{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T15:17:35Z","timestamp":1781104655119,"version":"3.54.1"},"reference-count":38,"publisher":"National Academy of Sciences","issue":"45","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2008,11,11]]},"abstract":"<jats:p>\n                    Understanding how risk genes cumulatively impair brain function in schizophrenia could provide critical insights into its pathophysiology. Working memory impairment in schizophrenia has been associated with abnormal dopamine signaling in the prefrontal cortex, which is likely under complex genetic control. The catechol-\n                    <jats:italic>O<\/jats:italic>\n                    -methyltransferase (COMT) 158Val \u2192 Met polymorphism (rs4680), which affects the availability of prefrontal dopamine signaling, consistently stratifies prefrontal activation during working memory performance. However, the low-dopamine COMT 158Val allele does not confer increased risk for schizophrenia, and its effects on prefrontal function are not specific to the disorder. In the setting of other genetic variants influencing prefrontal dopamine signaling, COMT 158Val \u2192 Met genotype may exert disease-specific effects. A second polymorphism, methylenetetrahydrofolate reductase (MTHFR) 677C \u2192 T (rs1801133), has been associated with overall schizophrenia risk and executive function impairment in patients, and may influence dopamine signaling through mechanisms upstream of COMT effects. We found that the hypofunctional 677T variant was associated with decreased working memory load-dependent activation in the prefrontal and insular cortices in 79 schizophrenia patients, but not in 75 demographically matched healthy controls. Further, significant MTHFR \u00d7 COMT genotype interactions were observed, which differed by diagnostic group: Reduced prefrontal activation was associated with the 677T and 158Val alleles in patients, but with 677C\/C and 158Met\/Met genotype in controls. These findings are consistent with epistatic effects of the COMT and MTHFR polymorphisms on prefrontal dopamine signaling, and suggest that in schizophrenia patients, the MTHFR 677T allele exacerbates prefrontal dopamine deficiency. The findings also suggest the importance of weighing COMT effects on prefrontal function within the context of MTHFR genotype.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0803727105","type":"journal-article","created":{"date-parts":[[2008,11,6]],"date-time":"2008-11-06T21:25:48Z","timestamp":1226006748000},"page":"17573-17578","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":82,"title":["MTHFR 677C \u2192 T genotype disrupts prefrontal function in schizophrenia through an interaction with COMT 158Val \u2192 Met"],"prefix":"10.1073","volume":"105","author":[{"given":"Joshua L.","family":"Roffman","sequence":"first","affiliation":[{"name":"Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Randy L.","family":"Gollub","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vince D.","family":"Calhoun","sequence":"additional","affiliation":[{"name":"Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque, NM 87131;"},{"name":"The MIND Research Network, Albuquerque, NM 87131;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas H.","family":"Wassink","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of Iowa, Iowa City, IA 52242;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony P.","family":"Weiss","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beng C.","family":"Ho","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of Iowa, Iowa City, IA 52242;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tonya","family":"White","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of Minnesota, Minneapolis, MN 55455; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent P.","family":"Clark","sequence":"additional","affiliation":[{"name":"The MIND Research Network, Albuquerque, NM 87131;"},{"name":"Department of Psychology, University of New Mexico, Albuquerque, NM 87131"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill","family":"Fries","sequence":"additional","affiliation":[{"name":"The MIND Research Network, Albuquerque, NM 87131;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy C.","family":"Andreasen","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of Iowa, Iowa City, IA 52242;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald C.","family":"Goff","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dara S.","family":"Manoach","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2008,11,11]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1176\/ajp.153.3.321"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1093\/schbul\/sbl055"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.111134598"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1176\/ajp.161.10.1798"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0931309100"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/mp.2008.19"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.mp.4001664"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.mp.4001973"},{"key":"e_1_3_3_9_2","first-page":"3101","article-title":"Multiple promoters of catechol-O-methyltransferase gene are selectively inactivated by CpG hypermethylation in endometrial cancer","volume":"63","author":"Sasaki M","year":"2003","unstructured":"M Sasaki, M Kaneuchi, N Sakuragi, R Dahiya, Multiple promoters of catechol-O-methyltransferase gene are selectively inactivated by CpG hypermethylation in endometrial cancer. 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