title: Investigating interactions between early life stress and two single nucleotide polymorphisms in HSD11B2 on the risk of schizophrenia.
abstract: BACKGROUND
  To examine the risk of schizophrenia in a Danish population after exposure to early life stress, and whether this risk is modified by DNA sequence variation, specifically two single nucleotide polymorphisms (SNPs) (rs5479 and rs56303414) from the gene HSD11B2. This gene encodes the enzyme 11-β hydroxysteroid dehydrogenase type 2 which converts active cortisol into inactive cortisone.
  
  
  METHODS
  A two-stage analysis involving (1) a population-based cohort study, and (2) a nested case-control study using genotype information. Stage 1 included 1,141,447 people; here, we calculated incidence rate ratios (IRR) for the risk of schizophrenia among children of mothers who experienced loss or serious illness of close relatives before, during, and after pregnancy. In stage 2, we genotyped rs5479 and rs56303414 among 1275 schizophrenia cases and 1367 controls, and investigated interactions between genotypes and early life stress on the risk of schizophrenia.
  
  
  RESULTS
  In stage 1, no increased risk of schizophrenia was found in offspring after exposure during pregnancy, but offspring exposed to early life stress at age 0-2 years had a significantly increased risk of schizophrenia (adjusted IRR 1.18, 95% confidence interval 1.07-1.31). For rs5479, the minor allele was nucleotide A, and the major allele was nucleotide C. No interaction was found between rs5479 and exposure during pregnancy. Individuals with the minor A allele of rs5479, however, had a significantly increased risk of schizophrenia after exposure to early life stress at age 3-9 years (adjusted IRR 2.06, 1.04-4.06). No interaction was found between rs56303414 and exposure in any of the time periods.
  
  
  CONCLUSIONS
  No association was found between exposure to early life stress during pregnancy and schizophrenia in the offspring investigated, whereas individuals exposed to early life stress within the first two years of life had an increased risk. No interaction was found between HSD11B2 and exposure during pregnancy, but individuals with the A allele of rs5479 had an increased risk of schizophrenia after exposure at age 3-9 years.
authors.affiliation: National Center for Register-based Research, Department of Economics and Business, Aarhus University, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark. Electronic address: jcd@econ.au.dk.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Debost
authors.affiliation: National Center for Register-based Research, Department of Economics and Business, Aarhus University, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark.
authors.forename: Liselotte
authors.initials: L
authors.lastname: Petersen
authors.affiliation: The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark; Department of Biomedicine, Aarhus University, Denmark; Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark; iSEQ, Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark.
authors.forename: Jakob
authors.initials: J
authors.lastname: Grove
authors.affiliation: The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark; Department of Biomedicine, Aarhus University, Denmark; Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark.
authors.forename: Anne
authors.initials: A
authors.lastname: Hedemand
authors.affiliation: The Irish Centre for Fetal and Neonatal Translational Research (INFANT), Department of Obstetrics and Gynaecology, University College Cork, Cork, Ireland; Department of Epidemiology and Public Health, University College Cork, Cork, Ireland.
authors.forename: Ali
authors.initials: A
authors.lastname: Khashan
authors.affiliation: Perinatal Epidemiology Research Unit, Department of Pediatrics, Aarhus University Hospital, Denmark.
authors.forename: Tine
authors.initials: T
authors.lastname: Henriksen
authors.affiliation: The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark; iSEQ, Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark; Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Denmark.
authors.forename: Ole
authors.initials: O
authors.lastname: Mors
authors.affiliation: Danish Centre for Neonatal Screening, Statens Serum Institut, Denmark.
authors.forename: Mads
authors.initials: M
authors.lastname: Hollegaard
authors.affiliation: Danish Centre for Neonatal Screening, Statens Serum Institut, Denmark.
authors.forename: David
authors.initials: D
authors.lastname: Hougaard
authors.affiliation: The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark; Department of Biomedicine, Aarhus University, Denmark; iSEQ, Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark.
authors.forename: Mette
authors.initials: M
authors.lastname: Nyegaard
authors.affiliation: The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark; Department of Biomedicine, Aarhus University, Denmark; iSEQ, Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Børglum
authors.affiliation: National Center for Register-based Research, Department of Economics and Business, Aarhus University, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark.
authors.forename: Preben Bo
authors.initials: PB
authors.lastname: Mortensen
mesh_terms: D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000235:genetics*; D000328:Adult; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004247:DNA / Q000235:genetics; D003718:Denmark / Q000453:epidemiology; D005260:Female; D005838:Genotype; D006801:Humans; D015994:Incidence; D007223:Infant; D007231:Infant, Newborn; D009035:Mothers; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000523:psychology; D012306:Risk; D012559:Schizophrenia / Q000453:epidemiology / Q000235:genetics*; D013315:Stress, Psychological / Q000235:genetics*
chemical_list: D004247:DNA; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; C468387:HSD11B2 protein, human
keywords: 11-β Hydroxysteroid dehydrogenase type 2; Early life stress; Epidemiology; Glucocorticoids; HSD11B2; Schizophrenia