Debette, S and Ibrahim Verbaas, CA and Bressler, J and Schuur, M and Smith, A and Bis, JC and Davies, G and Wolf, C and Gudnason, V and Chibnik, LB and Yang, Q and deStefano, AL and de Quervain, DJ and Srikanth, V and Lahti, J and Grabe, HJ and Smith, JA and Priebe, L and Yu, L and Karbalai, N and Hayward, C and Wilson, JF and Campbell, H and Petrovic, K and Fornage, M and Chauhan, G and Yeo, R and Boxall, R and Becker, J and Stegle, O and Mather, KA and Chouraki, V and Sun, Q and Rose, LM and Resnick, S and Oldmeadow, C and Kirin, M and Wright, AF and Jonsdottir, MK and Au, R and Becker, A and Amin, N and Nalls, MA and Turner, ST and Kardia, SL and Oostra, B and Windham, G and Coker, LH and Zhao, W and Knopman, DS and Heiss, G and Griswold, ME and Gottesman, RF and Vitart, V and Hastie, ND and Zgaga, L and Rudan, I and Polasek, O and Holliday, EG and Schofield, P and Choi, SH and Tanaka, T and An, Y and Perry, RT and Kennedy, RE and Sale, MM and Wang, J and Wadley, VG and Liewald, DC and Ridker, PM and Gow, AJ and Pattie, A and Starr, JM and Porteous, D and Liu, X and Thomson, R and Armstrong, NJ and Eiriksdottir, G and Assareh, AA and Kochan, NA and Widen, E and Palotie, A and Hsieh, YC and Eriksson, JG and Vogler, C and van Swieten, JC and Shulman, JM and Beiser, A and Rotter, J and Schmidt, CO and Hoffmann, W and Nothen, MM and Ferrucci, L and Attia, J and Uitterlinden, AG and Amouyel, P and Dartigues, JF and Amieva, H and Raikkonen, K and Garcia, M and Wolf, PA and Hofman, A and Longstreth Jr, WT and Psaty, BM and Boerwinkle, E and DeJager, PL and Sachdev, PS and Schmidt, R and Breteler, MM and Teumer, A and Lopez, OL and Cichon, S and Chasman, DI and Grodstein, F and Muller-Myhsok, B and Tzourio, C and Papassotiropoulos, A and Bennett, DA and Ikram, AM and Deary, IJ and van Duijn, CM and Launer, L and Fitzpatrick, AL and Seshadri, S and Mosley Jr, TH, Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium, Genome-wide Studies of Verbal Declarative Memory in Nondemented Older People: The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium, Biological Psychiatry: A Journal of Psychiatric Research, 77, (8) pp. 749-763. ISSN 0006-3223 (2015) [Refereed Article]
Copyright 2014 Society of Biological Psychiatry
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.
|Item Type:||Refereed Article|
|Keywords:||Alzheimer disease; Dementia; Epidemiology; Genetics; Population-based; Verbal declarative memory|
|Research Division:||Medical and Health Sciences|
|Research Group:||Public Health and Health Services|
|Objective Group:||Specific Population Health (excl. Indigenous Health)|
|Objective Field:||Health Related to Ageing|
|UTAS Author:||Srikanth, V (Dr Velandai Srikanth)|
|UTAS Author:||Thomson, R (Dr Russell Thomson)|
|Year Published:||2015 (online first 2014)|
|Web of Science® Times Cited:||26|
|Deposited By:||Menzies Institute for Medical Research|
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