Multi-Omics Characterization of Early- and Adult-Onset Major Depressive Disorder

• Published in: Journal of personalized medicine Vol. 12; no. 3; p. 412
• Main Authors: Grant, Caroline W, Barreto, Erin F, Kumar, Rakesh, Kaddurah-Daouk, Rima, Skime, Michelle, Mayes, Taryn, Carmody, Thomas, Biernacka, Joanna, Wang, Liewei, Weinshilboum, Richard, Trivedi, Madhukar H, Bobo, William V, Croarkin, Paul E, Athreya, Arjun P
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 06.03.2022; MDPI
• Subjects: Age; Amines; Amino acids; Annotations; Biogenic amines; Biomarkers; Children; Drug therapy; Embryogenesis; Gene expression; Genes; Genome-wide association studies; Genomes; Genomics; Integration; Mental depression; Metabolites; Metabolomics; Neuroimaging; Pharmacogenomics; Precision medicine; Quality control; Schizophrenia; Statistical analysis; White people; United States > US; genomics; network analysis; major depressive disorder; metabolomics; age at onset
• ISSN: 2075-4426; 2075-4426
• DOI: 10.3390/jpm12030412

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 (<age 18) and adult-onset depression. The most significant variant (p = 8.77 × 10−8) 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.