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

JC Bis; C DeCarli; AV Smith; Fedde Lijn; F Crivello; M Fornage; S Debette; JM Shulman; Heléna Schmidt; V Srikanth; Maaike Schuur; L Yu; SH Choi; S Sigurdsson; Ben Verhaaren; AL DeStefano; JC Lambert; CR Jack; M Struchalin; J Stankovich; Carla Verbaas; D Fleischman; A Zijdenbos; Tom Heijer; B Mazoyer; LH Coker; C Enzinger; P Danoy; Najaf Amin; K Arfanakis; MA van Buchem; Renee Bruijn; A Beiser; C Dufouil; JB Huang; M Cavalieri; R Thomson; Wiro Niessen; LB Chibnik; GK Gislason; Bert Hofman; A Pikula; P Amouyel; KB Freeman; TG Phan; Ben Oostra; JL Stein; SE Medland; AA Vasquez; DP Hibar; MJ Wright; B Franke; NG Martin; PM Thompson; MA Nalls; André Uitterlinden; R (Rhoda) Au; A Elbaz; RJ Beare; J.C. van Swieten; OL Lopez; TB Harris; V Chouraki; Monique Breteler; PL De Jager; JT Becker; Meike Vernooij; D Knopman; F Fazekas; PA Wolf; Aad van der Lugt; V Gudnason; WT Longstreth; MA Brown; DA Bennett; Cornelia Duijn; TH Mosley; R Schmidt; C Tzourio; LJ (Lenore) Launer; Arfan Ikram; S Seshadri

doi:10.1038/ng.2237

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

JC Bis, C DeCarli, AV Smith, Fedde Lijn, F Crivello, M Fornage, S Debette, JM Shulman, Heléna Schmidt, V Srikanth, Maaike Schuur, L Yu, SH Choi, S Sigurdsson, Ben Verhaaren, AL DeStefano, JC Lambert, CR Jack, M Struchalin, J StankovichCarla Verbaas, D Fleischman, A Zijdenbos, Tom Heijer, B Mazoyer, LH Coker, C Enzinger, P Danoy, Najaf Amin, K Arfanakis, MA van Buchem, Renee Bruijn, A Beiser, C Dufouil, JB Huang, M Cavalieri, R Thomson, Wiro Niessen, LB Chibnik, GK Gislason, Bert Hofman, A Pikula, P Amouyel, KB Freeman, TG Phan, Ben Oostra, JL Stein, SE Medland, AA Vasquez, DP Hibar, MJ Wright, B Franke, NG Martin, PM Thompson, MA Nalls, André Uitterlinden, R (Rhoda) Au, A Elbaz, RJ Beare, J.C. van Swieten, OL Lopez, TB Harris, V Chouraki, Monique Breteler, PL De Jager, JT Becker, Meike Vernooij, D Knopman, F Fazekas, PA Wolf, Aad van der Lugt, V Gudnason, WT Longstreth, MA Brown, DA Bennett, Cornelia Duijn, TH Mosley, R Schmidt, C Tzourio, LJ (Lenore) Launer, Arfan Ikram, S Seshadri

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

193 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 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.

Original language	Undefined/Unknown
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
Publication status	Published - 2012

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10.1038/ng.2237

http://hdl.handle.net/1765/59607

Cite this

Bis, JC., DeCarli, C., Smith, AV., Lijn, F., Crivello, F., Fornage, M., Debette, S., Shulman, JM., Schmidt, H., Srikanth, V., Schuur, M., Yu, L., Choi, SH., Sigurdsson, S., Verhaaren, B., DeStefano, AL., Lambert, JC., Jack, CR., 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

@article{aec3096412a54cd980a104cff728adfd,

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 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.",

author = "JC Bis and C DeCarli and AV Smith and Fedde Lijn and F Crivello and M Fornage and S Debette and JM Shulman and Hel{\'e}na Schmidt and V Srikanth and Maaike Schuur and L Yu and SH Choi and S Sigurdsson and Ben Verhaaren and AL DeStefano and JC Lambert and CR Jack and M Struchalin and J Stankovich and Carla Verbaas and D Fleischman and A Zijdenbos and Tom Heijer and B Mazoyer and LH Coker and C Enzinger and P Danoy and Najaf Amin and K Arfanakis and {van Buchem}, MA and Renee Bruijn and A Beiser and C Dufouil and JB Huang and M Cavalieri and R Thomson and Wiro Niessen and LB Chibnik and GK Gislason and Bert Hofman and A Pikula and P Amouyel and KB Freeman and TG Phan and Ben Oostra and JL Stein and SE Medland and AA Vasquez and DP Hibar and MJ Wright and B Franke and NG Martin and PM Thompson and MA Nalls and Andr{\'e} Uitterlinden and Au, {R (Rhoda)} and A Elbaz and RJ Beare and {van Swieten}, J.C. and OL Lopez and TB Harris and V Chouraki and Monique Breteler and {De Jager}, PL and JT Becker and Meike Vernooij and D Knopman and F Fazekas and PA Wolf and {van der Lugt}, Aad and V Gudnason and WT Longstreth and MA Brown and DA Bennett and Cornelia Duijn and TH Mosley and R Schmidt and C Tzourio and Launer, {LJ (Lenore)} and Arfan Ikram and S Seshadri",

year = "2012",

doi = "10.1038/ng.2237",

language = "Undefined/Unknown",

volume = "44",

pages = "545--551",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "5",

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Bis, JC, DeCarli, C, Smith, AV, Lijn, F, Crivello, F, Fornage, M, Debette, S, Shulman, JM, Schmidt, H, Srikanth, V, Schuur, M, Yu, L, Choi, SH, Sigurdsson, S, Verhaaren, B, DeStefano, AL, Lambert, JC, Jack, CR, Struchalin, M, Stankovich, J, Verbaas, C, Fleischman, D, Zijdenbos, A, Heijer, T, Mazoyer, B, Coker, LH, Enzinger, C, Danoy, P, Amin, N, Arfanakis, K, van Buchem, MA, Bruijn, R, Beiser, A, Dufouil, C, Huang, JB, Cavalieri, M, Thomson, R, Niessen, W, Chibnik, LB, Gislason, GK, Hofman, B, Pikula, A, Amouyel, P, Freeman, KB, Phan, TG, Oostra, B, Stein, JL, Medland, SE, Vasquez, AA, Hibar, DP, Wright, MJ, Franke, B, Martin, NG, Thompson, PM, Nalls, MA, Uitterlinden, A, Au, R, Elbaz, A, Beare, RJ, van Swieten, JC, Lopez, OL, Harris, TB, Chouraki, V, Breteler, M, De Jager, PL, Becker, JT, Vernooij, M, Knopman, D, Fazekas, F, Wolf, PA, van der Lugt, A, Gudnason, V, Longstreth, WT, Brown, MA, Bennett, DA, Duijn, C, Mosley, TH, Schmidt, R, Tzourio, C, Launer, LJ, Ikram, A & 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

TY - JOUR

T1 - Common variants at 12q14 and 12q24 are associated with hippocampal volume

AU - Bis, JC

AU - DeCarli, C

AU - Smith, AV

AU - Lijn, Fedde

AU - Crivello, F

AU - Fornage, M

AU - Debette, S

AU - Shulman, JM

AU - Schmidt, Heléna

AU - Srikanth, V

AU - Schuur, Maaike

AU - Yu, L

AU - Choi, SH

AU - Sigurdsson, S

AU - Verhaaren, Ben

AU - DeStefano, AL

AU - Lambert, JC

AU - Jack, CR

AU - Struchalin, M

AU - Stankovich, J

AU - Verbaas, Carla

AU - Fleischman, D

AU - Zijdenbos, A

AU - Heijer, Tom

AU - Mazoyer, B

AU - Coker, LH

AU - Enzinger, C

AU - Danoy, P

AU - Amin, Najaf

AU - Arfanakis, K

AU - van Buchem, MA

AU - Bruijn, Renee

AU - Beiser, A

AU - Dufouil, C

AU - Huang, JB

AU - Cavalieri, M

AU - Thomson, R

AU - Niessen, Wiro

AU - Chibnik, LB

AU - Gislason, GK

AU - Hofman, Bert

AU - Pikula, A

AU - Amouyel, P

AU - Freeman, KB

AU - Phan, TG

AU - Oostra, Ben

AU - Stein, JL

AU - Medland, SE

AU - Vasquez, AA

AU - Hibar, DP

AU - Wright, MJ

AU - Franke, B

AU - Martin, NG

AU - Thompson, PM

AU - Nalls, MA

AU - Uitterlinden, André

AU - Au, R (Rhoda)

AU - Elbaz, A

AU - Beare, RJ

AU - van Swieten, J.C.

AU - Lopez, OL

AU - Harris, TB

AU - Chouraki, V

AU - Breteler, Monique

AU - De Jager, PL

AU - Becker, JT

AU - Vernooij, Meike

AU - Knopman, D

AU - Fazekas, F

AU - Wolf, PA

AU - van der Lugt, Aad

AU - Gudnason, V

AU - Longstreth, WT

AU - Brown, MA

AU - Bennett, DA

AU - Duijn, Cornelia

AU - Mosley, TH

AU - Schmidt, R

AU - Tzourio, C

AU - Launer, LJ (Lenore)

AU - Ikram, Arfan

AU - Seshadri, S

PY - 2012

Y1 - 2012

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 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.

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 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.

U2 - 10.1038/ng.2237

DO - 10.1038/ng.2237

M3 - Article

C2 - 22504421

SN - 1061-4036

VL - 44

SP - 545

EP - 551

JO - Nature Genetics

JF - Nature Genetics

IS - 5

ER -