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Genomic and molecular characterization of preterm birth.

Abstract：

:Preterm birth (PTB) complications are the leading cause of long-term morbidity and mortality in children. By using whole blood samples, we integrated whole-genome sequencing (WGS), RNA sequencing (RNA-seq), and DNA methylation data for 270 PTB and 521 control families. We analyzed this combined dataset to identify genomic variants associated with PTB and secondary analyses to identify variants associated with very early PTB (VEPTB) as well as other subcategories of disease that may contribute to PTB. We identified differentially expressed genes (DEGs) and methylated genomic loci and performed expression and methylation quantitative trait loci analyses to link genomic variants to these expression and methylation changes. We performed enrichment tests to identify overlaps between new and known PTB candidate gene systems. We identified 160 significant genomic variants associated with PTB-related phenotypes. The most significant variants, DEGs, and differentially methylated loci were associated with VEPTB. Integration of all data types identified a set of 72 candidate biomarker genes for VEPTB, encompassing genes and those previously associated with PTB. Notably, PTB-associated genes RAB31 and RBPJ were identified by all three data types (WGS, RNA-seq, and methylation). Pathways associated with VEPTB include EGFR and prolactin signaling pathways, inflammation- and immunity-related pathways, chemokine signaling, IFN-γ signaling, and Notch1 signaling. Progress in identifying molecular components of a complex disease is aided by integrated analyses of multiple molecular data types and clinical data. With these data, and by stratifying PTB by subphenotype, we have identified associations between VEPTB and the underlying biology.

journal_name

Proc Natl Acad Sci U S A

journal_title

Proceedings of the National Academy of Sciences of the United States of America

authors

Knijnenburg TA,Vockley JG,Chambwe N,Gibbs DL,Humphries C,Huddleston KC,Klein E,Kothiyal P,Tasseff R,Dhankani V,Bodian DL,Wong WSW,Glusman G,Mauldin DE,Miller M,Slagel J,Elasady S,Roach JC,Kramer R,Leinonen K,Linth

doi

10.1073/pnas.1716314116

subject

Has Abstract

pub_date

2019-03-19 00:00:00

pages

5819-5827

issue

eissn

0027-8424

issn

1091-6490

pii

1716314116

journal_volume

116

pub_type

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Genomic and molecular characterization of preterm birth.