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 ; 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. Transethnic 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.

Placental multi-omics integration identifies candidate functional genes for birthweight

“…On the genotype dataset, we removed SNPs with >5% missing values, minor allele frequency <0.5%, and not in Hardy–Weinberg equilibrium ( P < 10 −4 ). SNP genotypes were imputed using the Michigan Imputation Server using the 1000 Genomes Phase 3 genotype reference 68 , and filters were applied to remove insertion–deletions, SNPs with minor allele frequency <0.5% and SNPs with imputation dosage r 2 < 0.3 8 , 12 , 25 , 67 . The present analysis included samples that passed quality control, i.e., 291 samples with fetal genotype and DNAm data for mQTL analysis, of which 71 samples also had RNA-seq data for eQTL analysis.…”

A new method for customized fetal growth reference percentiles

“…SGA indicating that smaller EFW associated with maternal constraint is both physiological and pathological [41]. Finally, other factors can influence fetal growth, such as genetic and external factors, including altitude, diet and lifestyle, and other environmental conditions beyond the six factors included in the customization profile that are often routinely and easily obtained during the antenatal period [29,[42][43][44][45][46][47].…”

Beta-Meta: a meta-analysis application considering heterogeneity among genome-wide association studies

“…Meta-analysis can improve signal detection when we account for not only between-study heterogeneity but also differences in linkage disequilibrium (LD) between ethnicities [35]; in addition, several trans-ethnic meta-analyses have identified unknown susceptibility genes [35][36][37]. As it is important to consider differences in LD, we utilize the haploR package [12] that queries HaploReg database [38] and returns alternative SNPs in LD.…”