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Genome-wide Studies of Verbal Declarative Memory in Nondemented Older People: The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium

Biol Psychiatry. 2014 Nov 25. pii: S0006-3223(14)00892-0. doi: 10.1016/j.biopsych.2014.08.027. [Epub ahead of print]

Authors/Editors: Debette S, Ibrahim Verbaas CA, Bressler J, Schuur M, Smith A, Bis JC, Davies G, Wolf C, Gudnason V, Chibnik LB, Yang Q, deStefano AL, de Quervain DJ, Srikanth V, Lahti J, Grabe HJ, Smith JA, Priebe L, Yu L, Karbalai N, Hayward C, Wilson JF, Campbell H, Petrovic K, Fornage M, Chauhan G, Yeo R, Boxall R, Becker J, Stegle O, Mather KA, Chouraki V, Sun Q, Rose LM, Resnick S, Oldmeadow C, Kirin M, Wright AF, Jonsdottir MK Au R, Becker A, Amin N, Nalls MA, Turner ST, Kardia SL, Oostra B, Windham G, Coker LH, Zhao W, Knopman DS, Heiss G, Griswold ME, Gottesman RF, Vitart V, Hastie ND, Zgaga L, Rudan I, Polasek O, Holliday EG, Schofield P, Choi SH, Tanaka T, An Y, Perry RT, Kennedy RE, Sale MM, Wang J, Wadley VG, Liewald DC, Ridker PM, Gow AJ, Pattie A, Starr JM, Porteous D, Liu X, Thomson R, Armstrong NJ, Eiriksdottir G, Assareh AA, Kochan NA, Widen E, Palotie A, Hsieh YC, Eriksson JG, Vogler C, van Swieten JC, Shulman JM, Beiser A, Rotter J, Schmidt CO, Hoffmann W, Nöthen MM, Ferrucci L, Attia J, Uitterlinden AG, Amouyel P, Dartigues JF, Amieva H, Räikkönen K, Garcia M, Wolf PA, Hofman A, Longstreth WT Jr, Psaty BM, Boerwinkle E, DeJager PL, Sachdev PS, Schmidt R, Breteler MM, Teumer A, Lopez OL, Cichon S, Chasman DI, Grodstein F, Müller-Myhsok B, Tzourio C, Papassotiropoulos A, Bennett DA, Ikram AM, Deary IJ, van Duijn CM, Launer L, Fitzpatrick AL, Seshadri S, Mosley TH Jr; Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium.
Publication Date: 2014

Abstract

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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