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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 749-763 |
| Number of pages | 15 |
| Journal | Biological psychiatry |
| Volume | 77 |
| Issue number | 8 |
| DOIs | |
| State | Published - 2015 |
Keywords
- Alzheimer disease
- Dementia
- Epidemiology
- Genetics
- Population-based
- Verbal declarative memory
ASJC Scopus subject areas
- Biological Psychiatry
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In: Biological psychiatry, Vol. 77, No. 8, 2015, p. 749-763.
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}
TY - JOUR
T1 - Genome-wide studies of verbal declarative memory in nondemented older people
T2 - The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium
AU - Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium
AU - Debette, Stéphanie
AU - Ibrahim Verbaas, Carla A.
AU - Bressler, Jan
AU - Schuur, Maaike
AU - Smith, Albert
AU - Bis, Joshua C.
AU - Davies, Gail
AU - Wolf, Christiane
AU - Gudnason, Vilmundur
AU - Chibnik, Lori B.
AU - Yang, Qiong
AU - DeStefano, Anita L.
AU - De Quervain, Dominique J.F.
AU - Srikanth, Velandai
AU - Lahti, Jari
AU - Grabe, Hans J.
AU - Smith, Jennifer A.
AU - Priebe, Lutz
AU - Yu, Lei
AU - Karbalai, Nazanin
AU - Hayward, Caroline
AU - Wilson, James F.
AU - Campbell, Harry
AU - Petrovic, Katja
AU - Fornage, Myriam
AU - Chauhan, Ganesh
AU - Yeo, Robin
AU - Boxall, Ruth
AU - Becker, James
AU - Stegle, Oliver
AU - Mather, Karen A.
AU - Chouraki, Vincent
AU - Sun, Qi
AU - Rose, Lynda M.
AU - Resnick, Susan
AU - Oldmeadow, Christopher
AU - Kirin, Mirna
AU - Wright, Alan F.
AU - Jonsdottir, Maria K.
AU - Au, Rhoda
AU - Becker, Albert
AU - Amin, Najaf
AU - Nalls, Mike A.
AU - Turner, Stephen T.
AU - Kardia, Sharon L.R.
AU - Oostra, Ben
AU - Windham, Gwen
AU - Coker, Laura H.
AU - Zhao, Wei
AU - Knopman, David S.
N1 - Funding Information: Hunter Community Study: We thank the men and women participating in the Hunter Community Study as well as all the staff, investigators, and collaborators who have supported or been involved in the project to date. The cohort was made possible with support from the University of Newcastle׳s Strategic Initiative Fund, the Vincent Fairfax Family Foundation, and the Hunter Medical Research Institute. Funding Information: Croatian Cohorts–Split and Korčula: The CROATIA-Korčula and CROATIA-Split studies were funded by Grants from the Medical Research Council (United Kingdom), European Commission Framework 6 project EUROSPAN (Contract No. LSHG-CT-2006-018947), and Republic of Croatia Ministry of Science, Education and Sports research Grants to IR (108-1080315-0302). We acknowledge the invaluable contributions of the recruitment teams in Korčula and Split, the administrative teams in Croatia and Edinburgh, and the people of Korčula and Split. The single nucleotide polymorphism genotyping for the CROATIA-Korčula cohort was performed in Helmholtz Zentrum München, Neuherberg, Germany. The single nucleotide polymorphism genotyping for the CROATIA-Split cohort was performed by AROS Applied Biotechnology, Aarhus, Denmark. Funding Information: Baltimore Longitudinal Study of Aging: The Baltimore Longitudinal Study of Aging is supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. Funding Information: Genetic Epidemiology Network of Arteriopathy: Support for the Genetic Epidemiology Network of Arteriopathy was provided by the National Heart, Lung and Blood Institute (HL054464, HL054457, HL054481, HL071917, and HL87660) and the National Institute of Neurological Disorders and Stroke (NS041558) of the National Institutes of Health. Genotyping was performed at the Mayo Clinic (STT, Mariza de Andrade, Julie Cunningham) and was made possible by the University of Texas Health Sciences Center (EB, Megan L. Grove-Gaona). We also thank the families that participated in the Genetic Epidemiology Network of Arteriopathy study. Funding Information: The Rotterdam Study: The generation and management of genome-wide association study genotype data for the Rotterdam Study is supported by the Netherlands Organisation of Scientific Research Investments (nr. 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research project nr. 050-060-810. We thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera, and Marjolein Peters for their help in creating the genome-wide association study database and Karol Estrada and Maksim V. Struchalin for their support in creation and analysis of imputed data. Funding Information: Aging Gene-Environment Susceptibility-Reykjavik Study: The research has been funded by National Institute on Aging contract N01-AG-12100 with contributions from National Eye Institute, National Institute on Deafness and Other Communication Disorders, and National Heart, Lung and Blood Institute; the National Institute on Aging Intramural Research Program; Hjartavernd (the Icelandic Heart Association); and the Althingi (the Icelandic Parliament). Funding Information: Lothian Birth Cohort 1921 and Lothian Birth Cohort 1936: We thank the cohort participants and team members who contributed to these studies. Phenotype collection in the Lothian Birth Cohort 1921 was supported by the Biotechnology and Biological Sciences Research Council, The Royal Society, and The Chief Scientist Office of the Scottish Government. Phenotype collection in the Lothian Birth Cohort 1936 was supported by Research Into Ageing (continues as part of Age United Kingdom The Disconnected Mind project). Genotyping of the cohorts was funded by the United Kingdom Biotechnology and Biological Sciences Research Council. The work was undertaken by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (G0700704/84698). Funding from the Biotechnology and Biological Sciences Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, and Medical Research Council is gratefully acknowledged. Funding Information: The Cardiovascular Health Study: This Cardiovascular Health Study research was supported by National Heart, Lung and Blood Institute contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086 and National Heart, Lung and Blood Institute Grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided through R01AG023629, R01AG20098 and R01AG05133 NIA. A full list of principal Cardiovascular Health Study investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported, in part, by the National Center for Advancing Translational Sciences, Clinical and Translational Sciences Institute Grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center Grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding Information: The Religious Order Study and Rush Memory and Aging Project: The Religious Order Study and Rush Memory and Aging Project Study are supported in part by National Institute on Aging Grants P30AG10161, R01AG15819, R01AG17917, R01AG30146, K08AG34290, and K25AG41906. Funding Information: The Tasmanian Study of Gait and Cognition is supported by Project Grants from the National Health and Medical Research Council (NHMRC IDs 403000, 491109, 606543) and a Grant from the Wicking Dementia Education and Research Centre, Hobart. Velandai Srikanth is supported by a National Health and Medical Research Council/National Heart Foundation Career Development Fellowship (ID 606544). Matthew Brown is supported by a National Health and Medical Research Council Principal Research Fellowship. Funding Information: The Atherosclerosis Risk in Communities Study: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL70825, R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. We thank the staff and participants of the Atherosclerosis Risk in Communities Study for their important contributions. Infrastructure was partly supported by Grant number UL1RR025005, a component of the National Institutes of Health and National Institutes of Health Roadmap for Medical Research. Funding Information: Sydney Memory and Ageing Study: We acknowledge and thank the Sydney Memory and Ageing Study participants and the Sydney Memory and Ageing Study Research Team. DNA was extracted by Genetic Repositories Australia, an Enabling Facility, supported by National Health & Medical Research Council Grant 401184. Preparation of the DNA samples was undertaken in the laboratory of Peter Schofield and John Kwok, Neuroscience Research Australia. Genome-wide genotyping was performed by the Ramaciotti Centre, University of New South Wales. The Sydney Memory and Ageing Study is supported by Australian National Health & Medical Research Council Program Grant 350833 and Capacity Building Grant 568940. Henry Brodaty is supported by the Australian Government-funded Dementia Collaborative Research Centre at the University of New South Wales. Nicola Armstrong is supported by the National Health & Medical Research Council Project Grant 525453. Funding Information: Erasmus Rucphen Family Study: This study is financially supported by the Netherlands Organization for Scientific Research, the Internationale Stichting Alzheimer Onderzoek, the Hersenstichting Nederland, and the Centre for Medical Systems Biology ( ⁎ 1 and 2 ⁎ ) in the framework of the Netherlands Genomics Initiative. We thank the participants from the Genetic Research in Isolated Populations, Erasmus Rucphen Family, who made this work possible. Funding Information: REasons for Geographic and Racial Differences in Stroke: This research project is supported by a cooperative agreement U01 NS041588 (G. Howard, Principal Investigator) from the National Institute of Neurological Disorders and Stroke, National Institutes of Health, Department of Health and Human Services. Genotyping was performed under Grant R01 DK084350 (Michele Sale, Principal Investigator). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke, the National Institute of Diabetes and Digestive and Kidney Diseases, or the National Institutes of Health. Representatives of the funding agency have been involved in the review of the manuscript but not directly involved in the collection, management, analysis, or interpretation of the data. We thank the other investigators, the staff, and the participants of the REasons for Geographic and Racial Differences in Stroke study for their valuable contributions. A full list of participating REasons for Geographic and Racial Differences in Stroke investigators and institutions can be found at http://www.regardsstudy.org. Funding Information: Women’s Genome Health Study: The Women’s Genome Health Study is supported by HL043851 and HL080467 from the National Heart, Lung, and Blood Institute and CA047988 from the National Cancer Institute, the Donald W. Reynolds Foundation, and the Fondation Leducq, with collaborative scientific support and funding for genotyping provided by Amgen. Funding Information: Nurses’ Health Study: This study was supported by research Grants CA87969, CA49449, HL34594, U01HG004399, DK058845, CA65725, CA67262, CA50385, 5UO1CA098233, EY09611, EY015473, HG004728, HL35464, CA55075, CA134958, and DK070756 from the National Institutes of Health. The genotyping was partly supported by an unrestricted Grant from Merck Research Laboratories. Dr. Sun is supported by a career development award K99HL098459 from the National Heart, Lung, and Blood Institute. Funding Information: Swiss Memory Genetics Study: This work was funded by the Swiss National Science Foundation (Sinergia grant CRSI33_130080 to DQ and AP). Funding Information: Orkney Complex Disease Study: Orkney Complex Disease Study was supported by the Chief Scientist Office of the Scottish Government, the Royal Society, the Medical Research Council Human Genetics Unit, Arthritis Research United Kingdom, and the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). DNA extractions were performed at the Wellcome Trust Clinical Research Facility in Edinburgh. We acknowledge the invaluable contributions of Lorraine Anderson and the research nurses in Orkney, the administrative team in Edinburgh, and the people of Orkney. Funding Information: Framingham Heart Study: From the Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine. This work was supported by the National Heart, Lung and Blood Institute’s Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (Contract No. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the Single Nucleotide Polymorphism Health Association Resource project. This study was also supported by Grants from the National Institute of Neurological Disorders and Stroke (NS17950) and the National Institute on Aging (AG08122, AG16495, AG033193, AG031287). Funding Information: Study of Health in Pomerania: Study of Health in Pomerania is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (Grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs, and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data have been supported by the Federal Ministry of Education and Research (Grant no. 03ZIK012) and a joint Grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. The University of Greifswald is a member of the Center of Knowledge Interchange program of the Siemens AG. This work was also funded by the German Research Foundation (DFG: GR 1912/5-1). Funding Information: The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly; the Ministry of Education, Culture and Science; the Ministry for Health, Welfare and Sports; the European Commission (DG XII), and the Municipality of Rotterdam. The Rotterdam Scan Study is supported by the Netherlands Organization of Scientific Research project nrs. 918-46-615, 904-61-096, 904-61-133, 948-00-010, and 916-13-054 (ZonMW) and International Parkinson Fonds. Dr. Ikram was supported by a ZonMW Veni Grant: 916.13.054. We are grateful to the study participants, the staff from the Rotterdam Study, and the participating general practitioners and pharmacists. Funding Information: Three City Study: We thank the staff and the participants of the Three City Study for their important contributions. The Three City Study is conducted under a partnership agreement between the Institut National de la Santé et de la Recherche Médicale, the Victor Segalen–Bordeaux II University, and Sanofi-Aventis. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The Three City Study is also supported by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, Mutuelle Générale de l’Education Nationale, Institut de la Longévité, Conseils Régionaux of Aquitaine and Bourgogne, Fondation de France, and Ministry of Research–Institut National de la Santé et de la Recherche Médicale Programme “Cohortes et collections de données biologiques.” Lille Génopole received an unconditional Grant from Eisai. We thank A. Boland (Centre National de Génotypage) for her technical help in preparing the DNA samples for analyses. This work was supported by the National Foundation for Alzheimer’s Disease and Related Disorders, the Institut Pasteur de Lille, and the Centre National de Génotypage. Stéphanie Debette is a recipient of a Chaire d’Excellence Grant from the French national research agency (Agence Nationale de la Recherche). Funding Information: Helsinki Birth Cohort Study: We thank all study participants as well as everybody involved in the Helsinki Birth Cohort Study. The Helsinki Birth Cohort Study has been supported by Grants from the Academy of Finland, the Finnish Diabetes Research Society, Folkhälsan Research Foundation, Novo Nordisk Foundation, Finska Läkaresällskapet, Signe and Ane Gyllenberg Foundation, University of Helsinki, Ministry of Education, Ahokas Foundation, Emil Aaltonen Foundation, Juho Vainio Foundation, and Wellcome Trust (Grant number WT089062). Publisher Copyright: © 2015 Society of Biological Psychiatry.
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
KW - Alzheimer disease
KW - Dementia
KW - Epidemiology
KW - Genetics
KW - Population-based
KW - Verbal declarative memory
UR - http://www.scopus.com/inward/record.url?scp=84928119304&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84928119304&partnerID=8YFLogxK
U2 - 10.1016/j.biopsych.2014.08.027
DO - 10.1016/j.biopsych.2014.08.027
M3 - Article
C2 - 25648963
AN - SCOPUS:84928119304
SN - 0006-3223
VL - 77
SP - 749
EP - 763
JO - Biological psychiatry
JF - Biological psychiatry
IS - 8
ER -