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

Abstract

Background: Maternal genetic variations, including variations in mitochondrial biogenesis (MB) and oxidative phosphorylation (OP), are associated with placental abruption (PA). However, the role of maternal-fetal genetic interactions (MFGI) and parent-of-origin (imprinting) effects in PA remain unknown.

Objective: To investigate MFGI in MB-OP, and imprinting effects in relation to risk of PA.

Methods: Among Peruvian mother-infant pairs (503 PA cases and 1052 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).

Results

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 (p-value = 1.2e-04) in calcium/calmodulin-dependent protein kinase [CaM kinase] II beta (CAMK2B), and, SNP rs73136795 (p-value = 1.9e-04) in peroxisome proliferator-activated receptor-gamma (PPARG), both MB genes. We identified 320 SNPs in 45 maternally-imprinted genes (including potassium voltage-gated channel subfamily Q member 1 [KCNQ1], neurotrimin [NTM], and, ATPase phospholipid transporting 10 A [ATP10A]) associated with abruption. Top hits included rs2012323 (p-value = 1.6E-16) and rs12221520 (p-value1.3e-13) in KCNQ1, rs8036892 (p-value = 9.3E-17) and rs188497582 in ATP10A, rs12589854 (p-value = 2.9E-11) and rs80203467 (p-value = 4.6e-11) in maternally expressed 8, small nucleolar RNA host (MEG8), and rs138281088 in solute carrier family 22 member 2 (SLC22A2) (p-value = 6.8e-9).

Conclusions

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.

Keywords:

• Genetic variation
• imprinting
• maternal
• fetal
• genetic interactions

Acknowledgments

The authors are indebted to the participants of the PAPE and PAGE studies for their cooperation. They are also grateful to Ms. Elena Sanchez and the dedicated staff members of Asociacion Civil Proyectos en Salud (PROESA), Peru for their expert technical assistance with this research. This work utilized the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov).

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

All relevant data are within the paper and its Supporting Information files. The participant level data are from the Peruvian Abruptio Placentae Epidemiology (PAPE) and Placental Abruption Genetic Epidemiology and Triggers (PAGE) studies whose authors may be contacted at [email protected]. The local ethical committee does not allow public deposition of the data.

Additional information

Funding

This research was supported by an award from the National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development [HD059827]. Tsegaselassie Workalemahu is supported by The Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. Additional support was obtained from the NIH Office of the Director, National Institute on Minority Health and Health Disparities.