Abstract

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.

Details

Title
Genome-wide association analysis of hippocampal volume identifies enrichment of neurogenesis-related pathways
Author
Horgusluoglu-Moloch, Emrin 1 ; Risacher, Shannon L 2 ; Crane, Paul K 3 ; Hibar, Derrek 4 ; Thompson, Paul M 5 ; Saykin, Andrew J 6   VIAFID ORCID Logo  ; Nho, Kwangsik 6 ; Weiner, Michael W 7 ; Aisen, Paul 8 ; Petersen, Ronald 9 ; Jack, Clifford R 10 ; Jagust, William 11 ; Trojanowki, John Q 12 ; Toga, Arthur W 13 ; Beckett, Laurel 14 ; Green, Robert C 15 ; Morris, John 16 ; Shaw, Leslie M 16 ; Kaye, Jeffrey 17 ; Quinn, Joseph 17 ; Silbert, Lisa 17 ; Lind, Betty 17 ; Carter, Raina 17 ; Dolen, Sara 17 ; Schneider, Lon S 13 ; Pawluczyk, Sonia 13 ; Beccera, Mauricio 13 ; Liberty Teodoro 13 ; Spann, Bryan M 13 ; Brewer, James 18 ; Vanderswag, Helen 18 ; Fleisher, Adam 18 ; Heidebrink, Judith L 19 ; Lord, Joanne L 19 ; Mason, Sara S 7 ; Albers, Colleen S 7 ; Knopman, David 7 ; Johnson, Kris 7 ; Doody, Rachelle S 20 ; Villanueva-Meyer, Javier 20 ; Chowdhury, Munir 20 ; Rountree, Susan 20 ; Dang, Mimi 20 ; Stern, Yaakov 21 ; Honig, Lawrence S 21 ; Bell, Karen L 21 ; Ances, Beau 16 ; Morris, John C 16 ; Carroll, Maria 16 ; Creech, Mary L 16 ; Franklin, Erin 16 ; Mintun, Mark A 16 ; Schneider, Stacy 16 ; Oliver, Angela 16 ; Marson, Daniel 22 ; Griffith, Randall 22 ; Clark, David 22 ; Geldmacher, David 22 ; Brockington, John 22 ; Roberson, Erik 22 ; Marissa Natelson Love 22 ; Grossman, Hillel 23 ; Mitsis, Effie 23 ; Shah, Raj C 24 ; deToledo-Morrell, Leyla 24 ; Duara, Ranjan 25 ; Varon, Daniel 25 ; Greig, Maria T 25 ; Roberts, Peggy 25 ; Albert, Marilyn 26 ; Onyike, Chiadi 26 ; Daniel D’Agostino 26 ; Kielb, Stephanie 26 ; Galvin, James E 27 ; Cerbone, Brittany 27 ; Michel, Christina A 27 ; Pogorelec, Dana M 27 ; Rusinek, Henry 27 ; de Leon, Mony J 27 ; Glodzik, Lidia 27 ; De Santi, Susan 27 ; Doraiswamy, P Murali 28 ; Petrella, Jeffrey R 28 ; Borges-Neto, Salvador 28 ; Wong, Terence Z 28 ; Coleman, Edward 28 ; Smith, Charles D 29 ; Jicha, Greg 29 ; Hardy, Peter 29 ; Sinha, Partha 29 ; Oates, Elizabeth 29 ; Conrad, Gary 29 ; Porsteinsson, Anton P 30 ; Goldstein, Bonnie S 30 ; Kim, Martin 30 ; Makino, Kelly M 30 ; M Saleem Ismail 30 ; Brand, Connie 30 ; Mulnard, Ruth A 31 ; Thai, Gaby 31 ; Mc-Adams-Ortiz, Catherine 31 ; Womack, Kyle 32 ; Mathews, Dana 32 ; Quiceno, Mary 32 ; Levey, Allan I 33 ; Lah, James J 33 ; Cellar, Janet S 33 ; Burns, Jeffrey M 34 ; Swerdlow, Russell H 34 ; Brooks, William M 34 ; Apostolova, Liana 35 ; Tingus, Kathleen 36 ; Woo, Ellen 36 ; Silverman, Daniel H S 36 ; Lu, Po H 36 ; Bartzokis, George 36 ; Graff-Radford, Neill R 37 ; Parfitt, Francine 37 ; Kendall, Tracy 37 ; Johnson, Heather 37 ; Farlow, Martin R 35 ; Hake, Ann Marie 35 ; Matthews, Brandy R 35 ; Brosch, Jared R 35 ; Herring, Scott 35 ; Hunt, Cynthia 35 ; van Dyck, Christopher H 38 ; Carson, Richard E 38 ; MacAvoy, Martha G 38 ; Varma, Pradeep 38 ; Chertkow, Howard 39 ; Bergman, Howard 39 ; Hosein, Chris 39 ; Black, Sandra 40 ; Stefanovic, Bojana 40 ; Caldwell, Curtis 40 ; Hsiung, Ging-Yuek Robin 41 ; Feldman, Howard 41 ; Mudge, Benita 41 ; Assaly, Michele 41 ; Finger, Elizabeth 42 ; Pasternack, Stephen 42 ; Rachisky, Irina 42 ; Trost, Dick 42 ; Kertesz, Andrew 42 ; Bernick, Charles 43 ; Munic, Donna 43 ; Mesulam, MarekMarsel 44 ; Lipowski, Kristine 44 ; Weintraub, Sandra 44 ; Bonakdarpour, Borna 44 ; Kerwin, Diana 44 ; Chuang-Kuo, Wu 44 ; Johnson, Nancy 44 ; Sadowsky, Carl 45 ; Villena, Teresa 45 ; Turner, Raymond Scott 46 ; Johnson, Kathleen 46 ; Reynolds, Brigid 46 ; Sperling, Reisa A 47 ; Johnson, Keith A 47 ; Marshall, Gad 47 ; Yesavage, Jerome 48 ; Taylor, Joy L 48 ; Lane, Barton 48 ; Rosen, Allyson 48 ; Tinklenberg, Jared 48 ; Sabbagh, Marwan N 49 ; Belden, Christine M 49 ; Jacobson, Sandra A 49 ; Sirrel, Sherye A 49 ; Kowall, Neil 50 ; Killiany, Ronald 50 ; Budson, Andrew E 50 ; Norbash, Alexander 50 ; Johnson, Patricia Lynn 50 ; Obisesan, Thomas O 51 ; Wolday, Saba 51 ; Allard, Joanne 51 ; Lerner, Alan 52 ; Ogrocki, Paula 52 ; Tatsuoka, Curtis 52 ; Fatica, Parianne 52 ; Fletcher, Evan 53 ; Maillard, Pauline 53 ; Olichney, John 53 ; DeCarli, Charles 53 ; Carmichael, Owen 53 ; Kittur, Smita 54 ; Borrie, Michael 55 ; T-Y, Lee 55 ; Bartha, Rob 55 ; Johnson, Sterling 56 ; Asthana, Sanjay 56 ; Carlsson, Cynthia M 56 ; Potkin, Steven G 57 ; Preda, Adrian 57 ; Nguyen, Dana 57 ; Tariot, Pierre 58 ; Burke, Anna 58 ; Trncic, Nadira 58 ; Reeder, Stephanie 58 ; Bates, Vernice 59 ; Capote, Horacio 59 ; Rainka, Michelle 59 ; Scharre, Douglas W 60 ; Kataki, Maria 60 ; Adeli, Anahita 60 ; Zimmerman, Earl A 61 ; Celmins, Dzintra 61 ; Brown, Alice D 61 ; Pearlson, Godfrey D 62 ; Blank, Karen 62 ; Anderson, Karen 62 ; Flashman, Laura A 63 ; Seltzer, Marc 63 ; Hynes, Mary L 63 ; Santulli, Robert B 63 ; Sink, Kaycee M 64 ; Gordineer, Leslie 64 ; Williamson, Jeff D 64 ; Garg, Pradeep 64 ; Watkins, Franklin 64 ; Ott, Brian R 65 ; Querfurth, Henry 65 ; Tremont, Geoffrey 65 ; Salloway, Stephen 66 ; Malloy, Paul 66 ; Correia, Stephen 66 ; Rosen, Howard J 67 ; Miller, Bruce L 67 ; Perry, David 67 ; Mintzer, Jacobo 68 ; Spicer, Kenneth 68 ; Bachman, David 68 ; Pomara, Nunzio 69 ; Hernando, Raymundo 69 ; Sarrael, Antero 69 ; Relkin, Norman 70 ; Chaing, Gloria 70 ; Lin, Michael 70 ; Ravdin, Lisa 70 ; Smith, Amanda 71 ; Balebail, Ashok Raj 71 ; Fargher, Kristin 71 

1  Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Genetics and Genomic Sciences, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA 
2  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 
3  Department of Medicine, University of Washington, School of Medicine, Seattle, WA, USA 
4  Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, USC Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Neuroscience Biomarkers, Janssen Research and Development, LLC, San Diego, CA, USA 
5  Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, USC Keck School of Medicine, University of Southern California, Los Angeles, CA, USA 
6  Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA; 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 
7  Magnetic Resonance Unit at the VA Medical Center and Radiology, Medicine, Psychiatry and Neurology, University of California, San Francisco, USA 
8  San Diego School of Medicine, University of California, California, USA 
9  Mayo Clinic, Minnesota, USA; Mayo Clinic, Rochester, USA 
10  Mayo Clinic, Rochester, USA 
11  University of California, Berkeley, USA 
12  University of Pennsylvania, Pennsylvania, USA 
13  University of Southern California, California, USA 
14  University of California, Davis, California, USA 
15  MPH Brigham and Women’s Hospital/Harvard Medical School, Massachusetts, USA 
16  Washington University St. Louis, Missouri, USA 
17  Oregon Health and Science University, Oregon, USA 
18  University of California–San Diego, California, USA 
19  University of Michigan, Michigan, USA 
20  Baylor College of Medicine, Houston, State of Texas, USA 
21  Columbia University Medical Center, South Carolina, USA 
22  University of Alabama –, Birmingham, Alabama, USA 
23  Mount Sinai School of Medicine, New York, USA 
24  Rush University Medical Center, Rush University, Illinois, USA 
25  Wien Center, Florida, USA 
26  Johns Hopkins University, Maryland, USA 
27  New York University, New York, NY, USA 
28  Duke University Medical Center, North Carolina, USA 
29  University of Kentucky, Kentucky, USA 
30  University of Rochester Medical Center, New York, NY, USA 
31  University of California, Irvine, California, USA 
32  University of Texas Southwestern Medical School, Texas, USA 
33  Emory University, Georgia, USA 
34  University of Kansas, Medical Center, Kansas, USA 
35  Indiana University, Indiana, USA 
36  University of California, Los Angeles, California, USA 
37  Mayo Clinic, Jacksonville, USA 
38  Yale University School of Medicine, Connecticut, USA 
39  McGill University, Montreal-Jewish General Hospital, Montreal, Canada 
40  Sunnybrook Health Sciences, Ontario, USA 
41  U.B.C. Clinic for AD & Related Disorders, Vancouver, Canada 
42  Cognitive Neurology - St. Joseph’s, Ontario, USA 
43  Cleveland Clinic Lou Ruvo Center for Brain Health, Ohio, USA 
44  Northwestern University, Evanston, USA 
45  Premiere Research Inst (Palm Beach Neurology), West Palm Beach, USA 
46  Georgetown University Medical Center, Washington D.C, USA 
47  Brigham and Women’s Hospital, Massachusetts, USA 
48  Stanford University, California, USA 
49  Banner Sun Health Research Institute, Sun City, USA 
50  Boston University, Massachusetts, USA 
51  Howard University, Washington D.C, USA 
52  Case Western Reserve University, Ohio, USA 
53  University of California, Davis – Sacramento, California, USA 
54  Neurological Care of CNY, New York, USA 
55  Parkwood Hospital, Pennsylvania, USA 
56  University of Wisconsin, Wisconsin, USA 
57  University of California, Irvine, BIC, USA 
58  Banner Alzheimer’s Institute, Phoenix, USA 
59  Dent Neurologic Institute, New York, NY, USA 
60  Ohio State University, Ohio, USA 
61  Albany Medical College, New York, NY, USA 
62  Hartford Hospital, Olin Neuropsychiatry Research Center, Connecticut, USA 
63  Dartmouth-Hitchcock Medical Center, New Hampshire, USA 
64  Wake Forest University Health Sciences, North Carolina, USA 
65  Rhode Island Hospital, state of Rhode Island, Providence, USA 
66  Butler Hospital, Providence, Rhode Island, USA 
67  University of California, San Francisco, USA 
68  Medical University South Carolina, Charleston, USA 
69  Nathan Kline Institute, Orangeburg, New York, USA 
70  Cornell University, Ithaca, New York, USA 
71  USF Health Byrd Alzheimer’s Institute, University of South Florida, Tampa, USA 
Pages
1-12
Publication year
2019
Publication date
Oct 2019
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41598-019-50507-3
ProQuest document ID
2303727076
Copyright
© 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.