Journal
NATURE GENETICS
Volume 44, Issue 5, Pages 545-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.2237
Keywords
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Categories
Funding
- US National Institute on Aging (NIA) [N01-AG-12100]
- US NHLBI [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, HL087641, HL59367, HL086694, HL7825, HL087652, HL105756]
- National Human Genome Research Institute [U01HG004402]
- NIH [HHSN268200625226C]
- NIH Roadmap for Medical Research [UL1RR025005]
- NHLBI [HL093029]
- NIA [AG20098, AG05133, AG08122, AG16495, AG033193, AG013846, AG031287]
- Austrian Science Fond (FWF) [P20545-P05, P13180]
- Netherlands Organisation for Scientific Research (NWO)
- Internationale Stichting Alzheimer Onderzoek (ISAO)
- Hersenstichting Nederland (HSN)
- Centre for Medical Systems Biology [CMSB1, CMSB2]
- US NIA [P30AG10161, AG17917, AG15819]
- Illinois Department of Public Health
- Rush Clinical Translational Science Consortium
- 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 the Boston University School of Medicine and Boston Medical Center
- NINDS [NS17950]
- NWO [175.010.2005.011, 911-03-012, 918-46-615, 904-61-096, 904-61-133, 948-00-010]
- Research Institute for Diseases in the Elderly (RIDE) [014-93-015]
- NGI-NWO [050-060-810]
- Erasmus Medical Center
- Erasmus University, Rotterdam
- Netherlands Organisation for Health Research and Development (ZonMw)
- RIDE2
- Dutch Ministry of Education, Culture and Science
- Dutch Ministry for Health, Welfare and Sports
- European Commission (DG XII)
- Municipality of Rotterdam
- Nederlandse Hartstichting [2009B102]
- Internationaal Parkinson Fonds
- National Health and Medical Research Council of Australia (NHMRC) [403000, 491109, 606543, APP1024879]
- Wicking Dementia Education and Research Centre, Hobart
- NHMRC-National Heart Foundation [606544]
- Fondation pour la Recherche Medicale
- Caisse Nationale Maladie des Travailleurs Salaries
- Direction Generale de la Sante
- Mutuelle Generale de l'Education Nationale (MGEN)
- Institut de la Longevite
- Conseils Regionaux de Aquitaine et Bourgogne
- Fondation de France
- French Ministry of Research-INSERM
- National Foundation for Alzheimer's Disease and Related Disorders
- Institut Pasteur de Lille
- Centre National de Genotypage
- MRC [G0701075, G1100616, G0901254, G1001245, G0700704] Funding Source: UKRI
- Austrian Science Fund (FWF) [P13180, P20545] Funding Source: Austrian Science Fund (FWF)
- Alzheimers Research UK [ART-PPG2011A-14] Funding Source: researchfish
- Austrian Science Fund (FWF) [P 20545] Funding Source: researchfish
- Medical Research Council [G0901254, G0700704, G1001245, G0701075, G1100616] Funding Source: researchfish
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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 x 10(-7). In two additional samples (n = 2,318), associations were replicated at 12q14 within MSRB3-WIF1 (discovery and replication; rs17178006; P = 5.3 x 10(-11)) and at 12q24 near HRK-FBXW8 (rs7294919; P = 2.9 x 10(-11)). Remaining associations included one SNP at 2q24 within DPP4 (rs6741949; P = 2.9 x 10(-7)) and nine SNPs at 9p33 within ASTN2 (rs7852872; P = 1.0 x 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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