@article{73c1a171f55d4d82b29c701bb7a5937b,
title = "Multi-Omics Characterization of Early-and Adult-Onset Major Depressive Disorder",
abstract = "Age at depressive onset (AAO) corresponds to unique symptomatology and clinical outcomes. Integration of genome-wide association study (GWAS) results with additional “omic” measures to evaluate AAO has not been reported and may reveal novel markers of susceptibility and/or resistance to major depressive disorder (MDD). To address this gap, we integrated genomics with metabolomics using data-driven network analysis to characterize and differentiate MDD based on AAO. This study first performed two GWAS for AAO as a continuous trait in (a) 486 adults from the Pharmacogenomic Research Network-Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS), and (b) 295 adults from the Combining Medications to Enhance Depression Outcomes (CO-MED) study. Variants from top signals were integrated with 153 p180-assayed metabolites to establish multi-omics network characterizations of early (−8) localized to an intron of SAMD3. In silico functional annotation of top signals (p < 1 × 10−5) demonstrated gene expression enrichment in the brain and during embryonic development. Network analysis identified differential associations between four variants (in/near INTU, FAT1, CNTN6, and TM9SF2) and plasma metabolites (phosphatidylcholines, carnitines, biogenic amines, and amino acids) in early-compared with adult-onset MDD. Multi-omics integration identified differential biosignatures of early-and adult-onset MDD. These biosignatures call for future studies to follow participants from childhood through adulthood and collect repeated-omics and neuroimaging measures to validate and deeply characterize the biomarkers of susceptibility and/or resistance to MDD development.",
keywords = "Age at onset, Genomics, Major depressive disorder, Metabolomics, Network analysis",
author = "Grant, {Caroline W.} and Barreto, {Erin F.} and Rakesh Kumar and Rima Kaddurah-Daouk and Michelle Skime and Taryn Mayes and Thomas Carmody and Joanna Biernacka and Liewei Wang and Richard Weinshilboum and Trivedi, {Madhukar H.} and Bobo, {William V.} and Croarkin, {Paul E.} and Athreya, {Arjun P.}",
note = "Funding Information: Funding: This work is supported by the Harry C. and Debra A. Stonecipher Predoctoral Fellowship at the Mayo Clinic Graduate School of Biomedical Sciences, National Science Foundation (NSF) under grant 2041339; National Institutes of Health (NIH) under grants U19 GM61388, R01 GM028157, R01 AA027486, R01 MH108348, R24 GM078233, RC2 GM092729, U19 AG063744, N01 MH90003, R01 AG04617, U01 AG061359, RF1 AG051550, R01 MH113700 and R01 MH124655; K23AI143882; the Hersh Foundation, the Duke Psychiatry Pharmacometabolomics Center, and The Mayo Clinic Center for Individualized Medicine. The CO-MED study received medications at no cost from Forest Pharmaceuticals, GlaxoSmithKline, Organon, and Wyeth Pharmaceuticals. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the NSF or the NIH. Funding Information: Conflicts of Interest: Barreto consults for FAST Biomedical and Wolters Kluwer, both unrelated to the present work. L. Wang and R. M. Weinshilboum are co-founders of and stockholders in OneOme, LLC. W. V. Bobo{\textquoteright}s research has been supported by the National Institute of Mental Health, the Agency for Healthcare Quality and Research, the National Science Foundation, the Myocarditis Foundation, and the Mayo Foundation for Medical Education and Research. He has contributed chapters to UpToDate concerning the pharmacological treatment of adults with bipolar major depression. P. E. Croarkin has received research grant support from Neuronetics, Inc., NeoSync, Inc., and Pfizer, Inc. He has received grant in-kind (equipment, supply, and genotyping support for research studies) from Assurex Health, Neuronetics, Inc., and MagVenture, Inc. P. E. Croarkin has served as a consultant for Engrail Therapeutics, Myriad Neuroscience, Procter & Gamble, and Suno-vion. M. H. Trivedi has provided consulting services to Acadia Pharmaceuticals, Inc., Alkermes Inc, Alto Neuroscience Inc, Axsome Therapeutics, GH Research Limited, GreenLight VitalSign6 Inc, Janssen, Merck Sharp & Dohme Corp., Mind Medicine (MindMed) Inc., Neurocrine Biosciences Inc, Orexo US Inc, Otsuka, SAGE Therapeutics, Signant Health, Titan Pharmaceuticals, Inc. He has received grant/research funding from NIMH, NIDA, NCATS, American Foundation for Suicide Prevention, Patient-Centered Outcomes Research Institute (PCORI), and Blue Cross Blue Shield of Texas. Additionally, he has received editorial compensation from Oxford University Press. T. Car-mody has provided consulting services to Alkermes, Inc. R. Kaddurah-Daouk is an inventor on key patents in the field of metabolomics in the study of CNS diseases and holds equity in Metabolon, Inc., a biotechnology company that provides metabolic profiling capabilities. All other authors declared no competing interests for this work. Funding Information: This work is supported by the Harry C. and Debra A. Stonecipher Predoctoral Fellowship at the Mayo Clinic Graduate School of Biomedical Sciences, National Science Foundation (NSF) under grant 2041339; National Institutes of Health (NIH) under grants U19 GM61388, R01 GM028157, R01 AA027486, R01 MH108348, R24 GM078233, RC2 GM092729, U19 AG063744, N01 MH90003, R01 AG04617, U01 AG061359, RF1 AG051550, R01 MH113700 and R01 MH124655; K23AI143882; the Hersh Foundation, the Duke Psychiatry Pharmacometabolomics Center, and The Mayo Clinic Center for Individualized Medicine. The CO-MED study received medications at no cost from Forest Pharmaceuticals, GlaxoSmithKline, Organon, and Wyeth Pharmaceuticals. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the NSF or the NIH. Publisher Copyright: {\textcopyright} 2022 by the authors. Licensee MDPI, Basel, Switzerland.",
year = "2022",
month = mar,
doi = "10.3390/jpm12030412",
language = "English (US)",
volume = "12",
journal = "Journal of Personalized Medicine",
issn = "2075-4426",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "3",
}