Emma E M Knowles1, Juan M Peralta2, Laura Almasy3, Vishwajit Nimgaonkar4, Francis J McMahon5, Andrew M McIntosh6, Pippa Thomson7, Samuel R Mathias8, Ruben C Gur9, Joanne E Curran2, Henriette Raventós10, Javier Contreras11, Assen Jablensky12, Johanna Badcock13, John Blangero2, Raquel E Gur9, David C Glahn14. 1. Department of Psychiatry, Boston Children's Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts. Electronic address: emma.knowles@childrens.harvard.edu. 2. South Texas Diabetes and Obesity Institute and Department of Human Genetics, University of Texas Rio Grande Valley School of Medicine, Brownsville, Texas. 3. Department of Genetics at University of Pennsylvania and Department of Biomedical and Health Informatics and Lifespan Brain Institute, Department of Child and Adolescent Psychiatry and Behavioral Sciences at Children's Hospital of Philadelphia, Pennsylvania. 4. Department of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Hospital, Pittsburgh, Pennsylvania; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania. 5. Human Genetics Branch, NIMH Intramural Research Program, NIH, DHHS, Bethesda, Maryland. 6. Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom; Centre for Cognitive Ageing and Cognitive Epidemiology, School of Philosophy, Psychology and Language Sciences, University of Edinburgh, Edinburgh, United Kingdom. 7. Centre for Genomic and Experimental Medicine, Institute for Genetic and Genomic Medicine, University of Edinburgh, Edinburgh, United Kingdom. 8. Department of Psychiatry, Boston Children's Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts. 9. Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania. 10. Centro de Investigación en Biología Celular y Molecular y Escuela de Biologia, Universidad de Costa Rica, San Jose, Costa Rica; Escuela de Biología, Universidad de Costa Rica, San Jose, Costa Rica. 11. Centro de Investigación en Biología Celular y Molecular y Escuela de Biologia, Universidad de Costa Rica, San Jose, Costa Rica. 12. Centre for Clinical Research in Neuropsychiatry, Division of Psychiatry, Medical School, University of Western Australia, Perth, Western Australia, Australia. 13. School of Psychological Science, University of Western Australia, Perth, Western Australia, Australia; Perth Voices Clinic, Murdoch, Western Australia, Australia. 14. Department of Psychiatry, Boston Children's Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts; Olin Neuropsychiatric Research Center, Institute of Living, Hartford Hospital, Hartford, Connecticut.
Abstract
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.
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.
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