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

Authors:
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 Karbalai Caroline 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 M B 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

Biol Psychiatry 2015 Apr 25;77(8):749-63. Epub 2014 Nov 25.

Department of Medicine and Neurology, University of Mississippi Medical Center, Jackson, Mississippi.

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.

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Source
http://dx.doi.org/10.1016/j.biopsych.2014.08.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4513651PMC
April 2015
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