Common variants at 12q14 and 12q24 are associated with hippocampal volume

Joshua C. Bis; Charles Decarli; Albert Vernon Smith; Fedde Van Der Lijn; Fabrice Crivello; Myriam Fornage; Stephanie Debette; Joshua M. Shulman; Helena Schmidt; Velandai Srikanth; Maaike Schuur; Lei Yu; Seung Hoan Choi; Sigurdur Sigurdsson; Benjamin F.J. Verhaaren; Anita L. Destefano; Jean Charles Lambert; Clifford R. Jack; Maksim Struchalin; Jim Stankovich; Carla A. Ibrahim-Verbaas; Debra Fleischman; Alex Zijdenbos; Tom Den Heijer; Bernard Mazoyer; Laura H. Coker; Christian Enzinger; Patrick Danoy; Najaf Amin; Konstantinos Arfanakis; Mark A. Van Buchem; Renée F.A.G. De Bruijn; Alexa Beiser; Carole Dufouil; Juebin Huang; Margherita Cavalieri; Russell Thomson; Wiro J. Niessen; Lori B. Chibnik; Gauti K. Gislason; Albert Hofman; Aleksandra Pikula; Philippe Amouyel; Kevin B. Freeman; Thanh G. Phan; Ben A. Oostra; Jason L. Stein; Sarah E. Medland; Alejandro Arias Vasquez; Derrek P. Hibar; Margaret J. Wright; Barbara Franke; Nicholas G. Martin; Paul M. Thompson; Michael A. Nalls; Andre G. Uitterlinden; Rhoda Au; Alexis Elbaz; Richard J. Beare; John C. Van Swieten; Oscar L. Lopez; Tamara B. Harris; Vincent Chouraki; Monique M.B. Breteler; Philip L. De Jager; James T. Becker; Meike W. Vernooij; David Knopman; Franz Fazekas; Philip A. Wolf; Aad Van Der Lugt; Vilmundur Gudnason; W. T. Longstreth; Matthew A. Brown; David A. Bennett; Cornelia M. Van Duijn; Thomas H. Mosley; Reinhold Schmidt; Christophe Tzourio; Lenore J. Launer; M. Arfan Ikram; Sudha Seshadri

doi:10.1038/ng.2237

Common variants at 12q14 and 12q24 are associated with hippocampal volume

Joshua C. Bis, Charles Decarli, Albert Vernon Smith, Fedde Van Der Lijn, Fabrice Crivello, Myriam Fornage, Stephanie Debette, Joshua M. Shulman, Helena Schmidt, Velandai Srikanth, Maaike Schuur, Lei Yu, Seung Hoan Choi, Sigurdur Sigurdsson, Benjamin F.J. Verhaaren, Anita L. Destefano, Jean Charles Lambert, Clifford R. Jack, Maksim Struchalin, Jim StankovichCarla A. Ibrahim-Verbaas, Debra Fleischman, Alex Zijdenbos, Tom Den Heijer, Bernard Mazoyer, Laura H. Coker, Christian Enzinger, Patrick Danoy, Najaf Amin, Konstantinos Arfanakis, Mark A. Van Buchem, Renée F.A.G. De Bruijn, Alexa Beiser, Carole Dufouil, Juebin Huang, Margherita Cavalieri, Russell Thomson, Wiro J. Niessen, Lori B. Chibnik, Gauti K. Gislason, Albert Hofman, Aleksandra Pikula, Philippe Amouyel, Kevin B. Freeman, Thanh G. Phan, Ben A. Oostra, Jason L. Stein, Sarah E. Medland, Alejandro Arias Vasquez, Derrek P. Hibar, Margaret J. Wright, Barbara Franke, Nicholas G. Martin, Paul M. Thompson, Michael A. Nalls, Andre G. Uitterlinden, Rhoda Au, Alexis Elbaz, Richard J. Beare, John C. Van Swieten, Oscar L. Lopez, Tamara B. Harris, Vincent Chouraki, Monique M.B. Breteler, Philip L. De Jager, James T. Becker, Meike W. Vernooij, David Knopman, Franz Fazekas, Philip A. Wolf, Aad Van Der Lugt, Vilmundur Gudnason, W. T. Longstreth, Matthew A. Brown, David A. Bennett, Cornelia M. Van Duijn, Thomas H. Mosley, Reinhold Schmidt, Christophe Tzourio, Lenore J. Launer, M. Arfan Ikram, Sudha Seshadri

Research output: Contribution to journal › Article › peer-review

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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 (US)
Pages (from-to)	545-551
Number of pages	7
Journal	Nature Genetics
Volume	44
Issue number	5
DOIs	https://doi.org/10.1038/ng.2237
State	Published - May 2012

ASJC Scopus subject areas

Genetics

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Bis, J. C., Decarli, C., Smith, A. V., Van Der Lijn, F., Crivello, F., Fornage, M., Debette, S., Shulman, J. M., Schmidt, H., Srikanth, V., Schuur, M., Yu, L., Choi, S. H., Sigurdsson, S., Verhaaren, B. F. J., Destefano, A. L., Lambert, J. C., Jack, C. R., Struchalin, M., ... Seshadri, S. (2012). Common variants at 12q14 and 12q24 are associated with hippocampal volume. Nature Genetics, 44(5), 545-551. https://doi.org/10.1038/ng.2237

Bis, JC, Decarli, C, Smith, AV, Van Der Lijn, F, Crivello, F, Fornage, M, Debette, S, Shulman, JM, Schmidt, H, Srikanth, V, Schuur, M, Yu, L, Choi, SH, Sigurdsson, S, Verhaaren, BFJ, Destefano, AL, Lambert, JC, Jack, CR, Struchalin, M, Stankovich, J, Ibrahim-Verbaas, CA, Fleischman, D, Zijdenbos, A, Den Heijer, T, Mazoyer, B, Coker, LH, Enzinger, C, Danoy, P, Amin, N, Arfanakis, K, Van Buchem, MA, De Bruijn, RFAG, Beiser, A, Dufouil, C, Huang, J, Cavalieri, M, Thomson, R, Niessen, WJ, Chibnik, LB, Gislason, GK, Hofman, A, Pikula, A, Amouyel, P, Freeman, KB, Phan, TG, Oostra, BA, Stein, JL, Medland, SE, Vasquez, AA, Hibar, DP, Wright, MJ, Franke, B, Martin, NG, Thompson, PM, Nalls, MA, Uitterlinden, AG, Au, R, Elbaz, A, Beare, RJ, Van Swieten, JC, Lopez, OL, Harris, TB, Chouraki, V, Breteler, MMB, De Jager, PL, Becker, JT, Vernooij, MW, Knopman, D, Fazekas, F, Wolf, PA, Van Der Lugt, A, Gudnason, V, Longstreth, WT, Brown, MA, Bennett, DA, Van Duijn, CM, Mosley, TH, Schmidt, R, Tzourio, C, Launer, LJ, Ikram, MA & Seshadri, S 2012, 'Common variants at 12q14 and 12q24 are associated with hippocampal volume', Nature Genetics, vol. 44, no. 5, pp. 545-551. https://doi.org/10.1038/ng.2237

@article{15b0c05a63e847eab19aa28e4a7fc7ea,

title = "Common variants at 12q14 and 12q24 are associated with hippocampal volume",

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.",

author = "Bis, {Joshua C.} and Charles Decarli and Smith, {Albert Vernon} and {Van Der Lijn}, Fedde and Fabrice Crivello and Myriam Fornage and Stephanie Debette and Shulman, {Joshua M.} and Helena Schmidt and Velandai Srikanth and Maaike Schuur and Lei Yu and Choi, {Seung Hoan} and Sigurdur Sigurdsson and Verhaaren, {Benjamin F.J.} and Destefano, {Anita L.} and Lambert, {Jean Charles} and Jack, {Clifford R.} and Maksim Struchalin and Jim Stankovich and Ibrahim-Verbaas, {Carla A.} and Debra Fleischman and Alex Zijdenbos and {Den Heijer}, Tom and Bernard Mazoyer and Coker, {Laura H.} and Christian Enzinger and Patrick Danoy and Najaf Amin and Konstantinos Arfanakis and {Van Buchem}, {Mark A.} and {De Bruijn}, {Ren{\'e}e F.A.G.} and Alexa Beiser and Carole Dufouil and Juebin Huang and Margherita Cavalieri and Russell Thomson and Niessen, {Wiro J.} and Chibnik, {Lori B.} and Gislason, {Gauti K.} and Albert Hofman and Aleksandra Pikula and Philippe Amouyel and Freeman, {Kevin B.} and Phan, {Thanh G.} and Oostra, {Ben A.} and Stein, {Jason L.} and Medland, {Sarah E.} and Vasquez, {Alejandro Arias} and Hibar, {Derrek P.} and Wright, {Margaret J.} and Barbara Franke and Martin, {Nicholas G.} and Thompson, {Paul M.} and Nalls, {Michael A.} and Uitterlinden, {Andre G.} and Rhoda Au and Alexis Elbaz and Beare, {Richard J.} and {Van Swieten}, {John C.} and Lopez, {Oscar L.} and Harris, {Tamara B.} and Vincent Chouraki and Breteler, {Monique M.B.} and {De Jager}, {Philip L.} and Becker, {James T.} and Vernooij, {Meike W.} and David Knopman and Franz Fazekas and Wolf, {Philip A.} and {Van Der Lugt}, Aad and Vilmundur Gudnason and Longstreth, {W. T.} and Brown, {Matthew A.} and Bennett, {David A.} and {Van Duijn}, {Cornelia M.} and Mosley, {Thomas H.} and Reinhold Schmidt and Christophe Tzourio and Launer, {Lenore J.} and Ikram, {M. Arfan} and Sudha Seshadri",

note = "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{\textquoteright}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).",

year = "2012",

month = may,

doi = "10.1038/ng.2237",

language = "English (US)",

volume = "44",

pages = "545--551",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "5",

}

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.

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UR - http://www.scopus.com/inward/citedby.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 -

Common variants at 12q14 and 12q24 are associated with hippocampal volume

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