{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T23:24:00Z","timestamp":1783466640683,"version":"3.55.0"},"posted":{"date-parts":[[2026,7,4]]},"group-title":"Genetic and Genomic Medicine","reference-count":49,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T00:00:00Z","timestamp":1783123200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Major depressive disorder (MDD) is a complex psychiatric disorder, characterized by a range of mood, cognitive, and neurovegetative symptoms. Current diagnostic criteria treat opposite symptom directions as equivalent; weight gain or loss, and increased or decreased sleep, each count toward a single diagnosis. We defined three subgroups of individuals meeting criteria for MDD:\n                  <jats:italic>AERS+<\/jats:italic>\n                  (hypersomnia with increased appetite\/weight gain),\n                  <jats:italic>AERS\u2212<\/jats:italic>\n                  (insomnia with appetite\/weight loss), and an Uncategorized group, and conducted genome-wide association meta-analyses for each (\n                  <jats:italic>\n                    N\n                    <jats:sub>eff<\/jats:sub>\n                  <\/jats:italic>\n                  = 47,858, 156,624, and 215,828, respectively). We identified 27 genome-wide significant loci across subtypes, 4 for\n                  <jats:italic>AERS+<\/jats:italic>\n                  , 10 for\n                  <jats:italic>AERS\u2212<\/jats:italic>\n                  and 13 for Uncategorized.\n                  <jats:italic>AERS+<\/jats:italic>\n                  showed higher SNP-based heritability (10.9%) and lower polygenicity (1.7% of SNPs) than\n                  <jats:italic>AERS\u2212<\/jats:italic>\n                  (7.9%; 2.9%) or Uncategorized (8.6%; 5.3%), with larger effect sizes at its associated loci. The\n                  <jats:italic>AERS+<\/jats:italic>\n                  and\n                  <jats:italic>AERS\u2212<\/jats:italic>\n                  subtypes were moderately genetically correlated (\n                  <jats:italic>r<\/jats:italic>\n                  <jats:sub>g<\/jats:sub>\n                  = 0.64, se = 0.04). Metabolic traits emerged as a primary differentiator:\n                  <jats:italic>AERS+<\/jats:italic>\n                  correlated positively with BMI, metabolic syndrome, and related traits, whereas\n                  <jats:italic>AERS\u2212<\/jats:italic>\n                  correlated weakly in the opposite direction. These findings show that the directionality of neurovegetative symptoms indexes genetic heterogeneity within MDD, with metabolic biology as a central axis of differentiation.\n                <\/jats:p>","DOI":"10.64898\/2026.07.02.26357101","type":"posted-content","created":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T14:15:12Z","timestamp":1783174512000},"source":"Crossref","is-referenced-by-count":0,"title":["Atypical energy-related symptoms define biologically distinct subtypes of major depressive disorder"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5984-9207","authenticated-orcid":false,"given":"Arvid","family":"Harder","sequence":"first","affiliation":[{"name":"Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2574-990X","authenticated-orcid":false,"given":"Rujia","family":"Wang","sequence":"additional","affiliation":[{"name":"Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9279-6936","authenticated-orcid":false,"given":"Jacob","family":"Bergstedt","sequence":"additional","affiliation":[{"name":"Unit of Integrative Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7776-7988","authenticated-orcid":false,"given":"Floris","family":"Huider","sequence":"additional","affiliation":[{"name":"Biological Psychology, Faculty of Behavioral and Movement Sciences, Vrije 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