × 10-8; OR 7.2), that were replicated in an independent European cohort of 395 cases and 4151 controls. Fine mapping and functional genomic data mapped these loci to the transcription factor TBX5 and planar cell polarity gene PTK7, respectively, the encoded proteins of which were detected in the developing urinary tract of human embryos. We also observed enrichment of rare structural variation intersecting with candidate cis-regulatory elements, particularly inversions predicted to affect chromatin looping (p=3.1 × 10-5). These findings represent the first robust genetic associations of PUV, providing novel insights into the underlying biology of this poorly understood disorder and demonstrate how a diverse ancestry seqGWAS can be used for disease locus discovery in a rare disease.
影响因子：
3.5
作者：
Schierbaum LM;Schneider S;Herms S;Sivalingam S;Fabian J;Reutter H;Weber S;Merz WM;Tkaczyk M;Miklaszewska M;Sikora P;Szmigielska A;Krzemien G;Zachwieja K;Szczepanska M;Taranta-Janusz K;Kroll P;Polok M;Zaniew M;Hilger AC
通讯作者：
Hilger AC