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

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); log(10)BF>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. Author summary Abnormal fetal growth is a risk factor for infant morbidity and mortality, and adult cardiometabolic diseases. Genetic influences on fetal growth can vary at different gestation times. We performed trans-ethnic genome-wide meta-analyses of 1,849 pregnant women from four race/ethnic groups to identify maternal genetic loci associated with ultrasound-based fetal weight estimates at three gestational periods. We identified and validated a novel genome-wide significant association of rs746039 [G] in the ITPR1 gene with reduced fetal weight at end of second trimester. 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. We evaluated known birthweight loci and identified gestation time-specific associations of six maternal loci with fetal weight. A maternal genetic risk score of birthweight was associated with fetal weight from mid-gestation onwards among Whites. Our study sheds new light on the genetic regulation of gestation time-specific fetal growth.