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 T. R.

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 M

AU - Costain, Gregory

AU - Werge, Thomas M

AU - Degenhardt, Franziska

AU - Giegling, Ina

AU - Rujescu, Dan

AU - Hreidarsson, Stefán J

AU - Saemundsen, Evald

AU - Ahn, Joo Wook

AU - Ogilvie, Caroline M

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

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.

KW - Journal Article

U2 - 10.1371/journal.pgen.1005993

DO - 10.1371/journal.pgen.1005993

M3 - Journal article

C2 - 27153221

VL - 12

JO - P L o S Genetics

JF - P L o S Genetics

SN - 1553-7390

IS - 5

M1 - e1005993

ER -