title: Placental FKBP5 genetic and epigenetic variation is associated with infant neurobehavioral outcomes in the RICHS cohort.
abstract: Adverse maternal environments can lead to increased fetal exposure to maternal cortisol, which can cause infant neurobehavioral deficits. The placenta regulates fetal cortisol exposure and response, and placental DNA methylation can influence this function. FK506 binding protein (FKBP5) is a negative regulator of cortisol response, FKBP5 methylation has been linked to brain morphology and mental disorder risk, and genetic variation of FKBP5 was associated with post-traumatic stress disorder in adults. We hypothesized that placental FKBP5 methylation and genetic variation contribute to gene expression control, and are associated with infant neurodevelopmental outcomes assessed using the Neonatal Intensive Care Unit (NICU) Network Neurobehavioral Scales (NNNS). In 509 infants enrolled in the Rhode Island Child Health Study, placental FKBP5 methylation was measured at intron 7 using quantitative bisulfite pyrosequencing. Placental FKBP5 mRNA was measured in a subset of 61 infants by quantitative PCR, and the SNP rs1360780 was genotyped using a quantitative allelic discrimination assay. Relationships between methylation, expression and NNNS scores were examined using linear models adjusted for confounding variables, then logistic models were created to determine the influence of methylation on membership in high risk groups of infants. FKBP5 methylation was negatively associated with expression (P = 0.08, r = -0.22); infants with the TT genotype had higher expression than individuals with CC and CT genotypes (P = 0.06), and those with CC genotype displayed a negative relationship between methylation and expression (P = 0.06, r = -0.43). Infants in the highest quartile of FKBP5 methylation had increased risk of NNNS high arousal compared to infants in the lowest quartile (OR 2.22, CI 1.07-4.61). TT genotype infants had increased odds of high NNNS stress abstinence (OR 1.98, CI 0.92-4.26). Placental FKBP5 methylation reduces expression in a genotype specific fashion, and genetic variation supersedes this effect. These genetic and epigenetic differences in expression may alter the placenta's ability to modulate cortisol response and exposure, leading to altered neurobehavioral outcomes.
authors.affiliation: Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America.
authors.forename: Alison G
authors.initials: AG
authors.lastname: Paquette
authors.affiliation: Department of Pediatrics, Center for the Study of Children at Risk, Women and Infants Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.
authors.forename: Barry M
authors.initials: BM
authors.lastname: Lester
authors.affiliation: Department of Biostatistics, University of Kansas Medical Center, Kansas City, Kansas, United States of America.
authors.forename: Devin C
authors.initials: DC
authors.lastname: Koestler
authors.affiliation: Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America.
authors.forename: Corina
authors.initials: C
authors.lastname: Lesseur
authors.affiliation: Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America.
authors.forename: David A
authors.initials: DA
authors.lastname: Armstrong
authors.affiliation: Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America; Department of Community and Family Medicine, Section of Biostatistics and Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America.
authors.forename: Carmen J
authors.initials: CJ
authors.lastname: Marsit
mesh_terms: D000328:Adult; D001143:Arousal / Q000235:genetics; D015331:Cohort Studies; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D006854:Hydrocortisone / Q000502:physiology; D018730:Infant Behavior / Q000502:physiology; D007231:Infant, Newborn; D008297:Male; D008431:Maternal-Fetal Exchange / Q000235:genetics / Q000502:physiology; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics / Q000503:physiopathology / Q000523:psychology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D055815:Young Adult; D000099159:Tacrolimus Binding Protein 5
chemical_list: D006854:Hydrocortisone; D012333:RNA, Messenger; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5