Genetic basis of psychopathological dimensions shared between schizophrenia and bipolar disorder

Abstract

Shared genetic vulnerability between schizophrenia (SCZ) and bipolar disorder (BP) was demonstrated, but the genetic underpinnings of specific symptom domains are unclear. This study investigated which genes and gene sets may modulate specific psychopathological domains and if genome-wide significant loci previously associated with SCZ or BP may play a role. Genome-wide data were available in patients with SCZ (n = 226) or BP (n = 228). Phenotypes under investigation were depressive and positive symptoms severity, suicidal ideation, onset age and substance use disorder comorbidity. Genome-wide analyses were performed at gene and gene set level, while 148 genome-wide significant loci previously associated with SCZ and/or BP were investigated. Each sample was analyzed separately then a meta-analysis was performed. SH3GL2 and CLVS1 genes were associated with suicidal ideation in SCZ (p = 5.62e-08 and 0.01, respectively), the former also in the meta-analysis (p = .01). SHC4 gene was associated with depressive symptoms severity in BP (p = .003). A gene set involved in cellular differentiation (GO:0048661) was associated with substance disorder comorbidity in the meta-analysis (p = .03). Individual loci previously associated with SCZ or BP did not modulate the phenotypes of interest. This study provided confirmatory and new findings. SH3GL2 (endophilin A1) showed a role in suicidal ideation that may be due to its relevance to the glutamate system. SHC4 regulates BDNF-induced MAPK activation and was previously associated with depression. CLVS1 is involved in lysosome maturation and was for the first time associated with a psychiatric trait. GO:0048661 may mediate the risk of substance disorder through an effect on neurodevelopment/neuroplasticity.

Endophilin A1 drives acute structural plasticity of dendritic spines in response to Ca2+/calmodulin

“…Endophilin A1 is a member of the endophilin A protein family characterized by an amino-terminal N-BIN/amphiphysin/Rvs (BAR) domain and a carboxyl-terminal Src homology 3 (SH3) domain. The gene encoding endophilin A1 ( EEN1 , gene name sh3gl2 ) is almost exclusively expressed in brain ( Ringstad et al, 1997 ) and has been implicated in epilepsy, schizophrenia, and Alzheimer’s disease ( Corponi et al, 2019 ; Ren et al, 2008 ; Yu et al, 2018a ; Yu et al, 2018b ). Originally identified as a component of the endocytic machinery, endophilin As function in synaptic vesicle recycling ( Milosevic et al, 2011 ; Ringstad et al, 1997 ; Schuske et al, 2003 ; Verstreken et al, 2003 ; Watanabe et al, 2018 ), autophagosome formation, and protein homeostasis at presynaptic terminals ( Murdoch et al, 2016 ; Soukup et al, 2016 ).…”

A New Prognostic Risk Score: Based on the Analysis of Autophagy-Related Genes and Renal Cell Carcinoma

“…In addition, CLDN7 was found upregulated in mouse pancreas exposed to caerylein for 12 h and its function concerned tight junction formation, while destruction of tight might be closely related with autophagy’s detrimental effects ( Nakada et al, 2010 ; Wang S. et al, 2020 ). So far CLVS1 wasn’t found significant in tumorigenesis and progression, but research found it is involved in lysosome maturation and associated with psychiatric and steroid-sensitive nephrotic syndrome ( Corponi et al, 2019 ; Lane et al, 2021 ). GMIP is a protein coding gene that encodes ARHGAP family of Rho/Rac/Cdc42-like GTPase activating proteins.…”

The Role of Endophilin A1 in Lipopolysaccharide-Induced Parkinson’s Disease Model Mice

“…Endophilin A1 (EPA1) plays a crucial role in the regulation of nervous system diseases and tumor diseases [2,3]. Its structure includes an aminoterminal N-BIN/amphiphysin/Rvs (BAR) domain and a carboxy-terminal Src homology region 3 (SH3) domain, encoded by the SH3GL2 gene and expressed almost exclusively in the brain, and is associated with epilepsy and schizophrenia [4,5]. In addition to being associated with Alzheimer's disease (AD) [6,7], SH3GL2 was designated as a risk locus for PD by genome-wide association analysis [8].…”