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Literature-Informed Analysis of a Genome-Wide Association Study of Gestational Age in Norwegian Women and Children Suggests Involvement of Inflammatory Pathways

Artikel i vetenskaplig tidskrift
Författare Jonas Bacelis
Julius Juodakis
Verena Sengpiel
G. Zhang
R. Myhre
L. J. Muglia
Staffan Nilsson
Bo Jacobsson
Publicerad i PLoS ONE
Volym 11
Nummer/häfte 8
ISSN 1932-6203
Publiceringsår 2016
Publicerad vid Institutionen för matematiska vetenskaper, matematisk statistik
Institutionen för kliniska vetenskaper, Avdelningen för obstetrik och gynekologi
Språk en
Länkar dx.doi.org/10.1371/journal.pone.016...
https://gup.ub.gu.se/file/201797
Ämnesord Genome-wide association studies, Preterm birth, Pregnancy, Gene delivery, Genetic loci, Toll-like receptors, Labor and delivery, Genomic databases
Ämneskategorier Genetik

Sammanfattning

Background Five-to-eighteen percent of pregnancies worldwide end in preterm birth, which is the major cause of neonatal death and morbidity. Approximately 30% of the variation in gestational age at birth can be attributed to genetic factors. Genome-wide association studies (GWAS) have not shown robust evidence of association with genomic loci yet. We separately investigated 1921 Norwegian mothers and 1199 children from pregnancies with spontaneous onset of delivery. Individuals were further divided based on the onset of delivery: initiated by labor or prelabor rupture of membranes. Genetic association with ultrasound- dated gestational age was evaluated using three genetic models and adaptive permutations. The top-ranked loci were tested for enrichment in 12 candidate gene-sets generated by text-mining PubMed abstracts containing pregnancy-related keywords. The six GWAS did not reveal significant associations, with the most extreme empirical p = 5.1 x 10(-7). The top loci from maternal GWAS with deliveries initiated by labor showed significant enrichment in 10 PubMed gene-sets, e.g., p = 0.001 and 0.005 for keywords "uterus" and "preterm" respectively. Enrichment signals were mainly caused by infection/inflammation-related genes TLR4, NFKB1, ABCA1, MMP9. Literature-informed analysis of top loci revealed further immunity genes: IL1A, IL1B, CAMP, TREM1, TFRC, NFKBIA, MEFV, IRF8, WNT5A. Our analyses support the role of inflammatory pathways in determining pregnancy duration and provide a list of 32 candidate genes for a follow-up work. We observed that the top regions from GWAS in mothers with labor-initiated deliveries significantly more often overlap with pregnancy-related genes than would be expected by chance, suggesting that increased sample size would benefit similar studies.

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