Abstract
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.
Original language | English |
---|---|
Pages (from-to) | 545-551 |
Number of pages | 7 |
Journal | Nature Genetics |
Volume | 44 |
Issue number | 5 |
DOIs | |
State | Published - May 2012 |
Externally published | Yes |
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In: Nature Genetics, Vol. 44, No. 5, 05.2012, p. 545-551.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Common variants at 12q14 and 12q24 are associated with hippocampal volume
AU - Bis, Joshua C.
AU - Decarli, Charles
AU - Smith, Albert Vernon
AU - Van Der Lijn, Fedde
AU - Crivello, Fabrice
AU - Fornage, Myriam
AU - Debette, Stephanie
AU - Shulman, Joshua M.
AU - Schmidt, Helena
AU - Srikanth, Velandai
AU - Schuur, Maaike
AU - Yu, Lei
AU - Choi, Seung Hoan
AU - Sigurdsson, Sigurdur
AU - Verhaaren, Benjamin F.J.
AU - Destefano, Anita L.
AU - Lambert, Jean Charles
AU - Jack, Clifford R.
AU - Struchalin, Maksim
AU - Stankovich, Jim
AU - Ibrahim-Verbaas, Carla A.
AU - Fleischman, Debra
AU - Zijdenbos, Alex
AU - Den Heijer, Tom
AU - Mazoyer, Bernard
AU - Coker, Laura H.
AU - Enzinger, Christian
AU - Danoy, Patrick
AU - Amin, Najaf
AU - Arfanakis, Konstantinos
AU - Van Buchem, Mark A.
AU - De Bruijn, Renée F.A.G.
AU - Beiser, Alexa
AU - Dufouil, Carole
AU - Huang, Juebin
AU - Cavalieri, Margherita
AU - Thomson, Russell
AU - Niessen, Wiro J.
AU - Chibnik, Lori B.
AU - Gislason, Gauti K.
AU - Hofman, Albert
AU - Pikula, Aleksandra
AU - Amouyel, Philippe
AU - Freeman, Kevin B.
AU - Phan, Thanh G.
AU - Oostra, Ben A.
AU - Stein, Jason L.
AU - Medland, Sarah E.
AU - Vasquez, Alejandro Arias
AU - Hibar, Derrek P.
AU - Wright, Margaret J.
AU - Franke, Barbara
AU - Martin, Nicholas G.
AU - Thompson, Paul M.
AU - Nalls, Michael A.
AU - Uitterlinden, Andre G.
AU - Au, Rhoda
AU - Elbaz, Alexis
AU - Beare, Richard J.
AU - Van Swieten, John C.
AU - Lopez, Oscar L.
AU - Harris, Tamara B.
AU - Chouraki, Vincent
AU - Breteler, Monique M.B.
AU - De Jager, Philip L.
AU - Becker, James T.
AU - Vernooij, Meike W.
AU - Knopman, David
AU - Fazekas, Franz
AU - Wolf, Philip A.
AU - Van Der Lugt, Aad
AU - Gudnason, Vilmundur
AU - Longstreth, W. T.
AU - Brown, Matthew A.
AU - Bennett, David A.
AU - Van Duijn, Cornelia M.
AU - Mosley, Thomas H.
AU - Schmidt, Reinhold
AU - Tzourio, Christophe
AU - Launer, Lenore J.
AU - Ikram, M. Arfan
AU - Seshadri, Sudha
N1 - Funding Information: 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. Funding Information: 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. Funding Information: 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). Funding Information: The Cardiovascular Health Study (CHS): Coauthors were supported in part by Funding Information: 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. Funding Information: 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). Funding Information: 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. Funding Information: 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). Funding Information: 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).
PY - 2012/5
Y1 - 2012/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84860326795&partnerID=8YFLogxK
U2 - 10.1038/ng.2237
DO - 10.1038/ng.2237
M3 - Article
C2 - 22504421
AN - SCOPUS:84860326795
SN - 1061-4036
VL - 44
SP - 545
EP - 551
JO - Nature Genetics
JF - Nature Genetics
IS - 5
ER -