Journal
BIOLOGICAL PSYCHIATRY
Volume 77, Issue 8, Pages 749-763Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2014.08.027
Keywords
Alzheimer disease; Dementia; Epidemiology; Genetics; Population-based; Verbal declarative memory
Categories
Funding
- National Institute on Aging [N01-AG-12100, AG08122, AG16495, AG033193, AG031287]
- National Heart, Lung and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL70825, R01HL087641, R01HL59367, R01HL086694, HHSN268201200036C, HHSN268200800007C]
- National Human Genome Research Institute [U01HG004402]
- National Institutes of Health [HHSN268200625226C, CA87969, CA49449, HL34594, U01HG004399, DK058845, CA65725, CA67262, CA50385, 5UO1CA098233, EY09611, EY015473, HG004728, HL35464, CA55075, CA134958, DK070756]
- National Institutes of Health and National Institutes of Health Roadmap for Medical Research [UL1RR025005]
- National Institute of Neurological Disorders and Stroke
- NIA [R01AG023629, R01AG20098, R01AG05133]
- National Center for Advancing Translational Sciences, Clinical and Translational Sciences Institute Grant [UL1TR000124]
- National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center Grant [DK063491]
- Medical Research Council (United Kingdom)
- European Commission Framework 6 project EUROSPAN [LSHG-CT-2006-018947]
- Republic of Croatia Ministry of Science, Education and Sports research Grants [108-1080315-0302]
- Netherlands Organization for Scientific Research
- Internationale Stichting Alzheimer Onderzoek
- Hersenstichting Nederland
- Centre for Medical Systems Biology
- National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195]
- Affymetrix, Inc. [N02-HL-6-4278]
- Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine
- Boston Medical Center
- National Institute of Neurological Disorders and Stroke [NS17950]
- National Institute of Neurological Disorders and Stroke of the National Institutes of Health [NS041558]
- Academy of Finland
- Finnish Diabetes Research Society
- Folkhalsan Research Foundation
- Novo Nordisk Foundation
- Finska Lakaresallskapet
- Signe and Ane Gyllenberg Foundation
- University of Helsinki
- Ministry of Education
- Ahokas Foundation
- Emil Aaltonen Foundation
- Juho Vainio Foundation
- Wellcome Trust [WT089062]
- Biotechnology and Biological Sciences Research Council
- Royal Society
- Chief Scientist Office of the Scottish Government
- Research Into Ageing (continues as part of Age United Kingdom The Disconnected Mind project)
- United Kingdom Biotechnology and Biological Sciences Research Council
- Engineering and Physical Sciences Research Council
- Economic and Social Research Council
- Medical Research Council
- Medical Research Council Human Genetics Unit
- Arthritis Research United Kingdom
- European Union framework program 6 EUROSPAN project [LSHG-CT-2006-018947]
- Netherlands Organisation of Scientific Research Investments [175.010.2005.011, 911-03-012]
- Research Institute for Diseases in the Elderly [014-93-015, RIDE2]
- Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research project [050-060-810]
- National Institute on Aging Grants [P30AG10161, R01AG15819, R01AG17917, R01AG30146, K08AG34290, K25AG41906]
- Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012]
- Ministry of Cultural Affairs
- Social Ministry of the Federal State of Mecklenburg-West Pomerania
- Siemens Healthcare
- Erlangen, Germany
- Federal State of Mecklenburg-West Pomerania
- German Research Foundation (DFG) [GR 1912/5-1]
- National Health and Medical Research Council (NHMRC) [403000, 491109, 606543]
- Wicking Dementia Education and Research Centre, Hobart
- National Health and Medical Research Council/National Heart Foundation Career Development Fellowship [606544]
- National Health and Medical Research Council Principal Research Fellowship
- Intramural Research Program of the National Institutes of Health, National Institute on Aging
- University of Newcastle's Strategic Initiative Fund
- Vincent Fairfax Family Foundation
- Hunter Medical Research Institute
- National Institutes of Health
- Merck Research Laboratories
- National Heart, Lung, and Blood Institute [K99HL098459, HL043851, HL080467]
- National Institute of Neurological Disorders and Stroke, National Institutes of Health, Department of Health and Human Services [U01 NS041588]
- National Health & Medical Research Council Grant [401184]
- Australian National Health & Medical Research Council Program Grant [350833]
- Capacity Building Grant [568940]
- Australian Government-funded Dementia Collaborative Research Centre at the University of New South Wales
- National Health & Medical Research Council Project Grant [525453]
- Fondation pour la Recherche Medicale
- Caisse Nationale Maladie des Travailleurs Salaries Direction Generale de la Sante
- Mutuelle Generale de l'Education Nationale
- Institut de la Longevite
- Conseils Regionaux of Aquitaine and Bourgogne
- Fondation de France
- Ministry of Research-Institut National de la Sante et de la Recherche Medicale Programme Cohortes et collections de donnees biologiques
- Eisai
- National Foundation for Alzheimer's Disease and Related Disorders
- Institut Pasteur de Lille
- Centre National de Genotypage
- French national research agency (Agence Nationale de la Recherche)
- National Cancer Institute [CA047988]
- Donald W. Reynolds Foundation
- Fondation Leducq
- Amgen
- Swiss National Science Foundation [CRSI33_130080]
- German Federal Ministry of Education and Research
- National Heart, Lung and Blood Institute grant [N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, HL054464, HL054457, HL054481, HL071917, HL87660]
- [R01 DK084350]
- BBSRC [BB/F019394/1] Funding Source: UKRI
- MRC [G0700704, MC_PC_U127561128] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [S18386, BB/F019394/1] Funding Source: researchfish
- Medical Research Council [MC_PC_U127561128, MR/K026992/1, G0700704, G0700704B] Funding Source: researchfish
- Chief Scientist Office [ETM/55, CZB/4/505, CZB/4/710] Funding Source: researchfish
- DIVISION OF EPIDEMIOLOGY AND CLINICAL APPLICATIONS [N01HC085081, N01HC085082, N01HC025195, N01HC085083, N01HC085080, N01HC085079, N01HC085086, N01HC055222] Funding Source: NIH RePORTER
- NATIONAL CANCER INSTITUTE [UM1CA182913, P01CA087969, R01CA065725, U01CA049449, R01CA134958, P01CA055075, R01CA049449, R01CA067262, U01CA098233, R01CA050385, U01CA067262, R01CA047988] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [UL1TR000135, UL1TR000124] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [UL1RR025005] Funding Source: NIH RePORTER
- NATIONAL EYE INSTITUTE [R01EY015473, R01EY009611] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL086694, R01HL085083, R01HL087660, R01HL059367, R01HL043851, U01HL054464, R01HL034594, R01HL120393, U10HL054457, U10HL054464, R01HL087652, U01HL080295, R01HL103612, R01HL070825, R01HL087641, R01HL071917, R01HL080467, K99HL098459, R01HL035464, R01HL105756, R01HL064278, U01HL054457, U01HL096917, U10HL054481, U01HL054481] Funding Source: NIH RePORTER
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [U01HG004402, U01HG004728, U01HG004399] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK058845, P01DK070756, R01DK084350, P30DK063491] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS041558, R01NS017950, U01NS041588] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [U01AG049505, K25AG041906, ZIAAG007270, R01AG017917, R01AG033193, R01AG031287, R01AG023629, P50AG005133, R01AG008122, R01AG015819, N01AG012100, R01AG020098, RF1AG015819, R01AG016495, P30AG010161, ZIAAG000965, ZIAAG007380, K08AG034290, R01AG030146] Funding Source: NIH RePORTER
Ask authors/readers for more resources
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 x 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 = 55.7 x 10(-10)) and replication cohorts (p = 5.65 x 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 x 10(-8), and rs6813517 [SPOCK3], p = 2.58 x 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 similar to 40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.
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