Genome-wide studies of verbal declarative memory in nondemented older people: The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium

Stéphanie Debette*, Carla A. Ibrahim Verbaas, Jan Bressler, Maaike Schuur, Albert Smith, Joshua C. Bis, Gail Davies, Christiane Wolf, Vilmundur Gudnason, Lori B. Chibnik, Qiong Yang, Anita L. DeStefano, Dominique J.F. De Quervain, Velandai Srikanth, Jari Lahti, Hans J. Grabe, Jennifer A. Smith, Lutz Priebe, Lei Yu, Nazanin KarbalaiCaroline Hayward, James F. Wilson, Harry Campbell, Katja Petrovic, Myriam Fornage, Ganesh Chauhan, Robin Yeo, Ruth Boxall, James Becker, Oliver Stegle, Karen A. Mather, Vincent Chouraki, Qi Sun, Lynda M. Rose, Susan Resnick, Christopher Oldmeadow, Mirna Kirin, Alan F. Wright, Maria K. Jonsdottir, Rhoda Au, Albert Becker, Najaf Amin, Mike A. Nalls, Stephen T. Turner, Sharon L.R. Kardia, Ben Oostra, Gwen Windham, Laura H. Coker, Wei Zhao, David S. Knopman, Gerardo Heiss, Michael E. Griswold, Rebecca F. Gottesman, Veronique Vitart, Nicholas D. Hastie, Lina Zgaga, Igor Rudan, Ozren Polasek, Elizabeth G. Holliday, Peter Schofield, Seung Hoan Choi, Toshiko Tanaka, Yang An, Rodney T. Perry, Richard E. Kennedy, Michèle M. Sale, Jing Wang, Virginia G. Wadley, David C. Liewald, Paul M. Ridker, Alan J. Gow, Alison Pattie, John M. Starr, David Porteous, Xuan Liu, Russell Thomson, Nicola J. Armstrong, Gudny Eiriksdottir, Arezoo A. Assareh, Nicole A. Kochan, Elisabeth Widen, Aarno Palotie, Yi Chen Hsieh, Johan G. Eriksson, Christian Vogler, John C. Van Swieten, Joshua M. Shulman, Alexa Beiser, Jerome Rotter, Carsten O. Schmidt, Wolfgang Hoffmann, Markus M. Nöthen, Luigi Ferrucci, John Attia, Andre G. Uitterlinden, Philippe Amouyel, Jean François Dartigues, Hélène Amieva, Katri Räikkönen, Melissa Garcia, Philip A. Wolf, Albert Hofman, W. T. Longstreth, Bruce M. Psaty, Eric Boerwinkle, Philip L. DeJager, Perminder S. Sachdev, Reinhold Schmidt, Monique Breteler, Alexander Teumer, Oscar L. Lopez, Sven Cichon, Daniel I. Chasman, Francine Grodstein, Bertram Müller-Myhsok, Christophe Tzourio, Andreas Papassotiropoulos, David A. Bennett, M. Arfan Ikram, Ian J. Deary, Cornelia M. Van Duijn, Lenore Launer, Annette L. Fitzpatrick, Sudha Seshadri, Thomas H. Mosley, Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium

*Corresponding author for this work

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60 Citations (Scopus)


BACKGROUND: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting. METHODS: We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10-6) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults. RESULTS: rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10-10) and replication cohorts (p = 5.65 × 10-8). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10-8, and rs6813517 [SPOCK3], p = 2.58 × 10-8) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism. CONCLUSIONS: This largest study to date exploring the genetics of memory function in ∼40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.

Original languageEnglish
Pages (from-to)749-763
Number of pages15
JournalBiological Psychiatry
Issue number8
Publication statusPublished - 15 Apr 2015
Externally publishedYes


  • Alzheimer disease
  • Dementia
  • Epidemiology
  • Genetics
  • Population-based
  • Verbal declarative memory


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