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

Autoři: Fasil Tekola-Ayele aff001;  Cuilin Zhang aff001;  Jing Wu aff002;  Katherine L. Grantz aff001;  Mohammad L. Rahman aff001;  Deepika Shrestha aff001;  Marion Ouidir aff001;  Tsegaselassie Workalemahu aff001;  Michael Y. Tsai aff004
Působiště autorů: Epidemiology Branch, Division of Intramural Population Health Research, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America aff001;  Division of Intramural Population Health Research, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America aff002;  Department of Population Medicine and Harvard Pilgrim Healthcare Institute, Harvard Medical School, Boston, Massachusetts, United States of America aff003;  Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, United States of America aff004
Vyšlo v časopise: Trans-ethnic meta-analysis of genome-wide association studies identifies maternal ITPR1 as a novel locus influencing fetal growth during sensitive periods in pregnancy. PLoS Genet 16(5): e32767. doi:10.1371/journal.pgen.1008747
Kategorie: Research Article


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:, NCT00912132.

Klíčová slova:

DNA methylation – Genetic loci – Genome-wide association studies – Hispanic people – Metaanalysis – Molecular genetics – placenta – Pregnancy


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