Diverse ancestry whole-genome sequencing association study identifies TBX5 and PTK7 as susceptibility genes for posterior urethral valves.
Elife
; 112022 09 20.
Article
em En
| MEDLINE
| ID: mdl-36124557
ABSTRACT
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Sistema Urinário
/
Proteínas com Domínio T
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Estudo de Associação Genômica Ampla
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Child
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Humans
/
Male
Idioma:
En
Revista:
Elife
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Reino Unido