TY - JOUR
T1 - Genome-wide association analysis of hippocampal volume identifies enrichment of neurogenesis-related pathways
AU - Alzheimer’s Disease Neuroimaging Initiative (ADNI)
AU - Horgusluoglu-Moloch, Emrin
AU - Risacher, Shannon L.
AU - Crane, Paul K.
AU - Hibar, Derrek
AU - Thompson, Paul M.
AU - Saykin, Andrew J.
AU - Nho, Kwangsik
AU - Weiner, Michael W.
AU - Aisen, Paul
AU - Petersen, Ronald
AU - Jack, Clifford R.
AU - Jagust, William
AU - Trojanowki, John Q.
AU - Toga, Arthur W.
AU - Beckett, Laurel
AU - Green, Robert C.
AU - Morris, John C.
AU - Shaw, Leslie M.
AU - Kaye, Jeffrey
AU - Quinn, Joseph
AU - Silbert, Lisa
AU - Lind, Betty
AU - Carter, Raina
AU - Dolen, Sara
AU - Schneider, Lon S.
AU - Pawluczyk, Sonia
AU - Beccera, Mauricio
AU - Teodoro, Liberty
AU - Spann, Bryan M.
AU - Brewer, James
AU - Vanderswag, Helen
AU - Fleisher, Adam
AU - Heidebrink, Judith L.
AU - Lord, Joanne L.
AU - Mason, Sara S.
AU - Albers, Colleen S.
AU - Knopman, David
AU - Johnson, Kris
AU - Doody, Rachelle S.
AU - Villanueva-Meyer, Javier
AU - Chowdhury, Munir
AU - Rountree, Susan
AU - Dang, Mimi
AU - Stern, Yaakov
AU - Honig, Lawrence S.
AU - Bell, Karen L.
AU - Ances, Beau
AU - Carroll, Maria
AU - Creech, Mary L.
AU - Womack, Kyle
N1 - Funding Information:
Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen. Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health. (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. ENIGMA was supported in part by a Consortium grant (U54EB020403 to PMT) from the NIH Institutes contributing to the Big Data to Knowledge (BD2K) Initiative, including the NIBIB and NCI. Additional support for data analysis was provided by NLM R01 LM012535, NIA R03 AG054936, NIA R01 AG19771, NIA P30 AG10133, NLM R01 LM011360, NSF IIS-1117335, DOD W81XWH-14-2-0151, NCAA 14132004, NIGMS P50GM115318, NCATS UL1 TR001108, NIA K01 AG049050, NCI R01 CA129769 and R35 CA197289, the Alzheimer’s Association, the Indiana Clinical and Translational Science Institute, and the IU Health-IU School of Medicine Strategic Neuroscience Research Initiative. This manuscript is based in part on the published PhD thesis of Emrin Horgusluoglu in Medical and Molecular Genetics at Indiana University School of Medicine entitled “Neurogenesis in the adult brain, gene networks, and Alzheimer’s Disease”58, under the supervision of the corresponding authors.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Adult neurogenesis occurs in the dentate gyrus of the hippocampus during adulthood and contributes to sustaining the hippocampal formation. To investigate whether neurogenesis-related pathways are associated with hippocampal volume, we performed gene-set enrichment analysis using summary statistics from a large-scale genome-wide association study (N = 13,163) of hippocampal volume from the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium and two year hippocampal volume changes from baseline in cognitively normal individuals from Alzheimer’s Disease Neuroimaging Initiative Cohort (ADNI). Gene-set enrichment analysis of hippocampal volume identified 44 significantly enriched biological pathways (FDR corrected p-value < 0.05), of which 38 pathways were related to neurogenesis-related processes including neurogenesis, generation of new neurons, neuronal development, and neuronal migration and differentiation. For genes highly represented in the significantly enriched neurogenesis-related pathways, gene-based association analysis identified TESC, ACVR1, MSRB3, and DPP4 as significantly associated with hippocampal volume. Furthermore, co-expression network-based functional analysis of gene expression data in the hippocampal subfields, CA1 and CA3, from 32 normal controls showed that distinct co-expression modules were mostly enriched in neurogenesis related pathways. Our results suggest that neurogenesis-related pathways may be enriched for hippocampal volume and that hippocampal volume may serve as a potential phenotype for the investigation of human adult neurogenesis.
AB - Adult neurogenesis occurs in the dentate gyrus of the hippocampus during adulthood and contributes to sustaining the hippocampal formation. To investigate whether neurogenesis-related pathways are associated with hippocampal volume, we performed gene-set enrichment analysis using summary statistics from a large-scale genome-wide association study (N = 13,163) of hippocampal volume from the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium and two year hippocampal volume changes from baseline in cognitively normal individuals from Alzheimer’s Disease Neuroimaging Initiative Cohort (ADNI). Gene-set enrichment analysis of hippocampal volume identified 44 significantly enriched biological pathways (FDR corrected p-value < 0.05), of which 38 pathways were related to neurogenesis-related processes including neurogenesis, generation of new neurons, neuronal development, and neuronal migration and differentiation. For genes highly represented in the significantly enriched neurogenesis-related pathways, gene-based association analysis identified TESC, ACVR1, MSRB3, and DPP4 as significantly associated with hippocampal volume. Furthermore, co-expression network-based functional analysis of gene expression data in the hippocampal subfields, CA1 and CA3, from 32 normal controls showed that distinct co-expression modules were mostly enriched in neurogenesis related pathways. Our results suggest that neurogenesis-related pathways may be enriched for hippocampal volume and that hippocampal volume may serve as a potential phenotype for the investigation of human adult neurogenesis.
UR - http://www.scopus.com/inward/record.url?scp=85073100926&partnerID=8YFLogxK
U2 - 10.1038/s41598-019-50507-3
DO - 10.1038/s41598-019-50507-3
M3 - Article
C2 - 31601890
AN - SCOPUS:85073100926
SN - 2045-2322
VL - 9
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 14498
ER -