Genetic Overlap Profiles of Cognitive Ability in Psychotic and Affective Illnesses: A Multisite Study of Multiplex Pedigrees

Emma E.M. Knowles, Juan M. Peralta, Laura Almasy, Vishwajit Nimgaonkar, Francis J. McMahon, Andrew M. McIntosh, Pippa Thomson, Samuel R. Mathias, Ruben C. Gur, Joanne E. Curran, Henriette Raventós, Javier Contreras, Assen Jablensky, Johanna Badcock, John Blangero, Raquel E. Gur, David C. Glahn

Research output: Contribution to journalArticlepeer-review


Background: Cognitive impairment is a key feature of psychiatric illness, making cognition an important tool for exploring of the genetics of illness risk. It remains unclear which measures should be prioritized in pleiotropy-guided research. Here, we generate profiles of genetic overlap between psychotic and affective disorders and cognitive measures in Caucasian and Hispanic groups. Methods: Data were from 4 samples of extended pedigrees (N = 3046). Coefficient of relationship analyses were used to estimate genetic overlap between illness risk and cognitive ability. Results were meta-analyzed. Results: Psychosis was characterized by cognitive impairments on all measures with a generalized profile of genetic overlap. General cognitive ability shared greatest genetic overlap with psychosis risk (average endophenotype ranking value [ERV] across samples from a random-effects meta-analysis = 0.32), followed by verbal memory (ERV = 0.24), executive function (ERV = 0.22), and working memory (ERV = 0.21). For bipolar disorder, there was genetic overlap with processing speed (ERV = 0.05) and verbal memory (ERV = 0.11), but these were confined to select samples. Major depressive disorder was characterized by enhanced working and face memory performance, as reflected in significant genetic overlap in 2 samples. Conclusions: There is substantial genetic overlap between risk for psychosis and a range of cognitive abilities (including general intelligence). Most of these effects are largely stable across of ascertainment strategy and ethnicity. Genetic overlap between affective disorders and cognition, on the other hand, tends to be specific to ascertainment strategy, ethnicity, and cognitive test battery.

Original languageEnglish (US)
Pages (from-to)373-384
Number of pages12
JournalBiological Psychiatry
Issue number6
StatePublished - Sep 15 2021
Externally publishedYes


  • Bipolar disorder
  • Cognition
  • Family-based genetics
  • Genetic epidemiology
  • Major depressive disorder
  • Psychotic disorders

ASJC Scopus subject areas

  • Biological Psychiatry


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