Differential effects of common variants in SCN2A on general cognitive ability, brain physiology, and messenger RNA expression in schizophrenia cases and control individuals

Abstract

Importance: One approach to understanding the genetic complexity of schizophrenia is to study associated behavioral and biological phenotypes that may be more directly linked to genetic variation.

Objective: To identify single-nucleotide polymorphisms associated with general cognitive ability (g) in people with schizophrenia and control individuals.

Design, setting, and participants: Genomewide association study, followed by analyses in unaffected siblings and independent schizophrenia samples, functional magnetic resonance imaging studies of brain physiology in vivo, and RNA sequencing in postmortem brain samples. The discovery cohort and unaffected siblings were participants in the National Institute of Mental Health Clinical Brain Disorders Branch schizophrenia genetics studies. Additional schizophrenia cohorts were from psychiatric treatment settings in the United States, Japan, and Germany. The discovery cohort comprised 339 with schizophrenia and 363 community control participants. Follow-up analyses studied 147 unaffected siblings of the schizophrenia cases and independent schizophrenia samples including a total of an additional 668 participants. Imaging analyses included 87 schizophrenia cases and 397 control individuals. Brain tissue samples were available for 64 cases and 61 control individuals.

Main outcomes and measures: We studied genomewide association with g, by group, in the discovery cohort. We used selected genotypes to test specific associations in unaffected siblings and independent schizophrenia samples. Imaging analyses focused on activation in the prefrontal cortex during working memory. Brain tissue studies yielded messenger RNA expression levels for RefSeq transcripts.

Results: The schizophrenia discovery cohort showed genomewide-significant association of g with polymorphisms in sodium channel gene SCN2A, accounting for 10.4% of g variance (rs10174400, P = 9.27 × 10(-10)). Control individuals showed a trend for g/genotype association with reversed allelic directionality. The genotype-by-group interaction was also genomewide significant (P = 1.75 × 10(-9)). Siblings showed a genotype association with g parallel to the schizophrenia group and the same interaction pattern. Parallel, but weaker, associations with cognition were found in independent schizophrenia samples. Imaging analyses showed a similar pattern of genotype associations by group and genotype-by-group interaction. Sequencing of RNA in brain revealed reduced expression in 2 of 3 SCN2A alternative transcripts in the patient group, with genotype-by-group interaction, that again paralleled the cognition effects.

Conclusions and relevance: The findings implicate SCN2A and sodium channel biology in cognitive impairment in schizophrenia cases and unaffected relatives and may facilitate development of cognition-enhancing treatments.

Figure 1. Manhattan plot (A.) and QQ plot (B.) for SCN2A GWAS findings in 334 people with schizophrenia

A: Manhattan plot of GWAS results from 495,089 SNPs tested for association with g in 334 individuals with schizophrenia. On the y-axis is −log10(P). The red line denotes the p-value of 5.0×10⁻⁸. B: Quantile–quantile (QQ) plots of actual versus expected −2log(e)P for g in cases and controls. −2log(e)P follows a χ² distribution with 2 degrees of freedom and can be used for statistical inference. Points above the horizontal line indicate an enrichment of low p-values beyond what would be expected by chance.

Figure 2. Effect of SCN2A rs10174400 genotype on g composite performance, by group, in 334 probands, 147 siblings, and 363 controls

On the y-axis are values of g. The blue triangles (schizophrenia), green circles (siblings), and red diamonds (controls) represent mean g values by genotype subgroups. The error bars are ± 2 standard errors.