Comprehensive Gene- and Pathway-Based Analysis of Depressive Symptoms in Older Adults
Open accessAbstract
Depressive symptoms are common in older adults and are particularly prevalent in those with or at elevated risk for dementia. Although the heritability of depression is estimated to be substantial, single nucleotide polymorphism-based genome-wide association studies of depressive symptoms have had limited success. In this study, we performed genome-wide gene- and pathway-based analyses of depressive symptom burden. Study participants included non-Hispanic Caucasian subjects (n = 6,884) from three independent cohorts, the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Health and Retirement Study (HRS), and the Indiana Memory and Aging Study (IMAS). Gene-based meta-analysis identified genome-wide significant associations (ANGPT4 and FAM110A, q-value = 0.026; GRM7-AS3 and LRFN5, q-value = 0.042). Pathway analysis revealed enrichment of association in 105 pathways, including multiple pathways related to ERK/MAPK signaling, GSK3 signaling in bipolar disorder, cell development, and immune activation and inflammation. GRM7, ANGPT4, and LRFN5 have been previously implicated in psychiatric disorders, including the GRM7 region displaying association with major depressive disorder. The ERK/MAPK signaling pathway is a known target of antidepressant drugs and has important roles in neuronal plasticity, and GSK3 signaling has been previously implicated in Alzheimer's disease and as a promising therapeutic target for depression. Our results warrant further investigation in independent and larger cohorts and add to the growing understanding of the genetics and pathobiology of depressive symptoms in aging and neurodegenerative disorders. In particular, the genes and pathways demonstrating association with depressive symptoms may be potential therapeutic targets for these symptoms in older adults.
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LRFN5 had previously been detected in gene- and pathway-based analyses of depressive symptom burden in three cohorts: ADNI, HRS, and IMAS.
“This gene was previously detected in genome-wide gene- and pathway based analyses of depressive symptom burden conducted in three cohorts from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), the Health and Retirement Study (HRS), and the Indiana Memory and Aging Study (IMAS).37”
From Bi-ancestral depression GWAS in the Million Veteran Program and meta-analysis in >1.2 million individuals highlight new therapeutic directions (2021) · cites this paper as [37]
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Self-citation
- Authors
- Nho, K., Ramanan, V. K., Horgusluoglu, E., Kim, S., Inlow, M. H., Risacher, S. L., McDonald, B. C., Farlow, M. R., Foroud, T. M., Gao, S., Callahan, C. M., Hendrie, H. C., Niculescu, A. B., Saykin, A. J., & (ADNI), F. T. A. D. N. I.
- Affiliations
- Indiana University Indianapolis (US)
- Rose–Hulman Institute of Technology (US)
- Indiana University School of Medicine (US)
- Corresponding author
- Saykin, Andrew J.
- ORCID
- Venue
- Journal of Alzheimer’s Disease
- Publisher
- SAGE Publications
- Published
- 2015-04-13
- Volume
- 45
- Issue
- 4
- Pages
- 1197-1206
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- PMC
- PMC4398648
- OpenAlex
- W1631734526
- Cited by
- 41
- References
- 64
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 1 · 2023: 6 · 2022: 1 · 2021: 4 · 2020: 3 · 2019: 3 · 2018: 4 · 2017: 5 · 2016: 3 · 2015: 4
- FWCI
- 3.64
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Michigan
- National Institutes of Health (UL1TR001108, 5u01ag024904-10)
- School of Medicine, Indiana University
- National Institute on Aging (U01-AG-024904, P30AG010133, R01 AG19771, RC2AG036495, U24 AG21886, RC4AG039029, R01AG019771, P30 AG-10133, U01AG009740, U24AG021886)
- U.S. National Library of Medicine (R00LM011384, K99LM011384)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- depressive symptoms, older adults
- MeSH terms
- Aged, Depression, Female, Humans, Male, Psychiatric Status Rating Scales, Cohort Studies, White People, Genotyping Techniques
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