Genome-wide association analysis of hippocampal volume identifies enrichment of neurogenesis-related pathways


Emrin Horgusluoglu-Moloch, Indiana University School of Medicine
Shannon L. Risacher, Indiana University School of Medicine
Paul K. Crane, University of Washington, Seattle
Derrek Hibar, Keck School of Medicine of USC
Paul M. Thompson, Keck School of Medicine of USC
Andrew J. Saykin, Indiana University School of Medicine
Kwangsik Nho, Indiana University School of Medicine
Michael W. Weiner, University of California, San Francisco
Paul Aisen, UC San Diego School of Medicine
Ronald Petersen, Mayo Clinic
Clifford R. Jack, Mayo Clinic
William Jagust, University of California, Berkeley
John Q. Trojanowki, University of Pennsylvania
Arthur W. Toga, University of Southern California
Laurel Beckett, University of California, Davis
Robert C. Green, Harvard Medical School
John Morris, Washington University in St. Louis
Leslie M. Shaw, Washington University in St. Louis
Jeffrey Kaye, Oregon Health & Science University
Joseph Quinn, Oregon Health & Science University
Lisa Silbert, Oregon Health & Science University
Betty Lind, Oregon Health & Science University
Raina Carter, Oregon Health & Science University
Sara Dolen, Oregon Health & Science University
Lon S. Schneider, University of Southern California
Sonia Pawluczyk, University of Southern California
Mauricio Beccera, University of Southern California
Liberty Teodoro, University of Southern California
Bryan M. Spann, University of Southern California
James Brewer, University of California, San Diego
Helen Vanderswag, University of California, San Diego
Adam Fleisher, University of California, San Diego

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Scientific Reports





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© 2019, The Author(s). 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.

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