Genomic and molecular characterization of preterm birth

被引:51
|
作者
Knijnenburg, Theo A. [1 ]
Vockley, Joseph G. [2 ,3 ]
Chambwe, Nyasha [1 ]
Gibbs, David L. [1 ]
Humphries, Crystal [1 ]
Huddleston, Kathi C. [2 ,3 ]
Klein, Elisabeth [2 ,3 ]
Kothiyal, Prachi [2 ,3 ]
Tasseff, Ryan [1 ]
Dhankani, Varsha [1 ]
Bodian, Dale L. [2 ,3 ]
Wong, Wendy S. W. [2 ,3 ]
Glusman, Gustavo [1 ]
Mauldin, Denise E. [1 ]
Miller, Michael [1 ]
Slagel, Joseph [1 ]
Elasady, Summer [1 ]
Roach, Jared C. [1 ]
Kramer, Roger [1 ]
Leinonen, Kalle [1 ]
Linthorst, Jasper [1 ]
Baveja, Rajiv [4 ]
Baker, Robin [4 ]
Solomon, Benjamin D. [2 ,3 ]
Eley, Greg [2 ,3 ]
Iyer, Ramaswamy K. [2 ,3 ]
Maxwell, George L. [2 ,3 ]
Bernard, Brady [1 ]
Shmulevich, Ilya [1 ]
Hood, Leroy [1 ]
Niederhuber, John E. [2 ,3 ,5 ,6 ,7 ]
机构
[1] Inst Syst Biol, Seattle, WA 98109 USA
[2] Inova Hlth Syst, Inova Translat Med Inst, Falls Church, VA 22042 USA
[3] Inova Fairfax Med Ctr, Falls Church, VA 22042 USA
[4] Inova Childrens Hosp, Fairfax Neonatal Associates, Falls Church, VA 22042 USA
[5] Johns Hopkins Univ, Sch Med, Dept Surg, Baltimore, MD 21287 USA
[6] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21287 USA
[7] Univ Virginia, Sch Med, Dept Publ Hlth Sci, Charlottesville, VA 22903 USA
关键词
preterm birth; whole genome sequencing; family trios; integrative computational analysis; genomic variants; GESTATIONAL-AGE; GENETIC-ANALYSIS; HUMAN PLACENTAS; EXPRESSION; ASSOCIATION; MICRORNAS; VARIANTS; DURATION; DATABASE; REVEALS;
D O I
10.1073/pnas.1716314116
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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-gamma 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.
引用
收藏
页码:5819 / 5827
页数:9
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