Maternal-fetal genetic interactions, imprinting, and risk of placental abruption

Abstract

AbstractMaternal genetic variations, including variations in mitochondrial biogenesis (MB) and oxidative phosphorylation (OP), have been associated with placental abruption (PA). However, the role of maternal-fetal genetic interactions (MFGI) and parent-of-origin (imprinting) effects in PA remain unknown. We investigated MFGI in MB-OP, and imprinting effects in relation to risk of PA. Among Peruvian mother-infant pairs (503 PA cases and 1,052 controls), independent single nucleotide polymorphisms (SNPs), with linkage-disequilibrium coefficient <0.80, were selected to characterize genetic variations in MB-OP (78 SNPs in 24 genes) and imprinted genes (2713 SNPs in 73 genes). For each MB-OP SNP, four multinomial models corresponding to fetal allele effect, maternal allele effect, maternal and fetal allele additive effect, and maternal-fetal allele interaction effect were fit under Hardy-Weinberg equilibrium, random mating, and rare disease assumptions. The Bayesian information criterion (BIC) was used for model selection. For each SNP in imprinted genes, imprinting effect was tested using a likelihood ratio test.Bonferroni corrections were used to determine statistical significance (p-value<6.4e-4 for MFGI and p-value<1.8e-5 for imprinting). Abruption cases were more likely to experience preeclampsia, have shorter gestational age, and deliver infants with lower birthweight compared with controls. Models with MFGI effects provided improved fit than models with only maternal and fetal genotype main effects for SNP rs12530904 (log-likelihood ratio=18.2; p-value=1.2e-04) in CAMK2B, and, SNP rs73136795 (log-likelihood ratio=21.7; p-value=1.9e-04) in PPARG, both MB genes. We identified 311 SNPs in 35 maternally-imprinted genes (including KCNQ1, NPM, and, ATP10A) associated with abruption. Top hits included rs8036892 (p-value=2.3e-15) in ATP10A, rs80203467 (p-value=6.7e-15) and rs12589854 (p-value=1.4e-14) in MEG8, and rs138281088 in SLC22A2 (p-value=1.7e-13). We identified novel PA-related maternal-fetal MB gene interactions and imprinting effects that highlight the role of the fetus in PA risk development. Findings can inform mechanistic investigations to understand the pathogenesis of PA.Author summaryPlacental Abruption (PA) is a complex multifactorial and heritable disease characterized by premature separation of the placenta from the wall of the uterus. PA is a consequence of complex interplay of maternal and fetal genetics, epigenetics, and metabolic factors. Previous studies have identified common maternal single nucleotide polymorphisms (SNPs) in several mitochondrial biogenesis (MB) and oxidative phosphorylation (OP) genes that are associated with PA risk, although findings were inconsistent. Using the largest assembled mother-infant dyad of PA cases and controls, that includes participants from a previous report, we identified novel PA-related maternal-fetal MB gene interactions and imprinting effects that highlight the role of the fetus in PA risk development. Our findings have the potential for enhancing our understanding of genetic variations in maternal and fetal genome that contribute to PA.