{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T09:58:43Z","timestamp":1792144723736,"version":"4.4.0"},"reference-count":64,"publisher":"National Academy of Sciences","issue":"12","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2001,6,5]]},"abstract":"<jats:p>\n                    Abnormalities of prefrontal cortical function are prominent\n features of schizophrenia and have been associated with genetic risk,\n suggesting that susceptibility genes for schizophrenia may impact on\n the molecular mechanisms of prefrontal function. A potential\n susceptibility mechanism involves regulation of prefrontal dopamine,\n which modulates the response of prefrontal neurons during working\n memory. We examined the relationship of a common functional\n polymorphism (Val\n                    <jats:sup>108\/158<\/jats:sup>\n                    Met) in the\n catechol-\n                    <jats:italic>O<\/jats:italic>\n                    -methyltransferase (COMT) gene, which accounts\n for a 4-fold variation in enzyme activity and dopamine catabolism, with\n both prefrontally mediated cognition and prefrontal cortical\n physiology. In 175 patients with schizophrenia, 219 unaffected\n siblings, and 55 controls, COMT genotype was related in allele dosage\n fashion to performance on the Wisconsin Card Sorting Test of executive\n cognition and explained 4% of variance (\n                    <jats:italic>P<\/jats:italic>\n                    = 0.001)\n in frequency of perseverative errors. Consistent with other evidence\n that dopamine enhances prefrontal neuronal function, the load of the\n low-activity Met allele predicted enhanced cognitive performance. We\n then examined the effect of COMT genotype on prefrontal physiology\n during a working memory task in three separate subgroups\n (\n                    <jats:italic>n<\/jats:italic>\n                    = 11\u201316) assayed with functional MRI. Met\n allele load consistently predicted a more efficient physiological\n response in prefrontal cortex. Finally, in a family-based association\n analysis of 104 trios, we found a significant increase in transmission\n of the Val allele to the schizophrenic offspring. These data suggest\n that the COMT Val allele, because it increases prefrontal dopamine\n catabolism, impairs prefrontal cognition and physiology, and by this\n mechanism slightly increases risk for schizophrenia.\n                  <\/jats:p>","DOI":"10.1073\/pnas.111134598","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:44:19Z","timestamp":1027680259000},"page":"6917-6922","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":1993,"title":["Effect of COMT Val\n                    <sup>108\/158<\/sup>\n                    Met genotype on frontal lobe function and risk for schizophrenia"],"prefix":"10.1073","volume":"98","author":[{"given":"Michael F.","family":"Egan","sequence":"first","affiliation":[{"name":"Clinical Brain Disorders Branch, Building 10, Center Drive,\r National Institute of Mental Health, Bethesda, MD 20892;\r Laboratory of Neurogenetics, 12501 Washington\r Avenue, Park 5, 451 National Institute of Alcohol Abuse and Alcoholism,\r Rockville, MD 20852; and Department of Psychiatry,\r Virginia Commonwealth University, Richmond, VA 23298"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terry E.","family":"Goldberg","sequence":"additional","affiliation":[{"name":"Clinical Brain Disorders Branch, Building 10, Center Drive,\r National Institute of Mental Health, Bethesda, MD 20892;\r Laboratory of Neurogenetics, 12501 Washington\r Avenue, Park 5, 451 National Institute of Alcohol Abuse and Alcoholism,\r Rockville, MD 20852; and Department of Psychiatry,\r Virginia Commonwealth University, Richmond, VA 23298"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhaskar S.","family":"Kolachana","sequence":"additional","affiliation":[{"name":"Clinical Brain Disorders Branch, Building 10, Center Drive,\r National Institute of Mental Health, Bethesda, MD 20892;\r Laboratory of Neurogenetics, 12501 Washington\r Avenue, Park 5, 451 National Institute of Alcohol Abuse and Alcoholism,\r Rockville, MD 20852; and Department of Psychiatry,\r Virginia Commonwealth University, Richmond, VA 23298"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph H.","family":"Callicott","sequence":"additional","affiliation":[{"name":"Clinical Brain Disorders Branch, Building 10, Center Drive,\r National Institute of Mental Health, Bethesda, MD 20892;\r Laboratory of Neurogenetics, 12501 Washington\r Avenue, Park 5, 451 National Institute of Alcohol Abuse and Alcoholism,\r Rockville, MD 20852; and Department of Psychiatry,\r Virginia Commonwealth University, Richmond, VA 23298"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara M.","family":"Mazzanti","sequence":"additional","affiliation":[{"name":"Clinical Brain Disorders Branch, Building 10, Center Drive,\r National Institute of Mental Health, Bethesda, MD 20892;\r Laboratory of Neurogenetics, 12501 Washington\r Avenue, Park 5, 451 National Institute of Alcohol Abuse and Alcoholism,\r Rockville, MD 20852; and Department of Psychiatry,\r Virginia Commonwealth University, Richmond, VA 23298"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard E.","family":"Straub","sequence":"additional","affiliation":[{"name":"Clinical Brain Disorders Branch, Building 10, Center Drive,\r National Institute of Mental Health, Bethesda, MD 20892;\r Laboratory of Neurogenetics, 12501 Washington\r Avenue, Park 5, 451 National Institute of Alcohol Abuse and Alcoholism,\r Rockville, MD 20852; and Department of Psychiatry,\r Virginia Commonwealth University, Richmond, VA 23298"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Goldman","sequence":"additional","affiliation":[{"name":"Clinical Brain Disorders Branch, Building 10, Center Drive,\r National Institute of Mental Health, Bethesda, MD 20892;\r Laboratory of Neurogenetics, 12501 Washington\r Avenue, Park 5, 451 National Institute of Alcohol Abuse and Alcoholism,\r Rockville, MD 20852; and Department of Psychiatry,\r Virginia Commonwealth University, Richmond, VA 23298"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel R.","family":"Weinberger","sequence":"additional","affiliation":[{"name":"Clinical Brain Disorders Branch, Building 10, Center Drive,\r National Institute of Mental Health, Bethesda, MD 20892;\r Laboratory of Neurogenetics, 12501 Washington\r Avenue, Park 5, 451 National Institute of Alcohol Abuse and Alcoholism,\r Rockville, MD 20852; and Department of Psychiatry,\r Virginia Commonwealth University, Richmond, VA 23298"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2001,5,29]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.288.5466.678"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1195-287"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320540108"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.273.5281.1516"},{"key":"e_1_3_3_5_2","first-page":"222","volume":"46","author":"Risch N","year":"1990","unstructured":"N Risch Am J Hum Genet 46, 222\u2013228 (1990).","journal-title":"Am J Hum Genet"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.39.1.19"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-0173(99)00050-8"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1097\/00041444-199723000-00001"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1097\/00041444-199623000-00005"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.mp.4000638"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3223(97)00202-3"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3223(99)00098-0"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.2.587"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1093\/schbul\/20.1.103"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1086\/303006"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1001\/archpsyc.1990.01810230082013"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1001\/archpsyc.1986.01800020020004"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1176\/ajp.155.9.1285"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3223(98)00318-7"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1093\/cercor\/10.11.1078"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1093\/schbul\/14.2.179"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1001\/archpsyc.1995.03950220031007"},{"key":"e_1_3_3_23_2","first-page":"5493","volume":"57","author":"Lavigne J A","year":"1997","unstructured":"J A Lavigne, K J Helzlsouer, H Y Huang, P T Strickland, D A Bell, O Selmin, M A Watson, S Hoffman, G W Comstock, J D Yager Cancer Res 57, 5493\u20135497 (1997).","journal-title":"Cancer Res"},{"key":"e_1_3_3_24_2","unstructured":"Egan M. 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