Aging is associated with reductions in hippocampal volume that are accelerated by Alzheimer's disease and vascular risk factors. Our genome-wide association study (GWAS) of dementia-free persons (n = 9,232) identified 46 SNPs at four loci with P values of <4.0 × 10−7. In two additional samples (n = 2,318), associations were replicated at 12q14 within MSRB3-WIF1 (discovery and replication; rs17178006; P = 5.3 × 10−11) and at 12q24 near HRK-FBXW8 (rs7294919; P = 2.9 × 10−11). Remaining associations included one SNP at 2q24 within DPP4 (rs6741949; P = 2.9 × 10−7) and nine SNPs at 9p33 within ASTN2 (rs7852872; P = 1.0 × 10−7); along with the chromosome 12 associations, these loci were also associated with hippocampal volume (P < 0.05) in a third younger, more heterogeneous sample (n = 7,794). The SNP in ASTN2 also showed suggestive association with decline in cognition in a largely independent sample (n = 1,563). These associations implicate genes related to apoptosis (HRK), development (WIF1), oxidative stress (MSR3B), ubiquitination (FBXW8) and neuronal migration (ASTN2), as well as enzymes targeted by new diabetes medications (DPP4), indicating new genetic influences on hippocampal size and possibly the risk of cognitive decline and dementia.
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The authors thank the ENIGMA Consortium, which is represented by J.L.S., S.E.M., A.A.V., D.P.H., M.J.W., B.F., N.G.M. and P.M.T.
Aging Gene-Environment Susceptibility–Reykjavik Study (AGES): Research was funded by the US National Institute on Aging (NIA; N01-AG-12100), with contributions from the National Eye Institute (NEI), the National Institute on Deafness and Other Communication Disorders (NIDCD), the US National Heart, Lung, and Blood Institute (NHLBI), the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association) and the Althingi (the Icelandic Parliament).
The Atherosclerosis Risk in Communities Study (ARIC): The authors thank the staff and participants of the ARIC study for their important contributions. Research was carried out as a collaborative study supported by the US NHLBI (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, HL087641, HL59367, HL086694 and HL7825); the National Human Genome Research Institute (U01HG004402) and the NIH (HHSN268200625226C). Infrastructure was partly supported by a component of the NIH and the NIH Roadmap for Medical Research (UL1RR025005). This project was also supported by NHLBI grant HL093029.
The Cardiovascular Health Study (CHS): Coauthors were supported in part by US NHLBI grants (HL087652 and HL105756), as well as by NIA grants (AG20098 and AG05133).
The Austrian Stroke Prevention Study (ASPS): The authors thank the staff and the participants of ASPS for their valuable contributions. We thank B. Reinhart for her long-term administrative commitment and I.J. Semmler for technical assistance in creating the DNA bank. The research reported here was funded by the Austrian Science Fond (FWF; P20545-P05 and P13180). The Medical University of Graz supports the databank of ASPS.
Erasmus Rucphen Family Study (ERF): We thank the participants from the Genetic Research in Isolated Populations in the Erasmus Rucphen Family Study who made this work possible. This study is financially supported by the Netherlands Organisation for Scientific Research (NWO), the Internationale Stichting Alzheimer Onderzoek (ISAO), the Hersenstichting Nederland (HSN) and the Centre for Medical Systems Biology (CMSB1 and CMSB2) in the framework of the Netherlands Genomics Initiative (NGI).
Framingham Heart Study (FHS): This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (contract N01-HC-25195) and its contract with Affymetrix, Inc, for genotyping services (contract N02-HL-6-4278). A portion of this research used the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at the 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 SNP Health Association Resource (SHARe) project. This study was also supported by grants from the NINDS (NS17950) and the NIA (AG08122, AG16495, AG033193, AG013846 and AG031287).
The Religious Order Study and the Rush Memory and Aging Project: ROS and R-MAP data used in this study were obtained with support from the US NIA (grants P30AG10161, AG17917 and AG15819), the Illinois Department of Public Health and the Rush Clinical Translational Science Consortium and a gift from M. Dowd.
The Rotterdam Study (RS): The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. The authors also thank P. Arp, M. Jhamai, M. Verkerk, L. Herrera and M. Peters for their help in creating the GWAS database and K. Estrada and M.V. Struchalin for their support in the creation and analysis of imputed data. The generation and management of GWAS genotype data for the Rotterdam Study are supported by NWO Investments (nr. 175.010.2005.011 and 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (RIDE2; 014-93-015) and the NGI-NWO project (nr. 050-060-810). The Rotterdam Study is funded by the Erasmus Medical Center and Erasmus University, Rotterdam, the Netherlands Organisation for Health Research and Development (ZonMw), RIDE2, the Dutch Ministry of Education, Culture and Science, the Dutch Ministry for Health, Welfare and Sports, the European Commission (DG XII) and the Municipality of Rotterdam. The Rotterdam Scan Study is supported by the NWO (project nrs. 918-46-615, 904-61-096, 904-61-133 and 948-00-010), Nederlandse Hartstichting (2009B102) and Internationaal Parkinson Fonds.
The Tasmanian Study of Gait and Cognition (TASCOG): This study is supported by project grants from the National Health and Medical Research Council of Australia (NHMRC; 403000, 491109 and 606543) and a grant from the Wicking Dementia Education and Research Centre, Hobart. V.S. is supported by an NHMRC–National Heart Foundation Career Development Fellowship (606544). M.A.B. is supported by an NHMRC Senior Principal Research Fellowship (APP1024879).
Three City Study (3C): We thank the staff and participants of the 3C Study for their important contributions. We also thank A. Boland for her technical help in preparing the DNA samples for analyses. The 3C Study is conducted under a partnership agreement between INSERM, Victor Segalen–Bordeaux II University and Sanofi-Aventis. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study is also supported by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, Mutuelle Générale de l'Education Nationale (MGEN), Institut de la Longévité, Conseils Régionaux de Aquitaine et Bourgogne, Fondation de France and the French Ministry of Research–INSERM Programme Cohortes et Collections de Données Biologiques. 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.
Supplementary Tables 1–7, Supplementary Figures 1–3 and Supplementary Note
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Molecular Psychiatry (2018)