The effects of a muscarinic receptor 1 gene variant on executive and non-executive cognition in schizophrenia spectrum disorders

Highlights

• rs2067477 variation has been linked to executive dysfunction in schizophrenia.

• Executive function in schizophrenia spectrum was unaffected by rs2067477.

• Non-executive cognition was also unaffected by rs2067477.

Abstract

Individuals with schizophrenia who are homozygous at the c.267C > A (rs2067477) single nucleotide polymorphism within the muscarinic M1 receptor gene have been reported to perform less well on the Wisconsin Card Sorting Test (WCST). We investigated if rs2067477 genotype variation influenced WCST performance and non-executive cognition cross-diagnostically in a sample of 147 schizophrenia spectrum participants (SSD) and 294 healthy controls. We were unable to detect any significant differences in executive and non-executive cognitive performance across genotype. A broader genetic focus should be considered when investigating the association between the muscarinic system and cognition in SSD.

Introduction

Previous results from association, pharmacological intervention and animal-model studies has suggested an abnormal central muscarinic system, particularly the muscarinic M1 receptor (CHRM1) in the facilitation of clinical and cognitive symptoms in schizophrenia spectrum disorders (SSD; Carruthers et al., 2015). Two independent studies have reported that individuals with schizophrenia who are C-allele homozygotes at the CHRM1 c.267C > A (rs2067477) single nucleotide polymorphism (SNP) exhibit more pronounced executive functioning deficits on the Wisconsin Card Sorting Test (WCST) compared to those who are 267C/A heterozygous (Liao et al., 2003, Scarr et al., 2012). However, rs2067477 genotype variation in these studies had no association with premorbid IQ, symptom severity, illness-related factors or verbal fluency and did not confer altered risk for schizophrenia.

Associations between the rs2067477 genotype and psychomotor speed, working and visual memory in SSD were detected in a large sample (N = 447) as part of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Study (Need et al., 2009); however, no directions were reported. Cropley et al. (2015) showed that C/C homozygosity in SSD had no influence on working memory, verbal fluency, visuospatial-construction and attention, however could not comment on perseveration or cognitive flexibility due to an absence of WCST data. It was also revealed that C/C homozygosity in SSD was associated with reduced grey matter volume in a large cluster within the right precentral gyrus, incorporating the dorsal and ventral aspects of the premotor cortex; a structural change that was not detected in the cortical thickness or surface area of patients in a follow-up study (Carruthers et al., 2018). Previous research has implicated the premotor cortex in the set-shifting and response execution stages of the WCST (Abe and Hanakawa, 2009). Taken together, it appears that rs2067477 genotype variation in schizophrenia is linked to processes specific to performance on the WCST; particularly perseveration or cognitive flexibility. The aim of the present study was to further investigate the association between rs2067477 genotype variation and cognition. As previous research investigating the association between rs2067477 genotype variation and performance on the WCST has been restricted only to patients with a diagnosis of schizophrenia, we sought to explore the previously reported association amongst a group of SSD patients cross-diagnostically in a combined patient-healthy control group and more broadly using a multidimensional neuropsychological test battery.