Comprehensive gene- and pathway-based analysis of depressive symptoms in older adults.

TitleComprehensive gene- and pathway-based analysis of depressive symptoms in older adults.
Publication TypeJournal Article
Year of Publication2015
AuthorsNho, K, Ramanan, VK, Horgusluoglu, E, Kim, S, Inlow, MH, Risacher, SL, McDonald, BC, Farlow, MR, Foroud, TM, Gao, S, Callahan, CM, Hendrie, HC, Niculescu, AB, Saykin, AJ
Corporate AuthorsAlzheimer’s Disease Neuroimaging Initiative (ADNI)
JournalJournal of Alzheimer's Disease
Volume45
Issue4
Pagination1197-206
Date Published2015
ISSN Number1875-8908
KeywordsDepressive symptoms, Genetics, Older Adults, Women and Minorities
Abstract

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.

DOI10.3233/JAD-148009
Alternate JournalJ. Alzheimers Dis.
Citation Key8617
PubMed ID25690665
PubMed Central IDPMC4398648
Grant ListK99 LM011384 / LM / NLM NIH HHS / United States
P30 AG010133 / AG / NIA NIH HHS / United States
P30 AG10133 / AG / NIA NIH HHS / United States
R00 LM011384 / LM / NLM NIH HHS / United States
R00 LM011384 / LM / NLM NIH HHS / United States
R01 AG019771 / AG / NIA NIH HHS / United States
R01 AG19771 / AG / NIA NIH HHS / United States
RC2 AG036495 / AG / NIA NIH HHS / United States
RC2AG036495 / AG / NIA NIH HHS / United States
RC4 AG039029 / AG / NIA NIH HHS / United States
RC4AG039029 / AG / NIA NIH HHS / United States
U01 AG009740 / AG / NIA NIH HHS / United States
U01 AG024904 / AG / NIA NIH HHS / United States
U01 AG024904 / AG / NIA NIH HHS / United States
U01AG009740 / AG / NIA NIH HHS / United States
U24 AG021886 / AG / NIA NIH HHS / United States
U24 AG21886 / AG / NIA NIH HHS / United States
UL1 TR001108 / TR / NCATS NIH HHS / United States