Research
Print page Print page
Switch language
The Capital Region of Denmark - a part of Copenhagen University Hospital
Published

Parental Origin of Interstitial Duplications at 15q11.2-q13.3 in Schizophrenia and Neurodevelopmental Disorders

Research output: Contribution to journalJournal articleResearchpeer-review

  1. AMPK signaling linked to the schizophrenia-associated 1q21.1 deletion is required for neuronal and sleep maintenance

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Replicative and non-replicative mechanisms in the formation of clustered CNVs are indicated by whole genome characterization

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. Human genetic variation in GLS2 is associated with development of complicated Staphylococcus aureus bacteremia

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. Genetic anticipation in Swedish Lynch syndrome families

    Research output: Contribution to journalJournal articleResearchpeer-review

  5. Correction: Genome-wide physical activity interactions in adiposity - A meta-analysis of 200,452 adults

    Research output: Contribution to journalComment/debateResearchpeer-review

  1. Autism spectrum disorder and attention deficit hyperactivity disorder have a similar burden of rare protein-truncating variants

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Reduced neonatal brain-derived neurotrophic factor is associated with autism spectrum disorders

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. Genome-wide association study implicates CHRNA2 in cannabis use disorder

    Research output: Contribution to journalJournal articleResearchpeer-review

  • Anthony R Isles
  • Andrés Ingason
  • Chelsea Lowther
  • James Walters
  • Micha Gawlick
  • Gerald Stöber
  • Elliott Rees
  • Joanna Martin
  • Rosie B Little
  • Harry Potter
  • Lyudmila Georgieva
  • Lucilla Pizzo
  • Norio Ozaki
  • Branko Aleksic
  • Itaru Kushima
  • Masashi Ikeda
  • Nakao Iwata
  • Douglas F Levinson
  • Pablo V Gejman
  • Jianxin Shi
  • Alan R Sanders
  • Jubao Duan
  • Joseph Willis
  • Sanjay Sisodiya
  • Gregory Costain
  • Thomas M Werge
  • Franziska Degenhardt
  • Ina Giegling
  • Dan Rujescu
  • Stefan J Hreidarsson
  • Evald Saemundsen
  • Joo Wook Ahn
  • Caroline Ogilvie
  • Santhosh D Girirajan
  • Hreinn Stefansson
  • Kari Stefansson
  • Michael C O'Donovan
  • Michael J Owen
  • Anne Bassett
  • George Kirov
View graph of relations

Duplications at 15q11.2-q13.3 overlapping the Prader-Willi/Angelman syndrome (PWS/AS) region have been associated with developmental delay (DD), autism spectrum disorder (ASD) and schizophrenia (SZ). Due to presence of imprinted genes within the region, the parental origin of these duplications may be key to the pathogenicity. Duplications of maternal origin are associated with disease, whereas the pathogenicity of paternal ones is unclear. To clarify the role of maternal and paternal duplications, we conducted the largest and most detailed study to date of parental origin of 15q11.2-q13.3 interstitial duplications in DD, ASD and SZ cohorts. We show, for the first time, that paternal duplications lead to an increased risk of developing DD/ASD/multiple congenital anomalies (MCA), but do not appear to increase risk for SZ. The importance of the epigenetic status of 15q11.2-q13.3 duplications was further underlined by analysis of a number of families, in which the duplication was paternally derived in the mother, who was unaffected, whereas her offspring, who inherited a maternally derived duplication, suffered from psychotic illness. Interestingly, the most consistent clinical characteristics of SZ patients with 15q11.2-q13.3 duplications were learning or developmental problems, found in 76% of carriers. Despite their lower pathogenicity, paternal duplications are less frequent in the general population with a general population prevalence of 0.0033% compared to 0.0069% for maternal duplications. This may be due to lower fecundity of male carriers and differential survival of embryos, something echoed in the findings that both types of duplications are de novo in just over 50% of cases. Isodicentric chromosome 15 (idic15) or interstitial triplications were not observed in SZ patients or in controls. Overall, this study refines the distinct roles of maternal and paternal interstitial duplications at 15q11.2-q13.3, underlining the critical importance of maternally expressed imprinted genes in the contribution of Copy Number Variants (CNVs) at this interval to the incidence of psychotic illness. This work will have tangible benefits for patients with 15q11.2-q13.3 duplications by aiding genetic counseling.

Original languageEnglish
JournalP L o S Genetics
Volume12
Issue number5
Pages (from-to)e1005993
ISSN1553-7390
DOIs
Publication statusPublished - May 2016

    Research areas

  • Journal Article

ID: 49618063