Transdiagnostic neurocognitive endophenotypes in major psychiatric illness

We aimed to characterize potential transdiagnostic neurocognitive endophenotypes in a large cohort of multiplex families affected with two or more individuals having a major psychiatric illness(MPI) i.e., schizophrenia(SCZ), bipolar disorder(BPAD), substance use disorders(SUD) and obsessive-compulsive disorder(OCD). We recruited 640 individuals that included 256 affected individuals with MPI, 227 of their unaffected first-degree relatives(FDR) and 157 population healthy-controls(PHC). Neurocognitive battery included assessments of executive function, working memory, social cognition, verbal learning and recall. Linear mixed effects models were applied to the neurocognitive components to examine their transdiagnostic and endophenotype status after accounting for demographic and family variables. We also examined the relationship of cognitive domains with diagnosis-specific Family History Density score(FHD). The deficits in cognitive flexibility, working memory and social cognition were transdiagnostic; processing speed was impaired in SCZ and BPAD groups while verbal learning and recall in SCZ, BPAD and SUD groups. These deficits with the exception of social cognition, worsened with age and parental education had protective effect. The unaffected FDRs had deficits in all the domains except processing speed in comparison to PHC; social cognition deficits were comparable to affected individuals. The diagnosis-specific FHD analysis showed that deficits in cognitive flexibility, working memory and social cognition were endophenotypes across disorders. Evaluation of neurocognitive functions across multiple affected individuals in a large multiplex family-based cross-disorder cohort, has the potential to elucidate transdiagnostic as well as endophenotype vulnerabilities to psychiatric illness. This study adds to the emerging conceptualization of psychiatric illness as a combination of both diagnosis-specific and transdiagnostic markers.