Genetic underpinnings of left superior temporal gyrus thickness in patients with schizophrenia

Abstract

Objectives Schizophrenia is a highly disabling psychiatric disorder with a heterogeneous phenotypic appearance. We aimed to further the understanding of some of the underlying genetics of schizophrenia, using left superior temporal gyrus (STG) gray matter thickness reduction as an endophenoptype in a genome-wide association (GWA) study. Methods Structural magnetic resonance imaging (MRI) and genetic data of the Mind Clinical Imaging Consortium (MCIC) study of schizophrenia were used to analyze the interaction effects between 1,067,955 single nucleotide polymorphisms (SNPs) and disease status on left STG thickness in 126 healthy controls and 113 patients with schizophrenia. We next used a pathway approach to detect underlying pathophysiological pathways that may be related to schizophrenia. Results No SNP by diagnosis interaction effect reached genome-wide significance (5 × 10-8) in our GWA study, but ten SNPs reached p-values less than 10-6. The most prominent pathways included those involved in insulin, calcium, PI3K-Akt and MAPK signaling. Conclusions Our strongest findings in the GWA study and pathway analysis point towards an involvement of glucose metabolism in left STG thickness reduction in patients with schizophrenia only. These results are in line with recently published studies, which showed an increased prevalence of psychosis among patients with metabolic syndrome-related illnesses including diabetes.

Isoform-specific roles for AKT in affective behavior, spatial memory, and extinction related to psychiatric disorders

“…Functional studies provide strong evidence for AKT involvement in schizophrenia. Magnetic resonance imaging studies have linked AKT signaling and SNPs in the pathway to structural and functional brain abnormalities in schizophrenia patients ( Jagannathan et al, 2010 ; Nicodemus et al, 2010 ; Wolthusen et al, 2015 ). Antipsychotics for treating schizophrenia, which antagonize dopamine receptor-2 function, activate AKT and inhibit its substrate GSK3 ( Emamian et al, 2004 ; Alimohamad et al, 2005 ; Li et al, 2007 ; Beaulieu et al, 2009 ).…”

The metabolic basis of cognitive insight in psychosis: A positron emission tomography study

“…Moreover neuroimaging studies found structural and functional abnormalities in the superior temporal gyrus among SZ patients [ 77 , 78 , 79 ] and decreased gray matter volume in prefrontal and temporal regions which related to low insight scores in a group of first-episode drug naïve psychotic patients, in comparison with a control group [ 80 ]. Nevertheless, to date, the role of this area in insight is still not well elucidated.…”

Identification of Novel Genes Associated with Cortical Thickness in Alzheimer’s Disease: Systems Biology Approach to Neuroimaging Endophenotype

“…Although previous GWAS identified some SNPs associated with cortical thickness [23,36,37], identified variants could explain a small proportion of phenotypic variance of cortical thickness. SNP-based GWAS ignored the loci with moderate association signals due to the adoption of a stringent significance threshold.…”

“…have been widely studied to demonstrate their abnormal reduction in patients with AD compared with cognitively normal control subjects [30][31][32][33][34]. The heritability of cortical thickness is reported as 69% [35], and identified genetic variants from previous studies that are associated with cortical thickness [23,36,37], accounted for a small portion of the variance. Correspondingly, more susceptibility genes need to be identified to explain the missing heritability of cortical thickness.…”