Comprehensive Gene- and Pathway-Based Analysis of Depressive Symptoms in Older Adults

Article type: Research Article

Authors: Nho, Kwangsik^{a; b; c} | Ramanan, Vijay K.^{a; d; e} | Horgusluoglu, Emrin^{a; d} | Kim, Sungeun^{a; b; c} | Inlow, Mark H.^f | Risacher, Shannon L.^{a; b} | McDonald, Brenna C.^{a; b; g} | Farlow, Martin R.^{b; g} | Foroud, Tatiana M.^{b; d} | Gao, Sujuan^{b; h} | Callahan, Christopher M.ⁱ | Hendrie, Hugh C.^{b; j} | Niculescu, Alexander B.^j | Saykin, Andrew J.^{a; b; c; d; g; *} | for the Alzheimer's Disease Neuroimaging Initiative (ADNI)¹

Affiliations: [a] Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA | [b] Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA | [c] Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA | [d] Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA | [e] Medical Scientist Training Program, Indiana University School of Medicine, Indianapolis, IN, USA | [f] Department of Mathematics, Rose-Hulman Institute of Technology, Terre Haute, IN, USA | [g] Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA | [h] Department of Biostatistics, Indiana University School of Medicine, Indianapolis, IN, USA | [i] Center for Aging Research, Indiana University School of Medicine, Indianapolis, IN, USA | [j] Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA

Correspondence: [*] Correspondence to: Andrew J. Saykin, PsyD, Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA. Tel.: +1 317 963 7501; Fax: +1 317 963 7547; E-mail: asaykin@iu.edu.

Note: [1] Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.usc.edu/). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf.

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.

Keywords: ANGPT4, depressive symptoms, genome-wide association study, GRM7, GSK3, MAPK-ERK

DOI: 10.3233/JAD-148009

Journal: Journal of Alzheimer's Disease, vol. 45, no. 4, pp. 1197-1206, 2015