Exome sequence analysis and follow up genotyping implicates rare ULK1 variants to be involved in susceptibility to schizophrenia

Summary Schizophrenia (SCZ) is a severe, highly heritable psychiatric disorder. Elucidation of the genetic architecture of the disorder will facilitate greater understanding of the altered underlying neurobiological mechanisms. The aim of this study was to identify likely aetiological variants in su...

Full description

Saved in:
Bibliographic Details
Published inAnnals of human genetics Vol. 82; no. 2; pp. 88 - 92
Main Authors Al Eissa, Mariam M., Fiorentino, Alessia, Sharp, Sally I., O'Brien, Niamh L., Wolfe, Kate, Giaroli, Giovanni, Curtis, David, Bass, Nicholas J., McQuillin, Andrew
Format Journal Article
LanguageEnglish
Published England Wiley Subscription Services, Inc 01.03.2018
John Wiley and Sons Inc
Subjects
association
Autophagy
Autophagy-Related Protein-1 Homolog - genetics
burden analysis
Case-Control Studies
Exome
Exome Sequencing
Genotype
Genotyping
Humans
Intracellular Signaling Peptides and Proteins - genetics
Introns
Kinases
Mental disorders
Mutation, Missense
olanzapine
Original
Phagocytosis
Schizophrenia
Schizophrenia - genetics
Signal transduction
Sweden
TOR protein
Sweden
olanzapine
association
burden analysis
Online AccessGet full text

Cover

More Information
Summary:Summary Schizophrenia (SCZ) is a severe, highly heritable psychiatric disorder. Elucidation of the genetic architecture of the disorder will facilitate greater understanding of the altered underlying neurobiological mechanisms. The aim of this study was to identify likely aetiological variants in subjects affected with SCZ. Exome sequence data from a SCZ cas–control sample from Sweden was analysed for likely aetiological variants using a weighted burden test. Suggestive evidence implicated the UNC‐51‐like kinase (ULK1) gene, and it was observed that four rare variants that were more common in the Swedish SCZ cases were also more common in UK10K SCZ cases, as compared to obesity cases. These three missense variants and one intronic variant were genotyped in the University College London cohort of 1304 SCZ cases and 1348 ethnically matched controls. All four variants were more common in the SCZ cases than controls and combining them produced a result significant at P = 0.02. The results presented here demonstrate the importance of following up exome sequencing studies using additional datasets. The roles of ULK1 in autophagy and mTOR signalling strengthen the case that these pathways may be important in the pathophysiology of SCZ. The findings reported here await independent replication.
Bibliography:Funding information
http://www.ncbi.nlm.nih.gov/gap
Genetic analysis of the UCL cohort has been supported by UK Medical Research Council project grants G9623693N, G0500791, G0701007, and G1000708. MMAE is funded by a PhD studentship scholarship from the Kingdom of Saudi Arabia, Ministry of Health. Drs McQuillin and Bass are supported by the UCLH NIHR BRC. The UK10K project was funded by Wellcome Trust grant WT091310. The Swedish case control datasets used for the analysis described in this manuscript were obtained from dbGaP at
through dbGaP accession number phs000473. Samples used for data analysis were provided by the Swedish Cohort Collection supported by the NIMH grant R01MH077139, the Sylvan C. Herman Foundation, the Stanley Medical Research Institute and The Swedish Research Council (grants 2009–4959 and 2011–4659). Support for the exome sequencing was provided by the NIMH Grand Opportunity grant RCMH089905, the Sylvan C. Herman Foundation, a grant from the Stanley Medical Research Institute and multiple gifts to the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard. The UCL clinical and control samples were collected with the support from the Neuroscience Research Charitable Trust, the Central London NHS Blood Transfusion Service, the Camden and Islington NHS Foundation Trust and 10 other NHS Mental Health Trusts, the Stanley Foundation, the National Institute for Health Research Mental Health Research Network, and the NIHR supported Primary Care Research Network.
ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 14
content type line 23
Funding information: Genetic analysis of the UCL cohort has been supported by UK Medical Research Council project grants G9623693N, G0500791, G0701007, and G1000708. MMAE is funded by a PhD studentship scholarship from the Kingdom of Saudi Arabia, Ministry of Health. Drs McQuillin and Bass are supported by the UCLH NIHR BRC. The UK10K project was funded by Wellcome Trust grant WT091310. The Swedish case control datasets used for the analysis described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000473. Samples used for data analysis were provided by the Swedish Cohort Collection supported by the NIMH grant R01MH077139, the Sylvan C. Herman Foundation, the Stanley Medical Research Institute and The Swedish Research Council (grants 2009–4959 and 2011–4659). Support for the exome sequencing was provided by the NIMH Grand Opportunity grant RCMH089905, the Sylvan C. Herman Foundation, a grant from the Stanley Medical Research Institute and multiple gifts to the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard. The UCL clinical and control samples were collected with the support from the Neuroscience Research Charitable Trust, the Central London NHS Blood Transfusion Service, the Camden and Islington NHS Foundation Trust and 10 other NHS Mental Health Trusts, the Stanley Foundation, the National Institute for Health Research Mental Health Research Network, and the NIHR supported Primary Care Research Network.
ISSN:0003-4800
1469-1809
1469-1809
DOI:10.1111/ahg.12226