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

Abstract

SummarySchizophrenia (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.

mTOR-Related Brain Dysfunctions in Neuropsychiatric Disorders

“…While recent advances in molecular psychiatry have identified several mTOR-related schizophrenia risk genes, the role of autophagy in schizophrenia has been recently investigated. Remarkably, the identification of rare genetic variants of ULK1 in a cohort of schizophrenic patients by means of exome sequence analysis strengthens the idea of a key role of both disrupted mTOR signaling and autophagy in the pathophysiology and susceptibility to schizophrenia [ 248 ] ( Figure 3 ). The first evidence of a dysregulation of autophagy in schizophrenia was provided in 2011 by the Horesh group, who performed gene expression profile analysis in different brain areas of post-mortem schizophrenic patients compared with healthy controls, with no evidence of concomitant dementia [ 249 ].…”

Rare variant analysis in multiply affected families, association studies and functional analysis suggest a role for the ITGΒ4 gene in schizophrenia and bipolar disorder

“…The UCL case-control samples sample and the recruitment methods have been previously described ( Al Eissa et al, 2017 ; Fiorentino et al, 2014 ). Briefly, the sample comprised 1917 bipolar disorder (BP) participants, 1304 SCZ participants and 1348 control participants recruited from the UK.…”

The Unfolded Protein Response and Autophagy as Drug Targets in Neuropsychiatric Disorders

“…The serine/threonine protein kinases, Unc-51 like autophagy activating kinase (Ulk1/2) are parts of a molecular complex regulating autophagy downstream of mTOR (Walker and Ktistakis, 2019 ). Rare variants of Ulk1 is associated with schizophrenia (Al Eissa et al, 2018 ), whilst Ulk2 heterozygous mice show behavioral defects associated with a reduced surface expression of GABA A receptors in pyramidal neurons of the PFC (Sumitomo et al, 2018 ). In these mice, the autophagy adaptor protein, sequestosome-1 (SQSTM1/p62) was increased, and downregulation of p62 restored the behavior defects and GABARAP mediated localization of the GABA A receptors.…”