Cognitive intermediate phenotype and genetic risk for psychosis

- General cognitive ability and working memory are robust intermediate phenotypes.
- Molecular genetic analyses advanced heritability and genetic overlap estimation.
- Use of cognitive intermediate phenotypes in genomic studies is gaining momentum.
- Intermediate phenotypes may aid functional characterization of psychosis risk genes.

Intermediate phenotypes (IPs) are defined as measurable liability traits underlying complex phenotypes, posited to be more genetically tractable than the phenotypes themselves. Here we review evidence for cognition as an IP of psychosis, and highlight topical advances in the literature: first, heritability estimation of cognitive abilities using genomewide complex-trait analysis; second, evidence that cognition lies upstream to schizophrenia liability; third, use of polygenic risk scores rather than single genetic variants to examine genetic overlap between cognitive IPs and schizophrenia; and fourth, use of cognitive IPs for schizophrenia risk gene discovery and functional characterization. We end with future directions in using cognitive IPs to study genetic risk of psychosis, including methodological refinements and shifting research focus from identifying IPs to using them.