Phenotypically distinct subtypes of psychosis accompany novel or rare variants in four different signaling genes

Highlights

• Rare gene variants and new mutations are important components of the genetic susceptibility to schizophrenia.

• Targeted exome capture of a gene panel revealed de novo mutations and rare missense coding polymorphisms in four genes among 48 new schizophrenia cases.

• These affected genes are: PTPRG (Protein Tyrosine Phosphatase, Receptor Type G), SLC39A13 (Solute Carrier Family 39 (Zinc Transporter) Member 13), TGM5 (Transglutaminase 5), ARMS/KIDINS220 (Ankyrin repeat-rich membrane spanning protein or Kinase D-Interacting Substrate of 220 kDa).

• One or more additional rare missense coding polymorphisms in any of these genes were identified in 31% of the sample (15 cases).

• Significant phenotypic differences existed among the subgroups of cases harboring genetic variants in these genes.

A challenge in schizophrenia is individual differences with respect to etiology and optimum treatments. Of note, rare gene variants are important components of schizophrenia susceptibility. These can arise as new mutations in the paternal germline and their number can increase with age and get transmitted to future generations. This study focused on four genes, which have previously shown to carry rare missense coding variants among two independent schizophrenia cohorts. Four or five missense coding polymorphisms or novel mutations across these genes occurred in 15/48 clinically intensively characterized cases, with some cases harboring two of these genes. Subgrouping cases by which gene displayed rare missense coding polymorphisms or novel mutations revealed differences in cognition, symptoms and clinical features. These may be relevant to person specific treatments.

Abstract

Background

Rare gene variants are important sources of schizophrenia vulnerability that likely interact with polygenic susceptibility loci. This study examined if novel or rare missense coding variants in any of four different signaling genes in sporadic schizophrenia cases were associated with clinical phenotypes in an exceptionally well-characterized sample.

Method

Structured interviews, cognition, symptoms and life course features were assessed in 48 ethnically-diverse cases with psychosis who underwent targeted exome sequencing of PTPRG (Protein Tyrosine Phosphatase, Receptor Type G), SLC39A13 (Solute Carrier Family 39 (Zinc Transporter) Member 13), TGM5 (transglutaminase 5) and ARMS/KIDINS220 (Ankyrin repeat-rich membrane spanning protein or Kinase D-Interacting Substrate of 220 kDa). Cases harboring rare missense coding polymorphisms or novel mutations in one or more of these genes were compared to other cases not carrying any rare missense coding polymorphisms or novel mutations in these genes and healthy controls.

Findings

Fifteen of 48 cases (31.25%) carried rare or novel missense coding variants in one or more of these genes. The subgroups significantly differed in important features, including specific working memory deficits for PTPRG (n = 5); severe negative symptoms, global cognitive deficits and poor educational attainment, suggesting a developmental disorder, for SLC39A13 (n = 4); slow processing speed, childhood attention deficit disorder and milder symptoms for TGM5 (n = 4); and global cognitive deficits with good educational attainment suggesting neurodegeneration for ARMS/KIDINS220 (n = 5). Case vignettes are included in the appendix.

Interpretation

Genes prone to missense coding polymorphisms and/or mutations in sporadic cases may highlight influential genes for psychosis and illuminate heterogeneous pathways to schizophrenia. Ethnicity appears less important at the level of genetic variability. The sequence variations that potentially alter the function of specific genes or their signaling partners may contribute to particular subtypes of psychosis. This approach may be applicable to other complex disorders.