Genetic association study of Preterm birth and Gestational age in a population-based case-control study in Peru

Abstract

Preterm birth (PTB) is an adverse pregnancy outcome affecting [~]15 million pregnancies worldwide. Genetic studies have identified several candidate loci for PTB, but results remain inconclusive and limited to European populations. Thus, we conducted a genome-wide association study (GWAS) of PTB and gestational age at delivery (GA) among 2,212 Peruvian women. PTB cases delivered [≥] 20 weeks but < 37 weeks gestation, while controls delivered at term ([≥] 37 weeks but < 42 weeks). After imputation (TOPMED) and quality control, we assessed the association of [~]6 million SNPs with PTB and GA using multivariable regression models adjusted for maternal age and the first two genetic principal components. In silico functional analysis (FUMA-GWAS) was conducted among top signals detected with an arbitrary P < 1.0x10-5 in each GWAS. We sought to replicate genetic associations with PTB and GA identified in Europeans, and we developed a genetic risk score for GA based on European markers. Mean GA was 30 {+/-} 4 weeks in PTB cases (N=933) and 39 {+/-} 1 in the controls (N=1,279). PTB cases were slightly older and had higher C-sections and vaginal bleeding than controls. No association was identified at genome-wide level. Top suggestive (P < 1.0x10-5) signals were seen at rs13151645 (LINC01182) for PTB, and at rs72824565 (CTNNA2) for GA. Top PTB variants were enriched for biological pathways associated with polyketide, progesterone, steroid hormones, and glycosyl metabolism. Top GA variants were enriched in intronic regions and cancer pathways, and these genes were upregulated in the brain and subcutaneous adipose tissue. In combination with non-genetic risk factors, top SNPs explained 14% and 15% of the phenotypic variance of PTB and GA in our sample, but these results need to be interpreted with caution. Variants in WNT4 associated with GA in Europeans were replicated in our study. The genetic risk score based in European markers, was associated with a 2-day longer GA (R2=0.003, P=0.002) per standard deviation increase in the score in our sample. This genetic association study identified various signals suggestively associated with PTB and GA in a non- European population; they were linked to relevant biological pathways related to the metabolism of progesterone, prostanoid, and steroid hormones, and genes associated with GA were significantly upregulated in relevant tissues for the pathophysiology of PTB based on the in- silico functional analysis. None of these top variants overlapped with signals previously identified for PTB or GA in Europeans.