Genetic variants associated with spontaneous preterm birth in women from India: a prospective cohort study

Abstract

Background: Despite having the highest number of preterm births globally, no genomic study on preterm birth was previously published from India or other South-Asian countries.

Methods: We conducted a genome-wide association (GWA) study of spontaneous preterm birth (sPTB) on 6211 women from India. We used a novel resampling procedure to identify the associated single nucleotide polymorphisms (SNPs) followed by haplotype association analysis and imputation.

Findings: We found that 512 maternal SNPs were associated with sPTB (p < 2.51e-3), of which minor allele at 19 SNPs (after Bonferroni correction) had increased genotype relative risk. Haplotypes containing six of the 19 SNPs (rs13011430, rs8179838, rs2327290, rs4798499, rs7629800, and rs13180906) were associated with sPTB (p < 9.9e-4; Bonferroni adjusted p-value <0.05). After imputation in regions around the 19 SNPs, 15 imputed SNPs were found to be associated with sPTB (Bonferroni adjusted p-value <0.05). One of these imputed SNPs, rs35760881, and three other SNPs (rs17307697, rs4308815, and rs10983507) were also reported to be associated with sPTB in women belonging to European ancestry. Moreover, we found that GG genotype at rs1152954, one of the associated SNPs, enhanced risk of sPTB and reduced telomere length.

Interpretation: This is the first study from South Asia on the genome-wide identification of maternal SNPs associated with sPTB. These SNPs are known to alter the expression of genes associated with major pathways in sPTB viz. inflammation, apoptosis, cervical ripening, telomere maintenance, selenocysteine biosynthesis, myometrial contraction, and innate immunity. From a public health perspective, the trans-ethnic association of four SNPs identified in our study may help to stratify women with risk of sPTB in most populations.

Funding: Department of Biotechnology (India), Grand Challenges India - All Children Thriving Program and Biotechnology Industry Research Assistance Council (BIRAC).

Keywords: Cluster file; GWAS; India; Maternal genome; Spontaneous preterm birth.

Fig. 1

Overflow of sample selection criteria. 6211 women from the cohort were genotyped and 5968 women passed the genotyping quality control. We then applied the selection criteria (gestational age at enrolment <14 weeks or difference between LMP dating and USG dating <7 days, participant's age ≥18 years, only spontaneous singleton live birth without any complications) on these 5968 women and 4682 women were selected among which 521 had spontaneous preterm delivery (<37 weeks) while 4161 had term delivery (≥37 weeks – ≤41 weeks). Next, we matched preterm and term delivering women in 1:2 ratio based on age, BMI, parity and occupational status for the association analysis.

Fig. 2

Manhattan plot showing strength of association (negative logarithm of p-value of association statistic) of the tested SNPs with sPTB. Horizontal lines indicate strength of associations i.e. p = 1.02e-4 and p = 2.51e-3 corresponding to the 1% (red) and 5% (blue) upper tail association statistic thresholds obtained from the empirical bootstrap frequency distribution, respectively.

Fig. 3

Mean and standard error of Telomere-to-Single Copy Gene ratio (T/S ratio) at 26–28 weeks of each genotype at rs1152954. A is the major allele and G is the minor allele. Mean value for each genotype is indicated in red. p values for testing the null hypothesis of equality of the mean T/S ratio between genotypes are also provided. Number of individuals with AA genotype: 164, AG genotype: 51, and GG genotype: 5.