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However, large\u2010scale studies examining their interactions on cognitive and symptomatic outcomes remain scarce. COMT rs4680 and DAOA rs947267 polymorphisms were measured in chronic schizophrenics (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009758) and controls (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009416), and cognition and psychiatric symptoms were assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Positive and Negative Syndrome Scale (PANSS). Both the dominant (OR\u2009=\u20090.582,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.024) and heterozygous (OR\u2009=\u20090.533,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.012) models revealed notable variations in genotype distribution between cases and controls for the COMT polymorphism. Among females, the COMT polymorphism conferred a risk under the recessive model (OR\u2009=\u20091.571,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.045) but a protective effect under heterozygous (OR\u2009=\u20090.378,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.026) and codominant (OR\u2009=\u20090.515,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.005) models. Additionally, we found that the COMT Val and DAOA A alleles interacted synergistically to worsen immediate memory in patients with schizophrenia. A significant COMT \u00d7 DAOA interaction on language (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.019) was revealed in schizophrenia but not in controls. Val\/Val + A schizophrenia carriers exhibit poorer language performance than Met + A carriers (AA\/CA genotypes) (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.019). Furthermore, Met + CC schizophrenia carriers demonstrated significantly higher PANSS\u2010G (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.020) or total PANSS scores (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.008) than Met + A carriers. These findings, derived from large\u2010scale empirical data, offer a more profound understanding of the complex regulatory mechanism between the dopamine and glutamate systems regarding cognition and clinical symptoms in chronic schizophrenia. This understanding may lead to the development of more effective treatments targeting both systems.\n                  <\/jats:p>","DOI":"10.1002\/ajmg.b.33067","type":"journal-article","created":{"date-parts":[[2025,11,15]],"date-time":"2025-11-15T10:15:47Z","timestamp":1763201747000},"page":"300-310","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>COMT rs4680<\/scp>\n                    and\n                    <scp>DAOA rs947267<\/scp>\n                    Polymorphism Interact to Influence Cognition and Psychiatric Symptoms in Chronic Schizophrenia"],"prefix":"10.1002","volume":"201","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6607-4166","authenticated-orcid":false,"given":"Pinhong","family":"Chen","sequence":"first","affiliation":[{"name":"Beijing Institute of Basic Medical Sciences  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lubin","family":"Wang","sequence":"additional","affiliation":[{"name":"Beijing Institute of Basic Medical Sciences  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-3364-5653","authenticated-orcid":false,"given":"Fuqiang","family":"Wang","sequence":"additional","affiliation":[{"name":"The Second Affiliated Hospital of Henan Medical University  Xinxiang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenhao","family":"Xu","sequence":"additional","affiliation":[{"name":"Beijing Institute of Basic Medical Sciences  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9230-7530","authenticated-orcid":false,"given":"Dongmei","family":"Wang","sequence":"additional","affiliation":[{"name":"Hefei Fourth People's Hospital, Anhui Mental Health Center Psychological Hospital of Anhui Medical University  Hefei China"},{"name":"Department of Psychology University of Chinese Academy of Sciences  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5125-8429","authenticated-orcid":false,"given":"Meihong","family":"Xiu","sequence":"additional","affiliation":[{"name":"Beijing Hui\u2010Long\u2010Guan Hospital, Peking University  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dachun","family":"Chen","sequence":"additional","affiliation":[{"name":"Beijing Hui\u2010Long\u2010Guan Hospital, Peking University  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Blake","family":"Lackey","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences The University of Texas Health Science Center at Houston  Houston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanjing E.","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences The University of Texas Health Science Center at Houston  Houston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3326-382X","authenticated-orcid":false,"given":"Xiangyang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Hefei Fourth People's Hospital, Anhui Mental Health Center Psychological Hospital of Anhui Medical University  Hefei China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,11,15]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.171"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0303343"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpsychires.2024.07.053"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/1744\u20109081\u20105\u201028"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23158617"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq614"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/schbul\/sbw146"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41380\u2010022\u201001649\u2010w"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.98.2.581"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/hbm.21047"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1080\/13546805.2012.698100"},{"issue":"6","key":"e_1_2_11_13_1","article-title":"Functional Analysis of Genetic Variation in Catechol\u2010O\u2010Methyltransferase (COMT): Effects on mRNA, Protein, and Enzyme Activity in Postmortem Human Brain","volume":"76","author":"Chen J. 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