16670
2016
eng
e1005993
5
12
article
1
2018-08-07
--
--
Parental Origin of Interstitial Duplications at 15q11.2-q13.3 in Schizophrenia and Neurodevelopmental Disorders
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.
PLoS Genetics
10.1371/journal.pgen.1005993
urn:nbn:de:bvb:20-opus-166706
PLoS Genetics 12(5):e1005993 (2016). DOI: 10.1371/journal.pgen.1005993
286213
279062
241909
false
true
CC 0: Public Domain Dedication
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
eng
uncontrolled
interstitial duplications
eng
uncontrolled
schizophrenia
eng
uncontrolled
developmental delay
eng
uncontrolled
autism spectrum disorder
eng
uncontrolled
parental origin
eng
uncontrolled
genetics
Biowissenschaften; Biologie
open_access
Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie
OpenAIRE
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/16670/Isles_PLoS_Genetics.PDF
13528
2012
eng
e35424
4
7
article
1
2016-06-22
--
--
DCLK1 Variants Are Associated across Schizophrenia and Attention Deficit/Hyperactivity Disorder
Doublecortin and calmodulin like kinase 1 (DCLK1) is implicated in synaptic plasticity and neurodevelopment. Genetic variants in DCLK1 are associated with cognitive traits, specifically verbal memory and general cognition. We investigated the role of DCLK1 variants in three psychiatric disorders that have neuro-cognitive dysfunctions: schizophrenia (SCZ), bipolar affective disorder (BP) and attention deficit/hyperactivity disorder (ADHD). We mined six genome wide association studies (GWASs) that were available publically or through collaboration; three for BP, two for SCZ and one for ADHD. We also genotyped the DCLK1 region in additional samples of cases with SCZ, BP or ADHD and controls that had not been whole-genome typed. In total, 9895 subjects were analysed, including 5308 normal controls and 4,587 patients (1,125 with SCZ, 2,496 with BP and 966 with ADHD). Several DCLK1 variants were associated with disease phenotypes in the different samples. The main effect was observed for rs7989807 in intron 3, which was strongly associated with SCZ alone and even more so when cases with SCZ and ADHD were combined (P-value = 4x10\(^{-5}\) and 4x10\(^{-6}\), respectively). Associations were also observed with additional markers in intron 3 (combination of SCZ, ADHD and BP), intron 19 (SCZ+BP) and the 3'UTR (SCZ+BP). Our results suggest that genetic variants in DCLK1 are associated with SCZ and, to a lesser extent, with ADHD and BP. Interestingly the association is strongest when SCZ and ADHD are considered together, suggesting common genetic susceptibility. Given that DCLK1 variants were previously found to be associated with cognitive traits, these results are consistent with the role of DCLK1 in neurodevelopment and synaptic plasticity.
PLoS One
10.1371/journal.pone.0035424
urn:nbn:de:bvb:20-opus-135285
PLoS ONE 7(4): e35424. doi:10.1371/journal.pone.0035424
245009
Bjarte Havik
Franziska A. Degenhardt
Stefan Johansson
Carla P. D. Fernandes
Anke Hinney
André Scherag
Helle Lybaek
Srdjan Djurovic
Andrea Christoforou
Kari M. Ersland
Sudheer Giddaluru
Michael C. O'Donovan
Michael J. Owen
Nick Craddock
Thomas W. Mühleisen
Manuel Mattheisen
Benno G. Schimmelmann
Tobias Renner
Andreas Warnke
Beate Herpertz-Dahlmann
Judith Sinzig
Özgür Albayrak
Marcella Rietschel
Markus M. Nöthen
Clive R. Bramham
Thomas Werge
Johannes Hebebrand
Jan Haavik
Ole A. Andreassen
Sven Cichon
Vidar M. Steen
Stephanie Le Hellard
eng
uncontrolled
psychosis
eng
uncontrolled
deficit hyperactivity disorder
eng
uncontrolled
genome-wide association
eng
uncontrolled
bipolar disorder
eng
uncontrolled
VAL66MET polymorphism
eng
uncontrolled
doublecortine-like
eng
uncontrolled
genes
eng
uncontrolled
kinase
eng
uncontrolled
BDNF
eng
uncontrolled
endophenotype
Gynäkologie, Geburtsmedizin, Pädiatrie, Geriatrie
open_access
Klinik und Poliklinik für Kinder- und Jugendpsychiatrie, Psychosomatik und Psychotherapie
OpenAIRE
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/13528/Havik_PLoSOne_2012.pdf