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 journalArticle

149 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)545-551
Number of pages7
JournalNature Genetics
Volume44
Issue number5
DOIs
StatePublished - May 2012

Fingerprint

Single Nucleotide Polymorphism
Dementia
Chromosomes, Human, Pair 12
Genome-Wide Association Study
Ubiquitination
Cognition
Alzheimer Disease
Oxidative Stress
Apoptosis
Enzymes
Genes

ASJC Scopus subject areas

  • Genetics

Cite this

Bis, J. C., DeCarli, C., Smith, A. V., Van Der Lijn, F., Crivello, F., Fornage, 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

Common variants at 12q14 and 12q24 are associated with hippocampal volume. / Bis, Joshua C.; DeCarli, Charles; Smith, Albert Vernon; Van Der Lijn, Fedde; Crivello, Fabrice; Fornage, Myriam; Debette, Stephanie; Shulman, Joshua M.; Schmidt, Helena; Srikanth, Velandai; Schuur, Maaike; Yu, Lei; Choi, Seung Hoan; Sigurdsson, Sigurdur; Verhaaren, Benjamin F J; Destefano, Anita L.; Lambert, Jean Charles; Jack, Clifford R.; Struchalin, Maksim; Stankovich, Jim; Ibrahim-Verbaas, Carla A.; Fleischman, Debra; Zijdenbos, Alex; Den Heijer, Tom; Mazoyer, Bernard; Coker, Laura H.; Enzinger, Christian; Danoy, Patrick; Amin, Najaf; Arfanakis, Konstantinos; Van Buchem, Mark A.; De Bruijn, Renée F A G; Beiser, Alexa; Dufouil, Carole; Huang, Juebin; Cavalieri, Margherita; Thomson, Russell; Niessen, Wiro J.; Chibnik, Lori B.; Gislason, Gauti K.; Hofman, Albert; Pikula, Aleksandra; Amouyel, Philippe; Freeman, Kevin B.; Phan, Thanh G.; Oostra, Ben A.; Stein, Jason L.; Medland, Sarah E.; Vasquez, Alejandro Arias; Hibar, Derrek P.; Wright, Margaret J.; Franke, Barbara; Martin, Nicholas G.; Thompson, Paul M.; Nalls, Michael A.; Uitterlinden, Andre G.; Au, Rhoda; Elbaz, Alexis; Beare, Richard J.; Van Swieten, John C.; Lopez, Oscar L.; Harris, Tamara B.; Chouraki, Vincent; Breteler, Monique M B; De Jager, Philip L.; Becker, James T.; Vernooij, Meike W.; Knopman, David; Fazekas, Franz; Wolf, Philip A.; Van Der Lugt, Aad; Gudnason, Vilmundur; Longstreth, W. T.; Brown, Matthew A.; Bennett, David A.; Van Duijn, Cornelia M.; Mosley, Thomas H.; Schmidt, Reinhold; Tzourio, Christophe; Launer, Lenore J.; Ikram, M. Arfan; Seshadri, Sudha.

In: Nature Genetics, Vol. 44, No. 5, 05.2012, p. 545-551.

Research output: Contribution to journalArticle

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
Bis JC, DeCarli C, Smith AV, Van Der Lijn F, Crivello F, Fornage M et al. Common variants at 12q14 and 12q24 are associated with hippocampal volume. Nature Genetics. 2012 May;44(5):545-551. https://doi.org/10.1038/ng.2237
Bis, Joshua C. ; DeCarli, Charles ; Smith, Albert Vernon ; Van Der Lijn, Fedde ; Crivello, Fabrice ; Fornage, Myriam ; Debette, Stephanie ; Shulman, Joshua M. ; Schmidt, Helena ; Srikanth, Velandai ; Schuur, Maaike ; Yu, Lei ; Choi, Seung Hoan ; Sigurdsson, Sigurdur ; Verhaaren, Benjamin F J ; Destefano, Anita L. ; Lambert, Jean Charles ; Jack, Clifford R. ; Struchalin, Maksim ; Stankovich, Jim ; Ibrahim-Verbaas, Carla A. ; Fleischman, Debra ; Zijdenbos, Alex ; Den Heijer, Tom ; Mazoyer, Bernard ; Coker, Laura H. ; Enzinger, Christian ; Danoy, Patrick ; Amin, Najaf ; Arfanakis, Konstantinos ; Van Buchem, Mark A. ; De Bruijn, Renée F A G ; Beiser, Alexa ; Dufouil, Carole ; Huang, Juebin ; Cavalieri, Margherita ; Thomson, Russell ; Niessen, Wiro J. ; Chibnik, Lori B. ; Gislason, Gauti K. ; Hofman, Albert ; Pikula, Aleksandra ; Amouyel, Philippe ; Freeman, Kevin B. ; Phan, Thanh G. ; Oostra, Ben A. ; Stein, Jason L. ; Medland, Sarah E. ; Vasquez, Alejandro Arias ; Hibar, Derrek P. ; Wright, Margaret J. ; Franke, Barbara ; Martin, Nicholas G. ; Thompson, Paul M. ; Nalls, Michael A. ; Uitterlinden, Andre G. ; Au, Rhoda ; Elbaz, Alexis ; Beare, Richard J. ; Van Swieten, John C. ; Lopez, Oscar L. ; Harris, Tamara B. ; Chouraki, Vincent ; Breteler, Monique M B ; De Jager, Philip L. ; Becker, James T. ; Vernooij, Meike W. ; Knopman, David ; Fazekas, Franz ; Wolf, Philip A. ; Van Der Lugt, Aad ; Gudnason, Vilmundur ; Longstreth, W. T. ; Brown, Matthew A. ; Bennett, David A. ; Van Duijn, Cornelia M. ; Mosley, Thomas H. ; Schmidt, Reinhold ; Tzourio, Christophe ; Launer, Lenore J. ; Ikram, M. Arfan ; Seshadri, Sudha. / Common variants at 12q14 and 12q24 are associated with hippocampal volume. In: Nature Genetics. 2012 ; Vol. 44, No. 5. pp. 545-551.
@article{4740dd60252b472fba1ca21591ee9c09,
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",
year = "2012",
month = "5",
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

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

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

VL - 44

SP - 545

EP - 551

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 5

ER -