Association of Alzheimer's disease GWAS loci with MRI markers of brain aging

Ganesh Chauhan; Hieab H.H. Adams; Joshua C. Bis; Galit Weinstein; Lei Yu; Anna Maria Töglhofer; Albert Vernon Smith; Sven J. van der Lee; Rebecca F. Gottesman; Russell Thomson; Jing Wang; Qiong Yang; Wiro J. Niessen; Oscar L. Lopez; James T. Becker; Thanh G. Phan; Richard J. Beare; Konstantinos Arfanakis; Debra Fleischman; Meike W. Vernooij; Bernard Mazoyer; Helena Schmidt; Velandai Srikanth; David S. Knopman; Clifford R. Jack; Philippe Amouyel; Albert Hofman; Charles DeCarli; Christophe Tzourio; Cornelia M. van Duijn; David A. Bennett; Reinhold Schmidt; William T. Longstreth; Thomas H. Mosley; Myriam Fornage; Lenore J. Launer; Sudha Seshadri; M. Arfan Ikram; Stephanie Debette

doi:10.1016/j.neurobiolaging.2014.12.028

Association of Alzheimer's disease GWAS loci with MRI markers of brain aging

Ganesh Chauhan, Hieab H.H. Adams, Joshua C. Bis, Galit Weinstein, Lei Yu, Anna Maria Töglhofer, Albert Vernon Smith, Sven J. van der Lee, Rebecca F. Gottesman, Russell Thomson, Jing Wang, Qiong Yang, Wiro J. Niessen, Oscar L. Lopez, James T. Becker, Thanh G. Phan, Richard J. Beare, Konstantinos Arfanakis, Debra Fleischman, Meike W. VernooijBernard Mazoyer, Helena Schmidt, Velandai Srikanth, David S. Knopman, Clifford R. Jack, Philippe Amouyel, Albert Hofman, Charles DeCarli, Christophe Tzourio, Cornelia M. van Duijn, David A. Bennett, Reinhold Schmidt, William T. Longstreth, Thomas H. Mosley, Myriam Fornage, Lenore J. Launer, Sudha Seshadri, M. Arfan Ikram, Stephanie Debette

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

66 Scopus citations

Abstract

Whether novel risk variants of Alzheimer's disease (AD) identified through genome-wide association studies also influence magnetic resonance imaging-based intermediate phenotypes of AD in the general population is unclear. We studied association of 24 AD risk loci with intracranial volume, total brain volume, hippocampal volume (HV), white matter hyperintensity burden, and brain infarcts in a meta-analysis of genetic association studies from large population-based samples (N= 8175-11,550). In single-SNP based tests, AD risk allele of APOE (rs2075650) was associated with smaller HV (. p= 0.0054) and CD33 (rs3865444) with smaller intracranial volume (. p= 0.0058). In gene-based tests, there was associations of HLA-DRB1 with total brain volume (. p= 0.0006) and BIN1 with HV (. p= 0.00089). Aweighted AD genetic risk score was associated with smaller HV (beta ± SE=-0.047 ± 0.013, p= 0.00041), even after excluding the APOE locus (. p= 0.029). However, only association of AD genetic risk score with HV, including APOE, was significant after multiple testing correction (including number of independent phenotypes tested). These results suggest that novel AD genetic risk variants may contribute to structural brain aging in nondemented older community persons.

Original language	English
Pages (from-to)	1765.e7-1765.e16
Journal	Neurobiology of Aging
Volume	36
Issue number	4
DOIs	https://doi.org/10.1016/j.neurobiolaging.2014.12.028
State	Published - 1 Apr 2015
Externally published	Yes

Keywords

Alzheimer
GWAS
Genetic risk score
Hippocampal volume
MRI-Markers

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10.1016/j.neurobiolaging.2014.12.028

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Chauhan, G., Adams, H. H. H., Bis, J. C., Weinstein, G., Yu, L., Töglhofer, A. M., Smith, A. V., van der Lee, S. J., Gottesman, R. F., Thomson, R., Wang, J., Yang, Q., Niessen, W. J., Lopez, O. L., Becker, J. T., Phan, T. G., Beare, R. J., Arfanakis, K., Fleischman, D., ... Debette, S. (2015). Association of Alzheimer's disease GWAS loci with MRI markers of brain aging. Neurobiology of Aging, 36(4), 1765.e7-1765.e16. https://doi.org/10.1016/j.neurobiolaging.2014.12.028

@article{a17174953b8e4f5199bbc8d441902d4b,

title = "Association of Alzheimer's disease GWAS loci with MRI markers of brain aging",

abstract = "Whether novel risk variants of Alzheimer's disease (AD) identified through genome-wide association studies also influence magnetic resonance imaging-based intermediate phenotypes of AD in the general population is unclear. We studied association of 24 AD risk loci with intracranial volume, total brain volume, hippocampal volume (HV), white matter hyperintensity burden, and brain infarcts in a meta-analysis of genetic association studies from large population-based samples (N= 8175-11,550). In single-SNP based tests, AD risk allele of APOE (rs2075650) was associated with smaller HV (. p= 0.0054) and CD33 (rs3865444) with smaller intracranial volume (. p= 0.0058). In gene-based tests, there was associations of HLA-DRB1 with total brain volume (. p= 0.0006) and BIN1 with HV (. p= 0.00089). Aweighted AD genetic risk score was associated with smaller HV (beta ± SE=-0.047 ± 0.013, p= 0.00041), even after excluding the APOE locus (. p= 0.029). However, only association of AD genetic risk score with HV, including APOE, was significant after multiple testing correction (including number of independent phenotypes tested). These results suggest that novel AD genetic risk variants may contribute to structural brain aging in nondemented older community persons.",

keywords = "Alzheimer, GWAS, Genetic risk score, Hippocampal volume, MRI-Markers",

author = "Ganesh Chauhan and Adams, {Hieab H.H.} and Bis, {Joshua C.} and Galit Weinstein and Lei Yu and T{\"o}glhofer, {Anna Maria} and Smith, {Albert Vernon} and {van der Lee}, {Sven J.} and Gottesman, {Rebecca F.} and Russell Thomson and Jing Wang and Qiong Yang and Niessen, {Wiro J.} and Lopez, {Oscar L.} and Becker, {James T.} and Phan, {Thanh G.} and Beare, {Richard J.} and Konstantinos Arfanakis and Debra Fleischman and Vernooij, {Meike W.} and Bernard Mazoyer and Helena Schmidt and Velandai Srikanth and Knopman, {David S.} and Jack, {Clifford R.} and Philippe Amouyel and Albert Hofman and Charles DeCarli and Christophe Tzourio and {van Duijn}, {Cornelia M.} and Bennett, {David A.} and Reinhold Schmidt and Longstreth, {William T.} and Mosley, {Thomas H.} and Myriam Fornage and Launer, {Lenore J.} and Sudha Seshadri and Ikram, {M. Arfan} and Stephanie Debette",

note = "Funding Information: The Religious Order Study (ROS) and Rush Memory and Aging Project (R-MAP): The R-MAP and ROS data used in this article was supported by National Institute on Aging grants P30AG10161 , R01AG17917 , and R01AG15819, National Institutes of Health grants (R01 AG040039, R21 NS076827, P20 MD006886) and the Illinois Department of Public Health . Funding Information: Cardiovascular Health Study: This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, N01HC15103; and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Funding Information: Erasmus Rucphen Family Study: This study is financially supported by the Netherlands Organization for Scientific Research (NWO), the Internationale Stichting Alzheimer Onderzoek (ISAO), the Hersenstichting Nederland (HSN), and the Centre for Medical Systems Biology (CMSB) in the framework of the Netherlands Genomics Initiative (NGI). The authors thank the participants from the Genetic Research in Isolated Populations, Erasmus Rucphen Family who made this work possible. Funding Information: Aging Gene-Environment Susceptibility-Reykjavik Study: The research has been funded by NIA contract N01-AG-12100 with contributions from NEI, NIDCD, and NHLBI, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). Funding Information: The Rotterdam Study: The GWA database of the Rotterdam Study was funded through the Netherlands Organization of Scientific Research NWO ( nr. 175.010.2005.011 ). This study was further supported by the Netherlands Genomics Initiative (NGI) / Netherlands Organisation for Scientific Research (NWO) project nr. 050-060-810. The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University , Rotterdam; the Netherlands Organization for Scientific Research (NWO), the Netherlands Organization for the Health Research and Development (ZonMw; Veni-grant 916.13.054 ), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health , Welfare and Sports , the European Commission (DG XII), the Municipality of Rotterdam , and the Internationale Stichting Alzheimer Onderzoek . Funding Information: Three City Study (3C): The authors thank the staff and the participants of the 3C Study for their important contributions. The 3C Study is conducted under a partnership agreement between the Institut National de la Sant{\'e} et de la Recherche M{\'e}dicale (INSERM), the Victor Segalen–Bordeaux II University, and Sanofi-Aventis. The Fondation pour la Recherche M{\'e}dicale funded the preparation and initiation of the study. The 3C Study is also supported by the Caisse Nationale Maladie des Travailleurs Salari{\'e}s , Direction G{\'e}n{\'e}rale de la Sant{\'e} , Mutuelle G{\'e}n{\'e}rale de l'Education Nationale (MGEN), Institut de la Long{\'e}vit{\'e} , Conseils R{\'e}gionaux of Aquitaine and Bourgogne , Fondation de France , and Ministry of Research –INSERM Programme “Cohortes et collections de donn{\'e}es biologiques.” Lille G{\'e}nop{\^o}le received an unconditional grant from Eisai . The authors thank A. Boland (Centre National de G{\'e}notypage) for her technical help in preparing the DNA samples for analyses. This work was supported by the National Foundation for Alzheimer's Disease and Related Disorders , the Institut Pasteur de Lille and the Centre National de G{\'e}notypage . Ganesh Chauhan and St{\'e}phanie Debette are supported by a grant from the Fondation Leducq and the Agence Nationale de la Recherche (Chaire d'Excellence). Funding Information: Framingham Heart Study: This work was supported by the Framingham Heart Study's National Heart, Lung, and Blood Institute contract (N01-HC-25195) and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6–4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center . It was also funded by grants from the National Institute on Aging ( R01 AG08122 , AG033193, P30 AG0101029 ) and the National Institute of Neurological Disorders and Stroke ( R01 NS17950 ). Funding Information: The Atherosclerosis Risk in Communities Study: The research is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641 , R01HL59367 and R01HL086694 and R01HL7825 ; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005 , a component of the National Institutes of Health (UL1RR025005) and NIH Roadmap for Medical Research . Funds for these projects were also supported by grant HL093029 to Myriam Fornage. Funding Information: The Austrian Stroke Prevention Study: The research reported in this article was funded by the Austrian Science Fond (FWF) grant number P20545-P05 and P13180 . The Medical University of Graz supports the databank of the ASPS . The authors thank the staff and the participants of the ASPS for their valuable contributions. The authors thank Birgit Reinhart for her long-term administrative commitment and Ing Johann Semmler for the technical assistance at creating the DNA bank. Funding Information: The Tasmanian Study of Gait and Cognition (TASCOG) is supported by Project Grants from the National Health and Medical Research Council (NHMRC IDs 403000, 491109, 606543), and a grant from the Wicking Dementia Education and Research Centre , Hobart. Velandai Srikanth is supported by an NHMRC /National Heart Foundation Career Development Fellowship (ID 606544). Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",

year = "2015",

month = apr,

day = "1",

doi = "10.1016/j.neurobiolaging.2014.12.028",

language = "English",

volume = "36",

pages = "1765.e7--1765.e16",

journal = "Neurobiology of Aging",

issn = "0197-4580",

publisher = "Elsevier Inc.",

number = "4",

}

Chauhan, G, Adams, HHH, Bis, JC, Weinstein, G, Yu, L, Töglhofer, AM, Smith, AV, van der Lee, SJ, Gottesman, RF, Thomson, R, Wang, J, Yang, Q, Niessen, WJ, Lopez, OL, Becker, JT, Phan, TG, Beare, RJ, Arfanakis, K, Fleischman, D, Vernooij, MW, Mazoyer, B, Schmidt, H, Srikanth, V, Knopman, DS, Jack, CR, Amouyel, P, Hofman, A, DeCarli, C, Tzourio, C, van Duijn, CM, Bennett, DA, Schmidt, R, Longstreth, WT, Mosley, TH, Fornage, M, Launer, LJ, Seshadri, S, Ikram, MA & Debette, S 2015, 'Association of Alzheimer's disease GWAS loci with MRI markers of brain aging', Neurobiology of Aging, vol. 36, no. 4, pp. 1765.e7-1765.e16. https://doi.org/10.1016/j.neurobiolaging.2014.12.028

TY - JOUR

T1 - Association of Alzheimer's disease GWAS loci with MRI markers of brain aging

AU - Chauhan, Ganesh

AU - Adams, Hieab H.H.

AU - Bis, Joshua C.

AU - Weinstein, Galit

AU - Yu, Lei

AU - Töglhofer, Anna Maria

AU - Smith, Albert Vernon

AU - van der Lee, Sven J.

AU - Gottesman, Rebecca F.

AU - Thomson, Russell

AU - Wang, Jing

AU - Yang, Qiong

AU - Niessen, Wiro J.

AU - Lopez, Oscar L.

AU - Becker, James T.

AU - Phan, Thanh G.

AU - Beare, Richard J.

AU - Arfanakis, Konstantinos

AU - Fleischman, Debra

AU - Vernooij, Meike W.

AU - Mazoyer, Bernard

AU - Schmidt, Helena

AU - Srikanth, Velandai

AU - Knopman, David S.

AU - Jack, Clifford R.

AU - Amouyel, Philippe

AU - Hofman, Albert

AU - DeCarli, Charles

AU - Tzourio, Christophe

AU - van Duijn, Cornelia M.

AU - Bennett, David A.

AU - Schmidt, Reinhold

AU - Longstreth, William T.

AU - Mosley, Thomas H.

AU - Fornage, Myriam

AU - Launer, Lenore J.

AU - Seshadri, Sudha

AU - Ikram, M. Arfan

AU - Debette, Stephanie

N1 - Funding Information: The Religious Order Study (ROS) and Rush Memory and Aging Project (R-MAP): The R-MAP and ROS data used in this article was supported by National Institute on Aging grants P30AG10161 , R01AG17917 , and R01AG15819, National Institutes of Health grants (R01 AG040039, R21 NS076827, P20 MD006886) and the Illinois Department of Public Health . Funding Information: Cardiovascular Health Study: This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, N01HC15103; and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Funding Information: Erasmus Rucphen Family Study: This study is financially supported by the Netherlands Organization for Scientific Research (NWO), the Internationale Stichting Alzheimer Onderzoek (ISAO), the Hersenstichting Nederland (HSN), and the Centre for Medical Systems Biology (CMSB) in the framework of the Netherlands Genomics Initiative (NGI). The authors thank the participants from the Genetic Research in Isolated Populations, Erasmus Rucphen Family who made this work possible. Funding Information: Aging Gene-Environment Susceptibility-Reykjavik Study: The research has been funded by NIA contract N01-AG-12100 with contributions from NEI, NIDCD, and NHLBI, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). Funding Information: The Rotterdam Study: The GWA database of the Rotterdam Study was funded through the Netherlands Organization of Scientific Research NWO ( nr. 175.010.2005.011 ). This study was further supported by the Netherlands Genomics Initiative (NGI) / Netherlands Organisation for Scientific Research (NWO) project nr. 050-060-810. The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University , Rotterdam; the Netherlands Organization for Scientific Research (NWO), the Netherlands Organization for the Health Research and Development (ZonMw; Veni-grant 916.13.054 ), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health , Welfare and Sports , the European Commission (DG XII), the Municipality of Rotterdam , and the Internationale Stichting Alzheimer Onderzoek . Funding Information: Three City Study (3C): The authors thank the staff and the participants of the 3C Study for their important contributions. The 3C Study is conducted under a partnership agreement between the Institut National de la Santé et de la Recherche Médicale (INSERM), the Victor Segalen–Bordeaux II University, and Sanofi-Aventis. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study is also supported by the Caisse Nationale Maladie des Travailleurs Salariés , Direction Générale de la Santé , Mutuelle Générale de l'Education Nationale (MGEN), Institut de la Longévité , Conseils Régionaux of Aquitaine and Bourgogne , Fondation de France , and Ministry of Research –INSERM Programme “Cohortes et collections de données biologiques.” Lille Génopôle received an unconditional grant from Eisai . The authors thank A. Boland (Centre National de Génotypage) for her technical help in preparing the DNA samples for analyses. This work was supported by the National Foundation for Alzheimer's Disease and Related Disorders , the Institut Pasteur de Lille and the Centre National de Génotypage . Ganesh Chauhan and Stéphanie Debette are supported by a grant from the Fondation Leducq and the Agence Nationale de la Recherche (Chaire d'Excellence). Funding Information: Framingham Heart Study: This work was supported by the Framingham Heart Study's National Heart, Lung, and Blood Institute contract (N01-HC-25195) and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6–4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center . It was also funded by grants from the National Institute on Aging ( R01 AG08122 , AG033193, P30 AG0101029 ) and the National Institute of Neurological Disorders and Stroke ( R01 NS17950 ). Funding Information: The Atherosclerosis Risk in Communities Study: The research is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641 , R01HL59367 and R01HL086694 and R01HL7825 ; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005 , a component of the National Institutes of Health (UL1RR025005) and NIH Roadmap for Medical Research . Funds for these projects were also supported by grant HL093029 to Myriam Fornage. Funding Information: The Austrian Stroke Prevention Study: The research reported in this article was funded by the Austrian Science Fond (FWF) grant number P20545-P05 and P13180 . The Medical University of Graz supports the databank of the ASPS . The authors thank the staff and the participants of the ASPS for their valuable contributions. The authors thank Birgit Reinhart for her long-term administrative commitment and Ing Johann Semmler for the technical assistance at creating the DNA bank. Funding Information: The Tasmanian Study of Gait and Cognition (TASCOG) is supported by Project Grants from the National Health and Medical Research Council (NHMRC IDs 403000, 491109, 606543), and a grant from the Wicking Dementia Education and Research Centre , Hobart. Velandai Srikanth is supported by an NHMRC /National Heart Foundation Career Development Fellowship (ID 606544). Publisher Copyright: © 2015 Elsevier Inc.

PY - 2015/4/1

Y1 - 2015/4/1

N2 - Whether novel risk variants of Alzheimer's disease (AD) identified through genome-wide association studies also influence magnetic resonance imaging-based intermediate phenotypes of AD in the general population is unclear. We studied association of 24 AD risk loci with intracranial volume, total brain volume, hippocampal volume (HV), white matter hyperintensity burden, and brain infarcts in a meta-analysis of genetic association studies from large population-based samples (N= 8175-11,550). In single-SNP based tests, AD risk allele of APOE (rs2075650) was associated with smaller HV (. p= 0.0054) and CD33 (rs3865444) with smaller intracranial volume (. p= 0.0058). In gene-based tests, there was associations of HLA-DRB1 with total brain volume (. p= 0.0006) and BIN1 with HV (. p= 0.00089). Aweighted AD genetic risk score was associated with smaller HV (beta ± SE=-0.047 ± 0.013, p= 0.00041), even after excluding the APOE locus (. p= 0.029). However, only association of AD genetic risk score with HV, including APOE, was significant after multiple testing correction (including number of independent phenotypes tested). These results suggest that novel AD genetic risk variants may contribute to structural brain aging in nondemented older community persons.

AB - Whether novel risk variants of Alzheimer's disease (AD) identified through genome-wide association studies also influence magnetic resonance imaging-based intermediate phenotypes of AD in the general population is unclear. We studied association of 24 AD risk loci with intracranial volume, total brain volume, hippocampal volume (HV), white matter hyperintensity burden, and brain infarcts in a meta-analysis of genetic association studies from large population-based samples (N= 8175-11,550). In single-SNP based tests, AD risk allele of APOE (rs2075650) was associated with smaller HV (. p= 0.0054) and CD33 (rs3865444) with smaller intracranial volume (. p= 0.0058). In gene-based tests, there was associations of HLA-DRB1 with total brain volume (. p= 0.0006) and BIN1 with HV (. p= 0.00089). Aweighted AD genetic risk score was associated with smaller HV (beta ± SE=-0.047 ± 0.013, p= 0.00041), even after excluding the APOE locus (. p= 0.029). However, only association of AD genetic risk score with HV, including APOE, was significant after multiple testing correction (including number of independent phenotypes tested). These results suggest that novel AD genetic risk variants may contribute to structural brain aging in nondemented older community persons.

KW - Alzheimer

KW - GWAS

KW - Genetic risk score

KW - Hippocampal volume

KW - MRI-Markers

UR - http://www.scopus.com/inward/record.url?scp=84925295495&partnerID=8YFLogxK

U2 - 10.1016/j.neurobiolaging.2014.12.028

DO - 10.1016/j.neurobiolaging.2014.12.028

M3 - Article

C2 - 25670335

AN - SCOPUS:84925295495

SN - 0197-4580

VL - 36

SP - 1765.e7-1765.e16

JO - Neurobiology of Aging

JF - Neurobiology of Aging

IS - 4

ER -

Association of Alzheimer's disease GWAS loci with MRI markers of brain aging

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