Genome-wide association study identifies a novel maternal gene × stress interaction associated with spontaneous preterm birth

Abstract

Background

Maternal stress is potentially a modifiable risk factor for spontaneous preterm birth (sPTB). However, epidemiologic findings on the maternal stress−sPTB relationship have been inconsistent.

Methods

To investigate whether the maternal stress−sPTB associations may be modified by genetic susceptibility, we performed genome-wide gene × stress interaction analyses in 1490 African-American women from the Boston Birth cohort who delivered term (n = 1033) or preterm (n = 457) infants. Genotyping was performed using Illumina HumanOmni 2.5 array. Replication was performed using data from the NICHD genomic and Proteomic Network (GPN) for PTB research.

Results

rs35331017, a T-allele insertion/deletion polymorphism in the protein-tyrosine phosphatase receptor Type D (PTPRD) gene, was the top hit that interacted significantly with maternal lifetime stress on risk of sPTB (PG × E = 4.7 × 10−8). We revealed a dose-responsive association between degree of stress and risk of sPTB in mothers carrying the insertion/insertion genotype, but an inverse association was observed in mothers carrying the heterozygous or deletion/deletion genotypes. This interaction was replicated in African-American (PG × E = 0.088) and Caucasian mothers (PG × E = 0.023) from the GPN study.

Conclusion

We demonstrated a significant maternal PTPRD × stress interaction on sPTB risk. This finding, if further confirmed, may provide new insight into individual susceptibility to stress-induced sPTB.

Impact

  • This was the first preterm study to demonstrate a significant genome-wide gene−stress interaction in African Americans, specifically, PTPRD gene variants can interact with maternal perceived stress to affect risk of spontaneous preterm birth.

  • The PTPRD × maternal stress interaction was demonstrated in African Americans and replicated in both African Americans and Caucasians from the GPN study.

  • Our findings highlight the importance of considering genetic susceptibility in assessing the role of maternal stress on spontaneous preterm birth.

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Fig. 1: Manhattan, quantile−quantile (Q−Q), and LocusZoom plot of the genome-wide interaction associations with maternal lifetime stress on spontaneous PTB, in 1490 African-American mothers from the Boston Birth Cohort.
Fig. 2: Joint associations between rs35331507 in the PTPRD gene and maternal perceived stress on sPTB in African-American mothers from the BBC.

References

  1. 1.

    Liu, L. et al. Global, regional, and national causes of under-5 mortality in 2000−15: an updated systematic analysis with implications for the Sustainable Development Goals. Lancet 388, 3027–3035 (2016).

    Article  Google Scholar 

  2. 2.

    Lawn, J. E. & Kinney, M. Preterm birth: now the leading cause of child death worldwide. Sci. Transl. Med. 6, 263ed221 (2014).

    Article  Google Scholar 

  3. 3.

    Pritchard, M. A. et al. Autism in toddlers born very preterm. Pediatrics 137, e20151949 (2016).

    Article  Google Scholar 

  4. 4.

    Wang, G. et al. Preterm birth and random plasma insulin levels at birth and in early childhood. JAMA: J. Am. Med. Assoc. 311, 587–596 (2014).

    CAS  Article  Google Scholar 

  5. 5.

    Martin, J. A., Hamilton, B. E., Osterman, M. J., Driscoll, A. K. & Mathews, T. J. Births: final data for 2015. Natl Vital-. Stat. Rep. 66, 1 (2017).

    PubMed  Google Scholar 

  6. 6.

    Grobman, W. A. et al. Racial/ethnic disparities in measures of self-reported psychosocial states and traits during pregnancy. Am. J. Perinatol. 33, 1426–1432 (2016).

    Article  Google Scholar 

  7. 7.

    Wadhwa, P. D., Entringer, S., Buss, C. & Lu, M. C. The contribution of maternal stress to preterm birth: issues and considerations. Clin. Perinatol. 38, 351–384 (2011).

    Article  Google Scholar 

  8. 8.

    Straub, H., Adams, M., Kim, J. J. & Silver, R. K. Antenatal depressive symptoms increase the likelihood of preterm birth. Am. J. Obstet. Gynecol. 207, 329 e321–324 (2012).

    Article  Google Scholar 

  9. 9.

    Lu, M. C. & Chen, B. Racial and ethnic disparities in preterm birth: the role of stressful life events. Am. J. Obstet. Gynecol. 191, 691–699 (2004).

    Article  Google Scholar 

  10. 10.

    Kramer, M. S. et al. Stress pathways to spontaneous preterm birth: the role of stressors, psychological distress, and stress hormones. Am. J. Epidemiol. 169, 1319–1326 (2009).

    Article  Google Scholar 

  11. 11.

    Dole, N. et al. Maternal stress and preterm birth. Am. J. Epidemiol. 157, 14–24 (2003).

    CAS  Article  Google Scholar 

  12. 12.

    Kitai, T. et al. A comparison of maternal and neonatal outcomes of pregnancy with mental disorders: results of an analysis using propensity score-based weighting. Arch. Gynecol. Obstet. 290, 883–889 (2014).

    Article  Google Scholar 

  13. 13.

    Krabbendam, L. et al. The impact of maternal stress on pregnancy outcome in a well-educated Caucasian population. Paediatr. Perinat. Epidemiol. 19, 421–425 (2005).

    Article  Google Scholar 

  14. 14.

    Yonkers, K. A. et al. Pregnant women with posttraumatic stress disorder and risk of preterm birth. JAMA Psychiatry 71, 897–904 (2014).

    Article  Google Scholar 

  15. 15.

    Boyce, T. W. The Orchid and the Dandelion: Why Some Children Struggle and How All Can Thrive (Knopf, New York, 2019).

  16. 16.

    Massey, S. H. et al. Does MAOA increase susceptibility to prenatal stress in young children? Neurotoxicol. Teratol. 61, 82–91 (2017).

    CAS  Article  Google Scholar 

  17. 17.

    Green, C. G. et al. Prenatal maternal depression and child serotonin transporter linked polymorphic region (5-HTTLPR) and dopamine receptor D4 (DRD4) genotype predict negative emotionality from 3 to 36 months. Dev. Psychopathol. 29, 901–917 (2017).

    Article  Google Scholar 

  18. 18.

    Mparmpakas, D. et al. Differential expression of placental glucocorticoid receptors and growth arrest-specific transcript 5 in term and preterm pregnancies: evidence for involvement of maternal stress. Obstet. Gynecol. Int. 2014, 239278 (2014).

    CAS  Article  Google Scholar 

  19. 19.

    Liu, X. et al. Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 associate with gestational duration. Nat. Commun. 10, 3927 (2019).

    Article  Google Scholar 

  20. 20.

    Zhang, G. et al. Genetic associations with gestational duration and spontaneous preterm birth. N. Engl. J. Med. 377, 1156–1167 (2017).

    CAS  Article  Google Scholar 

  21. 21.

    Wang, X. et al. Maternal cigarette smoking, metabolic gene polymorphism, and infant birth weight. JAMA 287, 195–202 (2002).

    CAS  Article  Google Scholar 

  22. 22.

    Hong, X. et al. Genome-wide approach identifies a novel gene-maternal pre-pregnancy BMI interaction on preterm birth. Nat. Commun. 8, 15608 (2017).

    Article  Google Scholar 

  23. 23.

    Wang, G. et al. Preterm birth and random plasma insulin levels at birth and in early childhood. JAMA 311, 587–596 (2014).

    CAS  Article  Google Scholar 

  24. 24.

    Delaneau, O., Marchini, J. & Zagury, J. F. A linear complexity phasing method for thousands of genomes. Nat. Methods 9, 179–181 (2012).

    CAS  Article  Google Scholar 

  25. 25.

    Howie, B., Fuchsberger, C., Stephens, M., Marchini, J. & Abecasis, G. R. Fast and accurate genotype imputation in genome-wide association studies through pre-phasing. Nat. Genet. 44, 955–959 (2012).

    CAS  Article  Google Scholar 

  26. 26.

    Price, A. L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).

    CAS  Article  Google Scholar 

  27. 27.

    Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

    CAS  Article  Google Scholar 

  28. 28.

    Gogarten, S. M. et al. GWASTools: an R/Bioconductor package for quality control and analysis of genome-wide association studies. Bioinformatics 28, 3329–3331 (2012).

    CAS  Article  Google Scholar 

  29. 29.

    Pruim, R. J. et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26, 2336–2337 (2010).

    CAS  Article  Google Scholar 

  30. 30.

    Zhang, H. et al. A genome-wide association study of early spontaneous preterm delivery. Genet. Epidemiol. 39, 217–226 (2015).

    Article  Google Scholar 

  31. 31.

    Vrekoussis, T. et al. The role of stress in female reproduction and pregnancy: an update. Ann. N. Y. Acad. Sci. 1205, 69–75 (2010).

    CAS  Article  Google Scholar 

  32. 32.

    Hobel, C. J., Dunkel-Schetter, C., Roesch, S. C., Castro, L. C. & Arora, C. P. Maternal plasma corticotropin-releasing hormone associated with stress at 20 weeks’ gestation in pregnancies ending in preterm delivery. Am. J. Obstet. Gynecol. 180, S257–S263 (1999).

    CAS  Article  Google Scholar 

  33. 33.

    Hobel, C. J., Dunkel-Schetter, C. & Roesch, S. Maternal stress as a signal to the fetus. Prenat. Neonat. Med. 3, 116–120 (1998).

    Google Scholar 

  34. 34.

    Coussons-Read, M. E., Okun, M. L. & Nettles, C. D. Psychosocial stress increases inflammatory markers and alters cytokine production across pregnancy. Brain Behav. Immun. 21, 343–350 (2007).

    CAS  Article  Google Scholar 

  35. 35.

    Christian, L. M., Franco, A., Glaser, R. & Iams, J. D. Depressive symptoms are associated with elevated serum proinflammatory cytokines among pregnant women. Brain Behav. Immun. 23, 750–754 (2009).

    CAS  Article  Google Scholar 

  36. 36.

    Yamagata, A. et al. Mechanisms of splicing-dependent trans-synaptic adhesion by PTPdelta-IL1RAPL1/IL-1RAcP for synaptic differentiation. Nat. Commun. 6, 6926 (2015).

    CAS  Article  Google Scholar 

  37. 37.

    Drgon, T. et al. “Replicated” genome wide association for dependence on illegal substances: genomic regions identified by overlapping clusters of nominally positive SNPs. Am. J. Med. Genet. B Neuropsychiatr. Genet. 156, 125–138 (2011).

    CAS  Article  Google Scholar 

  38. 38.

    Uhl, G. R. et al. Cocaine reward is reduced by decreased expression of receptor-type protein tyrosine phosphatase D (PTPRD) and by a novel PTPRD antagonist. Proc. Natl Acad. Sci. USA 115, 11597–11602 (2018).

    CAS  Article  Google Scholar 

  39. 39.

    Chen, T. et al. Genetic variants in PTPRD and risk of gestational diabetes mellitus. Oncotarget 7, 76101–76107 (2016).

    Article  Google Scholar 

  40. 40.

    Baer, R. J. et al. Risk of preterm birth among women using drugs during pregnancy with elevated alpha-fetoprotein. J. Perinatol. 37, 220–225 (2017).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank all of the study participants in the BBC for supporting this study. We are also grateful for the dedication and hard work of the field team at the Department of Pediatrics, Boston University School of Medicine, and for the support of the obstetric nursing staff at Boston Medical Center. Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to the Johns Hopkins University, contract numbers HSN268200782096C and HHSN268201200008I. The GWAS data cleaning was performed by Dr. Laurie and her team at Washington University following the GENEVA protocol. The authors thank Linda Rosen of the Boston University Clinical Data Warehouse for assistance in obtaining relevant clinical information; the Clinical Data Warehouse service is supported by Boston University Clinical and Translational Institute and the National Institutes of Health Clinical and Translational Science Award (grant U54-TR001012). This work is supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD; grant numbers include R03HD096136, R21HD085556, 2R01HD041702, R01HD086013 and HD098232) and the Johns Hopkins Population Center (NICHD R24HD042854). The Boston Birth Cohort (the parent study) is also supported in part by the Health Resources and Services Administration (HRSA) of the US Department of Health and Human Services (HHS) grants (R40MC27443 and UJ2MC31074). This information or content and conclusions are those of the authors and should not be construed as the official position or policy of, nor should any endorsements be inferred by NIH, HRSA, HHS or the US Government.

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All authors meet the journal’s authorship requirements and approved the final manuscript. X.W. is the principal investigator of the Boston Birth Cohort (the parent study) and obtained the study funding to support the study cohort. The subject recruitment and data collection were overseen by X.W. and conducted by a team of investigators including X.H., Y.J., B.Y.Z. et al. X.H. and X.W. took primary responsibility for the study design, have full access to all of the data in the study and are responsible for the accuracy of the data used to develop the concept for this analysis. X.H. and P.S. drafted the manuscript. X.H., B.Y.Z. and Y.J. conducted the data analysis, with guidance from H.J. C.P., S.C. and B.Z. supervised the field data collection. G.W. supervised the biospecimen processing and genotyping. All authors contributed to the analysis plan, data interpretation, and critically reviewed and edited the manuscript.

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Correspondence to Xiumei Hong.

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Each participant provided written informed consent prior to participation. The study protocol was approved by the Institutional Review Boards of Boston University Medical Center, and of the Johns Hopkins Bloomberg School of Public Health.

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Hong, X., Surkan, P.J., Zhang, B. et al. Genome-wide association study identifies a novel maternal gene × stress interaction associated with spontaneous preterm birth. Pediatr Res (2020). https://doi.org/10.1038/s41390-020-1093-1

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