Trans-ethnic meta-analysis of genome-wide association studies identifies maternal ITPR1 as a novel locus influencing fetal growth during sensitive periods in pregnancy

Abstract

Abnormal fetal growth is a risk factor for infant morbidity and mortality and is associated with cardiometabolic diseases in adults. Genetic influences on fetal growth can vary at different gestation times, but genome-wide association studies have been limited to birthweight. We performed trans-ethnic genome-wide meta-analyses and fine mapping to identify maternal genetic loci associated with fetal weight estimates obtained from ultrasound measures taken during pregnancy. Data included 1,849 pregnant women from four race/ethnic groups recruited through the NICHD Fetal Growth Studies. We identified a novel genome-wide significant association of rs746039 [G] (ITPR1) with reduced fetal weight from 24 to 33 weeks gestation (P<5x10-8; log10BF>6). Additional tests revealed that the SNP was associated with head circumference (P = 4.85x10-8), but not with abdominal circumference or humerus/femur lengths. Conditional analysis in an independent sample of mother-offspring pairs replicated the findings and showed that the effect was more likely maternal but not fetal. Trans-ethnic approaches successfully narrowed down the haplotype block that contained the 99% credible set of SNPs associated with head circumference. We further demonstrated that decreased placental expression of ITPR1 was correlated with increased placental epigenetic age acceleration, a risk factor for reduced fetal growth, among male fetuses (r = -0.4, P = 0.01). Finally, genetic risk score composed of known maternal SNPs implicated in birthweight among Europeans was associated with fetal weight from mid-gestation onwards among Whites only. The present study sheds new light on the role of common maternal genetic variants in the inositol receptor signaling pathway on fetal growth from late second trimester to early third trimester. Clinical Trial Registration: ClinicalTrials.gov, NCT00912132.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. Regional plot of the ITPR1 locus associated with fetal weight.

Data span 500 kb centered at the index SNP (rs746039). The x-axis denotes genomic position and the y axis denotes the log10 P-value, and recombination rate (cM/Mb). The purple circle point represents the index SNP. The color of each data point indicates its linkage disequilibrium value (r2) with the index SNP based on HapMap2.

Fig 2. Associations of rs746039 (ITPR1) with fetal weight and head circumference across 13–40 weeks gestation.

Y-axis shows change in fetal weight z-score per allele. Lower and upper bounds of 95% Confidence Intervals shown via the vertical lines along the mean points. Colors of vertical lines denote where genome-wide association P-values: red (P < 5x10-8), blue (5x10-8 ≤ P < 5x10-7), and black (5x10-7 ≤ P <5x10-4). A. Fetal weight. B. Head circumference.

Fig 3. Haplotype block structure of the ITPR1 locus associated with fetal weight among.

Numbers in parenthesis denote the size, in base pair units, of the haplotype block that harbors rs746039 (marked by a blue arrow). A. White (234 bp), B. Black (69 bp), C. Hispanic (872 bp), D. East Asian (872 bp) women.

Fig 4. Correlations between ITPR1 gene expression and epigenetic age acceleration in placenta.

A. Male fetuses. B. Female fetuses. Lower and upper bounds of 95% Confidence Intervals shown via the corresponding colored bands around the mean lines.

Fig 5. Associations between genetic risk score of birthweight-increasing maternal alleles and fetal weight across 13–40 weeks gestation.

A. White, B. Black, C. Hispanic, D. East Asian. Lower and upper bounds of 95% Confidence Intervals shown via the vertical lines along the mean points.