title: Are carriers of CYP21A2 mutations less vulnerable to psychological stress? A population-based national cohort study.
abstract: BACKGROUND
  Congenital adrenal hyperplasia (CAH) is one of the most common monogenic autosomal recessive disorders with an incidence of one in 15 000. About one in 70 individuals in the general population are carriers of a severe CYP21A2 mutation. It has been suggested that this confers a survival advantage, perhaps as a result of increased activity in the hypothalamic-pituitary-adrenal axis. We investigated vulnerability to psychological stress in obligate carriers.
  
  
  METHODS
  The Swedish CAH Registry encompasses more than 600 patients. Parents, that is obligate carriers of the CYP21A2 mutation, were identified through the Multigeneration Register. The diagnosis of the child was used as the psychological stressor. Psychiatric diagnoses before and after the birth of a child with CAH were compared to those of controls derived from (i) the general population, (ii) parents of children with hypospadias and (iii) parents of children with diabetes mellitus type 1 (T1DM).
  
  
  RESULTS
  Parents of children with CAH had less risk of being diagnosed with any psychiatric disorder (OR, 0·6), an affective disorder (OR, 0·5) or substance misuse (OR, 0·5) after the diagnosis of the child, compared to the general population. Their risk was also decreased compared to parents of a child with hypospadias (OR, 0·6, 0·4 and 0·2, respectively) and parents of a child with T1DM (OR 0·7, 0·6 and 0·2, respectively). The CYP21A2 carriers had a lower risk of developing mood and stress-related disorders after the diagnosis of the child.
  
  
  CONCLUSIONS
  Obligate CYP21A2 carriers had a reduced risk of a psychiatric diagnosis and were less vulnerable to a psychologically stressful situation, at least with respect to receiving a psychiatric diagnosis. This indicates a better ability to cope with psychological stress among heterozygous carriers of severe CYP21A2 mutations, which may contribute to the apparent survival advantage.
authors.affiliation: Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.|Department of Paediatric Endocrinology, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Nordenström
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.|Department of Child Psychiatry, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Butwicka
authors.affiliation: Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.|Department of Obstetrics and Gynaecology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Angelica
authors.initials: A
authors.lastname: Lindén Hirschberg
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.|Lung and Allergy Unit, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Catarina
authors.initials: C
authors.lastname: Almqvist
authors.affiliation: Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.|Centre for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.|Paediatric Surgery, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Agneta
authors.initials: A
authors.lastname: Nordenskjöld
authors.affiliation: Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden.|Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Falhammar
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.|Child and Adolescent Psychiatry Research Centre, Stockholm, Sweden.
authors.forename: Louise
authors.initials: L
authors.lastname: Frisén
mesh_terms: D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics; D000328:Adult; D015331:Cohort Studies; D003922:Diabetes Mellitus, Type 1; D006579:Heterozygote; D006801:Humans; D007021:Hypospadias; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010290:Parents / Q000523:psychology*; D012042:Registries; D013255:Steroid 21-Hydroxylase / Q000235:genetics*; D013315:Stress, Psychological / Q000235:genetics*; D055815:Young Adult
chemical_list: C531510:CYP21A2 protein, human; D013255:Steroid 21-Hydroxylase