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.
To identify single nucleotide polymorphisms associated with general cognitive ability (“g”) in people with schizophrenia and controls.
Genome-wide association study (GWAS), followed by analyses in unaffected siblings and independent schizophrenia samples, functional magnetic resonance imaging studies of brain physiology in vivo, and RNA sequencing in post-mortem brain samples.
The discovery cohort and unaffected siblings were participants in the NIMH 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 controls. Follow-up analyses studied 147 unaffected siblings of the schizophrenia cases, and independent schizophrenia samples of 279, 95 and 294 participants. Imaging analyses included 87 schizophrenia cases and 397 controls. Brain tissue samples were available for 64 cases and 61 controls.
Main Outcome Measures
We studied genome-wide 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 prefrontal cortex during working memory. Brain tissue studies yielded mRNA expression levels for RefSeq transcripts.
The schizophrenia discovery cohort showed GWAS-significant association of g with polymorphisms in sodium channel gene SCN2A, accounting for 10.4% of g variance (rs10174400, P=9.27×10−10). Controls showed a trend for g/genotype association with reversed allelic directionality. The genotype-by-group interaction was also GWAS-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. RNA sequencing 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.
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.