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

<div><p>Background</p><p>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.</p><p>Methods</p><p>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.</p><p>Results</p><p>The six GWAS did not reveal significant associations, with the most extreme empirical <i>p</i> = 5.1 × 10⁻⁷. The top loci from maternal GWAS with deliveries initiated by labor showed significant enrichment in 10 PubMed gene-sets, e.g., <i>p</i> = 0.001 and 0.005 for keywords "uterus" and "preterm" respectively. Enrichment signals were mainly caused by infection/inflammation-related genes <i>TLR4</i>, <i>NFKB1</i>, <i>ABCA1</i>, <i>MMP9</i>. Literature-informed analysis of top loci revealed further immunity genes: <i>IL1A</i>, <i>IL1B</i>, <i>CAMP</i>, <i>TREM1</i>, <i>TFRC</i>, <i>NFKBIA</i>, <i>MEFV</i>, <i>IRF8</i>, <i>WNT5A</i>.</p><p>Conclusion</p><p>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.</p></div

An overview of cervical insufficiency genes.

<p>An overview of cervical insufficiency genes.</p

Manhattan plot for maternal GWAS of gestational age in labor-initiated deliveries.

<p>In total 1 407 genomes were analysed. Each SNP was assigned the most extreme empirical p-value from the three genetic models (additive, recessive, dominant). The top line indicates a genome-wide significance level (5×10⁻⁸), while the bottom line marks a significance level (5×10⁻⁴) determining the number of “clumps” (independent loci that were used in gene-set enrichment analyses). Genes from gene-set enrichment analyses are marked in blue, while other biologically relevant genes (from the literature-informed analyses) are marked in black.</p

An overview of utero-placental perfusion genes.

<p>An overview of utero-placental perfusion genes.</p

An overview of infection-related genes.

<p>An overview of infection-related genes.</p

Overlap between top results in six GWAS.

<p>The top 1000 SNPs were selected from each GWA analysis. Numbers in the Venn diagrams represent the number of SNPs. Numbers of individuals in each analysis were 1743, 1407, 336 (mothers) and 1109, 884, 225 (children) for all together, labor-initiated and PROM-initiated deliveries respectively.</p

An overview of hormonal genes.

<p>An overview of hormonal genes.</p

Enrichment in gene-sets generated using PubMed abstract text-mining.

<p>The figure shows an overlap between the genes implicated in six GWA analyses (rows) and genes related to specific <i>keywords</i> (columns). The overlap is represented as probability (p-value) of similar or greater enrichment arising due to pure chance under the null hypothesis of no enrichment (i.e., if GWAS would rank genes in a random order). The 300 top independent loci (“clumps”) and their genes were used. The name of each gene-set indicates a <i>keyword</i> used in the PubMed abstract mining. The INRICH algorithm was used to estimate empirical p-values.</p

Loci of biological relevance from maternal GWAS of gestational age in labor-initiated deliveries.

<p>Loci of biological relevance from maternal GWAS of gestational age in labor-initiated deliveries.</p

Significantly enriched PubMed gene-sets in GWAS using mothers with labor-initiated deliveries.

<p>Significantly enriched PubMed gene-sets in GWAS using mothers with labor-initiated deliveries.</p