title: Comprehensive gene- and pathway-based analysis of depressive symptoms in older adults.
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.
authors.affiliation: Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Kwangsik
authors.initials: K
authors.lastname: Nho
authors.affiliation: Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA Medical Scientist Training Program, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Ramanan
authors.affiliation: Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Emrin
authors.initials: E
authors.lastname: Horgusluoglu
authors.affiliation: Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Sungeun
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Mathematics, Rose-Hulman Institute of Technology, Terre Haute, IN, USA.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Inlow
authors.affiliation: Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Risacher
authors.affiliation: Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Brenna C
authors.initials: BC
authors.lastname: McDonald
authors.affiliation: Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Farlow
authors.affiliation: Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Tatiana M
authors.initials: TM
authors.lastname: Foroud
authors.affiliation: Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA Department of Biostatistics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Sujuan
authors.initials: S
authors.lastname: Gao
authors.affiliation: Center for Aging Research, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Callahan
authors.affiliation: Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Hugh C
authors.initials: HC
authors.lastname: Hendrie
authors.affiliation: Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Alexander B
authors.initials: AB
authors.lastname: Niculescu
authors.affiliation: Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Saykin
mesh_terms: D000368:Aged; D015331:Cohort Studies; D003863:Depression / Q000235:genetics*; D005260:Female; D060005:Genotyping Techniques; D006801:Humans; D008297:Male; D011569:Psychiatric Status Rating Scales; D044465:White People / Q000235:genetics
keywords: ANGPT4; GRM7; GSK3; MAPK-ERK; depressive symptoms; genome-wide association study