Dataset Information

Schizophrenia Imaging Signatures and Their Associations With Cognition, Psychopathology, and Genetics in the General Population.

ABSTRACT:

Objective

The prevalence and significance of schizophrenia-related phenotypes at the population level is debated in the literature. Here, the authors assessed whether two recently reported neuroanatomical signatures of schizophrenia-signature 1, with widespread reduction of gray matter volume, and signature 2, with increased striatal volume-could be replicated in an independent schizophrenia sample, and investigated whether expression of these signatures can be detected at the population level and how they relate to cognition, psychosis spectrum symptoms, and schizophrenia genetic risk.

Methods

This cross-sectional study used an independent schizophrenia-control sample (N=347; ages 16-57 years) for replication of imaging signatures, and then examined two independent population-level data sets: typically developing youths and youths with psychosis spectrum symptoms in the Philadelphia Neurodevelopmental Cohort (N=359; ages 16-23 years) and adults in the UK Biobank study (N=836; ages 44-50 years). The authors quantified signature expression using support-vector machine learning and compared cognition, psychopathology, and polygenic risk between signatures.

Results

Two neuroanatomical signatures of schizophrenia were replicated. Signature 1 but not signature 2 was significantly more common in youths with psychosis spectrum symptoms than in typically developing youths, whereas signature 2 frequency was similar in the two groups. In both youths and adults, signature 1 was associated with worse cognitive performance than signature 2. Compared with adults with neither signature, adults expressing signature 1 had elevated schizophrenia polygenic risk scores, but this was not seen for signature 2.

Conclusions

The authors successfully replicated two neuroanatomical signatures of schizophrenia and describe their prevalence in population-based samples of youths and adults. They further demonstrated distinct relationships of these signatures with psychosis symptoms, cognition, and genetic risk, potentially reflecting underlying neurobiological vulnerability.

SUBMITTER: Chand GB

PROVIDER: S-EPMC9444886 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Publications

Schizophrenia Imaging Signatures and Their Associations With Cognition, Psychopathology, and Genetics in the General Population.

Chand Ganesh B GB Singhal Pankhuri P Dwyer Dominic B DB Wen Junhao J Erus Guray G Doshi Jimit J Srinivasan Dhivya D Mamourian Elizabeth E Varol Erdem E Sotiras Aristeidis A Hwang Gyujoon G Dazzan Paola P Kahn Rene S RS Schnack Hugo G HG Zanetti Marcus V MV Meisenzahl Eva E Busatto Geraldo F GF Crespo-Facorro Benedicto B Pantelis Christos C Wood Stephen J SJ Zhuo Chuanjun C Shinohara Russell T RT Shou Haochang H Fan Yong Y Koutsouleris Nikolaos N Kaczkurkin Antonia N AN Moore Tyler M TM Verma Anurag A Calkins Monica E ME Gur Raquel E RE Gur Ruben C RC Ritchie Marylyn D MD Satterthwaite Theodore D TD Wolf Daniel H DH Davatzikos Christos C

The American journal of psychiatry 20220412 9

<h4>Objective</h4>The prevalence and significance of schizophrenia-related phenotypes at the population level is debated in the literature. Here, the authors assessed whether two recently reported neuroanatomical signatures of schizophrenia-signature 1, with widespread reduction of gray matter volume, and signature 2, with increased striatal volume-could be replicated in an independent schizophrenia sample, and investigated whether expression of these signatures can be detected at the population ...[more]

PMID: 35410495

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Project description:Both, pharmacological and genome-wide association studies suggest N-methyl-D-aspartate receptor (NMDAR) dysfunction and excitatory/inhibitory (E/I)-imbalance as a major pathophysiological mechanism of schizophrenia. The identification of shared fMRI brain signatures of genetically and pharmacologically induced NMDAR dysfunction may help to define biomarkers for patient stratification. NMDAR-related genetic and pharmacological effects on functional connectivity were investigated by integrating three different datasets: (A) resting state fMRI data from 146 patients with schizophrenia genotyped for the disease-associated genetic variant rs7191183 of GRIN2A (encoding the NMDAR 2 A subunit) as well as 142 healthy controls. (B) Pharmacological effects of the NMDAR antagonist ketamine and the GABA-A receptor agonist midazolam were obtained from a double-blind, crossover pharmaco-fMRI study in 28 healthy participants. (C) Regional gene expression profiles were estimated using a postmortem whole-brain microarray dataset from six healthy donors. A strong resemblance was observed between the effect of the genetic variant in schizophrenia and the ketamine versus midazolam contrast of connectivity suggestive for an associated E/I-imbalance. This similarity became more pronounced for regions with high density of NMDARs, glutamatergic neurons, and parvalbumin-positive interneurons. From a functional perspective, increased connectivity emerged between striato-pallido-thalamic regions and cortical regions of the auditory-sensory-motor network, while decreased connectivity was observed between auditory (superior temporal gyrus) and visual processing regions (lateral occipital cortex, fusiform gyrus, cuneus). Importantly, these imaging phenotypes were associated with the genetic variant, the differential effect of ketamine versus midazolam and schizophrenia (as compared to healthy controls). Moreover, the genetic variant was associated with language-related negative symptomatology which correlated with disturbed connectivity between the left posterior superior temporal gyrus and the superior lateral occipital cortex. Shared genetic and pharmacological functional connectivity profiles were suggestive of E/I-imbalance and associated with schizophrenia. The identified brain signatures may help to stratify patients with a common molecular disease pathway providing a basis for personalized psychiatry.

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Dataset Information

Schizophrenia Imaging Signatures and Their Associations With Cognition, Psychopathology, and Genetics in the General Population.

Objective

Methods

Results

Conclusions

Publications

Schizophrenia Imaging Signatures and Their Associations With Cognition, Psychopathology, and Genetics in the General Population.

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