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Differential DNA methylation at birth associated with mental disorder in individuals with 22q11.2 deletion syndrome

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  • A Starnawska
  • C S Hansen, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark. aln@biomed.au.dk., Section of Neonatal Genetics, Department for Congenital Disorders, Danish Centre for Neonatal Screening, Statens Serum Institute, Copenhagen, Denmark.
  • ,
  • T Sparsø, Institute of Biological Psychiatry, Sct. Hans Mental Health Center, Copenhagen Mental Health Services, iPSYCH - The Lundbeck Foundation's Initiative for Integrative Psychiatric Research, Boserupvej, DK-4000, Roskilde, Denmark.
  • ,
  • W Mazin, Pediatric Oncology Research Laboratory, University Hospital Rigshospitalet, Copenhagen, Denmark.
  • ,
  • L Olsen, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark. aln@biomed.au.dk., Institute of Biological Psychiatry, Sct. Hans Mental Health Center, Copenhagen Mental Health Services, iPSYCH - The Lundbeck Foundation's Initiative for Integrative Psychiatric Research, Boserupvej, DK-4000, Roskilde, Denmark.
  • ,
  • M Bertalan, Institute of Biological Psychiatry, Sct. Hans Mental Health Center, Copenhagen Mental Health Services, iPSYCH - The Lundbeck Foundation's Initiative for Integrative Psychiatric Research, Boserupvej, DK-4000, Roskilde, Denmark.
  • ,
  • A Buil, Institute of Biological Psychiatry, Sct. Hans Mental Health Center, Copenhagen Mental Health Services, iPSYCH - The Lundbeck Foundation's Initiative for Integrative Psychiatric Research, Boserupvej, DK-4000, Roskilde, Denmark.
  • ,
  • J Bybjerg-Grauholm, Section of Neonatal Genetics, Department for Congenital Disorders, Danish Centre for Neonatal Screening, Statens Serum Institute, Copenhagen, Denmark.
  • ,
  • M Bækvad-Hansen, Section of Neonatal Genetics, Department for Congenital Disorders, Danish Centre for Neonatal Screening, Statens Serum Institute, Copenhagen, Denmark.
  • ,
  • D M Hougaard, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark. aln@biomed.au.dk., Section of Neonatal Genetics, Department for Congenital Disorders, Danish Centre for Neonatal Screening, Statens Serum Institute, Copenhagen, Denmark.
  • ,
  • P B Mortensen
  • C B Pedersen
  • M Nyegaard
  • T Werge, Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • ,
  • S Weinsheimer, Institute of Biological Psychiatry, Sct. Hans Mental Health Center, Copenhagen Mental Health Services, iPSYCH - The Lundbeck Foundation's Initiative for Integrative Psychiatric Research, Boserupvej, DK-4000, Roskilde, Denmark.

Individuals with 22q11.2 deletion syndrome (DS) have an increased risk of comorbid mental disorders including schizophrenia, attention deficit hyperactivity disorder, depression, as well as intellectual disability. Although most 22q11.2 deletion carriers have the long 3-Mb form of the hemizygous deletion, there remains a large variation in the development and progression of psychiatric disorders, which suggests that alternative factors contribute to the pathogenesis. In this study we investigated whether neonatal DNA methylation signatures in individuals with the 22q11.2 deletion associate with mental disorder later in life. DNA methylation was measured genome-wide from neonatal dried blood spots in a cohort of 164 individuals with 22q11.2DS, including 48 individuals diagnosed with a psychiatric disorder. Among several CpG sites with P-value<10(-6), we identified cg23546855 (P-value=2.15 × 10(-7)) mapping to STK32C to be associated with a later psychiatric diagnosis. Pathway analysis of the top findings resulted in the identification of several Gene Ontology pathways to be significantly enriched (P-value<0.05 after Benjamini-Hochberg correction); among them are the following: neurogenesis, neuron development, neuron projection development, astrocyte development, axonogenesis and axon guidance. In addition, we identified differentially methylated CpG sites in LRP2BP (P-value=5.37 × 10(-8)) to be associated with intellectual disability (F70-79), in TOP1 (P-value=1.86 × 10(-7)) with behavioral disorders (F90-98), in NOSIP (P-value=5.12 × 10(-8)) with disorders of psychological development (F80-89) and in SEMA4B (P-value=4.02 × 10(-7)) with schizophrenia spectrum disorders (F20-29). In conclusion, our study suggests an association of DNA methylation differences at birth with development of mental disorder later in life in 22q11.2DS individuals.

Original languageEnglish
Article number1221
JournalTranslational Psychiatry
Volume7
Issue8
Pages (from-to)e1221
Number of pages11
ISSN2158-3188
DOIs
Publication statusPublished - 29 Aug 2017

    Research areas

  • ADHESION MOLECULE NCAM, BRAIN, CARDIO-FACIAL-SYNDROME, COPY NUMBER VARIATION, EXPRESSION, GENE, PSYCHIATRIC-DISORDERS, SCHIZOPHRENIA, SPECTRUM DISORDERS, WIDE ASSOCIATION

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