{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:04:18Z","timestamp":1790553858600,"version":"4.1.0"},"reference-count":50,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2020,3,3]],"date-time":"2020-03-03T00:00:00Z","timestamp":1583193600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Neuroscience Research"],"published-print":{"date-parts":[[2020,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Individuals diagnosed with major depressive disorder not responding to at least two adequate treatments are defined as treatment\u2010refractory major depressive disorder (TR\u2010MDD). Some TR\u2010MDD patients have altered metabolic phenotypes that may be pharmacologically reversed. The characterization of these phenotypes and their underlying etiologies is paramount, particularly their genetic components. In this study, TR\u2010MDD patients (\n                    <jats:italic>n<\/jats:italic>\n                    \u00a0=\u00a0124) were recruited and metabolites were quantified in their cerebrospinal fluid (CSF) and peripheral blood. Three sub\u2010categories of deficiencies were examined, namely 5\u2010methyltetrahydrofolte (in CSF;\n                    <jats:italic>n<\/jats:italic>\n                    \u00a0=\u00a013), tetrahydrobiopterin (in CSF;\n                    <jats:italic>n<\/jats:italic>\n                    \u00a0=\u00a011), and abnormal acylcarnitine profiles (in peripheral blood;\n                    <jats:italic>n<\/jats:italic>\n                    \u00a0=\u00a08). Whole exome sequencing was performed on genomic DNA from the entire TR\u2010MDD cohort and exonic variant allele frequencies for cases were compared to a control cohort (1:5 matching on ancestry). Low frequency, damaging alleles were identified and used for\n                    <jats:italic>in silico<\/jats:italic>\n                    pathway analyses. Three association signals for TR\u2010MDD approached genome\u2010wide significance on chromosomes 22, 7, and 3. Three risk\u2010associated variants from a prior depression study were replicated. Relevant biological pathways were identified that contained an enrichment of rare, damaging variants in central nervous system (CNS)\u2010specific pathways, including neurotransmitter receptors, potassium channels, and synapse transmission. Some TR\u2010MDD patients had rare variants in genes that were previously associated with other psychiatric disorders, psychiatric endophenotypes, CNS structural defects, and CNS\u2010related cellular and molecular functions. Exome analysis of metabolically phenotyped TR\u2010MDD patients has identified potentially functional gene pathways and low frequency, deleterious gene variants for further investigation. Further studies in larger cohorts of biochemically phenotyped TR\u2010MDD patients are desirable to extend and confirm these findings.\n                  <\/jats:p>","DOI":"10.1002\/jnr.24609","type":"journal-article","created":{"date-parts":[[2020,3,4]],"date-time":"2020-03-04T02:34:40Z","timestamp":1583289280000},"page":"1322-1334","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Rare variants and biological pathways identified in treatment\u2010refractory depression"],"prefix":"10.1002","volume":"98","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0163-3689","authenticated-orcid":false,"given":"Lora Lee","family":"McClain","sequence":"first","affiliation":[{"name":"Department of Psychiatry Western Psychiatric Hospital University of Pittsburgh School of Medicine Pittsburgh PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Shaw","sequence":"additional","affiliation":[{"name":"Center for Fetal Medicine Magee\u2010Womens Research Institute Pittsburgh PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roisin","family":"Sabol","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Western Psychiatric Hospital University of Pittsburgh School of Medicine Pittsburgh PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Maria","family":"Chedia","sequence":"additional","affiliation":[{"name":"Center for Fetal Medicine Magee\u2010Womens Research Institute Pittsburgh PA USA"},{"name":"Creative and Performing Arts Magnet Pittsburgh Public Schools Pittsburgh PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Maria","family":"Segretti","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Western Psychiatric Hospital University of Pittsburgh School of Medicine Pittsburgh PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manivel","family":"Rengasamy","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Western Psychiatric Hospital University of Pittsburgh School of Medicine Pittsburgh PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David N.","family":"Finegold","sequence":"additional","affiliation":[{"name":"Department of Human Genetics University of Pittsburgh Graduate School of Public Health Pittsburgh PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Western Psychiatric Hospital University of Pittsburgh School of Medicine Pittsburgh PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4354-1125","authenticated-orcid":false,"given":"David Gerard","family":"Peters","sequence":"additional","affiliation":[{"name":"Center for Fetal Medicine Magee\u2010Womens Research Institute Pittsburgh PA USA"},{"name":"Department of Human Genetics University of Pittsburgh Graduate School of Public Health Pittsburgh PA USA"},{"name":"Department of Obstetrics, Gynecology and Reproductive Sciences University of Pittsburgh School of Medicine Pittsburgh PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,3,3]]},"reference":[{"issue":"4","key":"e_1_2_11_2_1","first-page":"312","article-title":"Diagnosis and management of cerebral folate deficiency. 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