TY - JOUR
T1 - Parental Origin of Interstitial Duplications at 15q11.2-q13.3 in Schizophrenia and Neurodevelopmental Disorders
AU - Isles, Anthony R.
AU - Ingason, Andrés
AU - Lowther, Chelsea
AU - Walters, James
AU - Gawlick, Micha
AU - Stöber, Gerald
AU - Rees, Elliott
AU - Martin, Joanna
AU - Little, Rosie B.
AU - Potter, Harry
AU - Georgieva, Lyudmila
AU - Pizzo, Lucilla
AU - Ozaki, Norio
AU - Aleksic, Branko
AU - Kushima, Itaru
AU - Ikeda, Masashi
AU - Iwata, Nakao
AU - Levinson, Douglas F.
AU - Gejman, Pablo V.
AU - Shi, Jianxin
AU - Sanders, Alan R.
AU - Duan, Jubao
AU - Willis, Joseph
AU - Sisodiya, Sanjay
AU - Costain, Gregory
AU - Werge, Thomas M.
AU - Degenhardt, Franziska
AU - Giegling, Ina
AU - Rujescu, Dan
AU - Hreidarsson, Stefan J.
AU - Saemundsen, Evald
AU - Ahn, Joo Wook
AU - Ogilvie, Caroline
AU - Girirajan, Santhosh D.
AU - Stefansson, Hreinn
AU - Stefansson, Kari
AU - O’Donovan, Michael C.
AU - Owen, Michael J.
AU - Bassett, Anne
AU - Kirov, George
N1 - Publisher Copyright:
© 2016 Public Library of Science. All Rights Reserved.
PY - 2016/5
Y1 - 2016/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84974566646&partnerID=8YFLogxK
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U2 - 10.1371/journal.pgen.1005993
DO - 10.1371/journal.pgen.1005993
M3 - Article
C2 - 27153221
AN - SCOPUS:84974566646
SN - 1553-7390
VL - 12
JO - PLoS genetics
JF - PLoS genetics
IS - 5
M1 - e1005993
ER -