Genome-wide studies of verbal declarative memory in nondemented older people: The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium

Stéphanie Debette, Carla A. Ibrahim Verbaas, Jan Bressler, Maaike Schuur, Albert Smith, Joshua C. Bis, Gail Davies, Christiane Wolf, Vilmundur Gudnason, Lori B. Chibnik, Qiong Yang, Anita L. DeStefano, Dominique J F De Quervain, Velandai Srikanth, Jari Lahti, Hans J. Grabe, Jennifer A. Smith, Lutz Priebe, Lei Yu, Nazanin KarbalaiCaroline Hayward, James F. Wilson, Harry Campbell, Katja Petrovic, Myriam Fornage, Ganesh Chauhan, Robin Yeo, Ruth Boxall, James Becker, Oliver Stegle, Karen A. Mather, Vincent Chouraki, Qi Sun, Lynda M. Rose, Susan Resnick, Christopher Oldmeadow, Mirna Kirin, Alan F. Wright, Maria K. Jonsdottir, Rhoda Au, Albert Becker, Najaf Amin, Mike A. Nalls, Stephen T. Turner, Sharon L R Kardia, Ben Oostra, Gwen Windham, Laura H. Coker, Wei Zhao, David S. Knopman, Gerardo Heiss, Michael E. Griswold, Rebecca F. Gottesman, Veronique Vitart, Nicholas D. Hastie, Lina Zgaga, Igor Rudan, Ozren Polasek, Elizabeth G. Holliday, Peter Schofield, Seung Hoan Choi, Toshiko Tanaka, Yang An, Rodney T. Perry, Richard E. Kennedy, Michèle M. Sale, Jing Wang, Virginia G. Wadley, David C. Liewald, Paul M. Ridker, Alan J. Gow, Alison Pattie, John M. Starr, David Porteous, Xuan Liu, Russell Thomson, Nicola J. Armstrong, Gudny Eiriksdottir, Arezoo A. Assareh, Nicole A. Kochan, Elisabeth Widen, Aarno Palotie, Yi Chen Hsieh, Johan G. Eriksson, Christian Vogler, John C. Van Swieten, Joshua M. Shulman, Alexa Beiser, Jerome Rotter, Carsten O. Schmidt, Wolfgang Hoffmann, Markus M. Nöthen, Luigi Ferrucci, John Attia, Andre G. Uitterlinden, Philippe Amouyel, Jean François Dartigues, Hélène Amieva, Katri Räikkönen, Melissa Garcia, Philip A. Wolf, Albert Hofman, W. T. Longstreth, Bruce M. Psaty, Eric Boerwinkle, Philip L. DeJager, Perminder S. Sachdev, Reinhold Schmidt, Monique Breteler, Alexander Teumer, Oscar L. Lopez, Sven Cichon, Daniel I. Chasman, Francine Grodstein, Bertram Müller-Myhsok, Christophe Tzourio, Andreas Papassotiropoulos, David A. Bennett, M. Arfan Ikram, Ian J. Deary, Cornelia M. Van Duijn, Lenore Launer, Annette L. Fitzpatrick, Sudha Seshadri, Thomas H. Mosley

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

BACKGROUND: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting. METHODS: We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p <5 × 10-6) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults. RESULTS: rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10-10) and replication cohorts (p = 5.65 × 10-8). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10-8, and rs6813517 [SPOCK3], p = 2.58 × 10-8) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism. CONCLUSIONS: This largest study to date exploring the genetics of memory function in ∼40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.

Original languageEnglish
Pages (from-to)749-763
Number of pages15
JournalBiological Psychiatry
Volume77
Issue number8
DOIs
Publication statusPublished - 2015

Fingerprint

Epidemiology
Genome
Research
Ubiquitin
Genome-Wide Association Study
African Americans
Cognition
Dementia
Young Adult
Autopsy
Hippocampus
Alzheimer Disease
Stroke
Pathology
Gene Expression
Genes

Keywords

  • Alzheimer disease
  • Dementia
  • Epidemiology
  • Genetics
  • Population-based
  • Verbal declarative memory

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Genome-wide studies of verbal declarative memory in nondemented older people : The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. / Debette, Stéphanie; Ibrahim Verbaas, Carla A.; Bressler, Jan; Schuur, Maaike; Smith, Albert; Bis, Joshua C.; Davies, Gail; Wolf, Christiane; Gudnason, Vilmundur; Chibnik, Lori B.; Yang, Qiong; DeStefano, Anita L.; De Quervain, Dominique J F; Srikanth, Velandai; Lahti, Jari; Grabe, Hans J.; Smith, Jennifer A.; Priebe, Lutz; Yu, Lei; Karbalai, Nazanin; Hayward, Caroline; Wilson, James F.; Campbell, Harry; Petrovic, Katja; Fornage, Myriam; Chauhan, Ganesh; Yeo, Robin; Boxall, Ruth; Becker, James; Stegle, Oliver; Mather, Karen A.; Chouraki, Vincent; Sun, Qi; Rose, Lynda M.; Resnick, Susan; Oldmeadow, Christopher; Kirin, Mirna; Wright, Alan F.; Jonsdottir, Maria K.; Au, Rhoda; Becker, Albert; Amin, Najaf; Nalls, Mike A.; Turner, Stephen T.; Kardia, Sharon L R; Oostra, Ben; Windham, Gwen; Coker, Laura H.; Zhao, Wei; Knopman, David S.; Heiss, Gerardo; Griswold, Michael E.; Gottesman, Rebecca F.; Vitart, Veronique; Hastie, Nicholas D.; Zgaga, Lina; Rudan, Igor; Polasek, Ozren; Holliday, Elizabeth G.; Schofield, Peter; Choi, Seung Hoan; Tanaka, Toshiko; An, Yang; Perry, Rodney T.; Kennedy, Richard E.; Sale, Michèle M.; Wang, Jing; Wadley, Virginia G.; Liewald, David C.; Ridker, Paul M.; Gow, Alan J.; Pattie, Alison; Starr, John M.; Porteous, David; Liu, Xuan; Thomson, Russell; Armstrong, Nicola J.; Eiriksdottir, Gudny; Assareh, Arezoo A.; Kochan, Nicole A.; Widen, Elisabeth; Palotie, Aarno; Hsieh, Yi Chen; Eriksson, Johan G.; Vogler, Christian; Van Swieten, John C.; Shulman, Joshua M.; Beiser, Alexa; Rotter, Jerome; Schmidt, Carsten O.; Hoffmann, Wolfgang; Nöthen, Markus M.; Ferrucci, Luigi; Attia, John; Uitterlinden, Andre G.; Amouyel, Philippe; Dartigues, Jean François; Amieva, Hélène; Räikkönen, Katri; Garcia, Melissa; Wolf, Philip A.; Hofman, Albert; Longstreth, W. T.; Psaty, Bruce M.; Boerwinkle, Eric; DeJager, Philip L.; Sachdev, Perminder S.; Schmidt, Reinhold; Breteler, Monique; Teumer, Alexander; Lopez, Oscar L.; Cichon, Sven; Chasman, Daniel I.; Grodstein, Francine; Müller-Myhsok, Bertram; Tzourio, Christophe; Papassotiropoulos, Andreas; Bennett, David A.; Ikram, M. Arfan; Deary, Ian J.; Van Duijn, Cornelia M.; Launer, Lenore; Fitzpatrick, Annette L.; Seshadri, Sudha; Mosley, Thomas H.

In: Biological Psychiatry, Vol. 77, No. 8, 2015, p. 749-763.

Research output: Contribution to journalArticle

Debette, S, Ibrahim Verbaas, CA, Bressler, J, Schuur, M, Smith, A, Bis, JC, Davies, G, Wolf, C, Gudnason, V, Chibnik, LB, Yang, Q, DeStefano, AL, De Quervain, DJF, Srikanth, V, Lahti, J, Grabe, HJ, Smith, JA, Priebe, L, Yu, L, Karbalai, N, Hayward, C, Wilson, JF, Campbell, H, Petrovic, K, Fornage, M, Chauhan, G, Yeo, R, Boxall, R, Becker, J, Stegle, O, Mather, KA, Chouraki, V, Sun, Q, Rose, LM, Resnick, S, Oldmeadow, C, Kirin, M, Wright, AF, Jonsdottir, MK, Au, R, Becker, A, Amin, N, Nalls, MA, Turner, ST, Kardia, SLR, Oostra, B, Windham, G, Coker, LH, Zhao, W, Knopman, DS, Heiss, G, Griswold, ME, Gottesman, RF, Vitart, V, Hastie, ND, Zgaga, L, Rudan, I, Polasek, O, Holliday, EG, Schofield, P, Choi, SH, Tanaka, T, An, Y, Perry, RT, Kennedy, RE, Sale, MM, Wang, J, Wadley, VG, Liewald, DC, Ridker, PM, Gow, AJ, Pattie, A, Starr, JM, Porteous, D, Liu, X, Thomson, R, Armstrong, NJ, Eiriksdottir, G, Assareh, AA, Kochan, NA, Widen, E, Palotie, A, Hsieh, YC, Eriksson, JG, Vogler, C, Van Swieten, JC, Shulman, JM, Beiser, A, Rotter, J, Schmidt, CO, Hoffmann, W, Nöthen, MM, Ferrucci, L, Attia, J, Uitterlinden, AG, Amouyel, P, Dartigues, JF, Amieva, H, Räikkönen, K, Garcia, M, Wolf, PA, Hofman, A, Longstreth, WT, Psaty, BM, Boerwinkle, E, DeJager, PL, Sachdev, PS, Schmidt, R, Breteler, M, Teumer, A, Lopez, OL, Cichon, S, Chasman, DI, Grodstein, F, Müller-Myhsok, B, Tzourio, C, Papassotiropoulos, A, Bennett, DA, Ikram, MA, Deary, IJ, Van Duijn, CM, Launer, L, Fitzpatrick, AL, Seshadri, S & Mosley, TH 2015, 'Genome-wide studies of verbal declarative memory in nondemented older people: The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium', Biological Psychiatry, vol. 77, no. 8, pp. 749-763. https://doi.org/10.1016/j.biopsych.2014.08.027
Debette, Stéphanie ; Ibrahim Verbaas, Carla A. ; Bressler, Jan ; Schuur, Maaike ; Smith, Albert ; Bis, Joshua C. ; Davies, Gail ; Wolf, Christiane ; Gudnason, Vilmundur ; Chibnik, Lori B. ; Yang, Qiong ; DeStefano, Anita L. ; De Quervain, Dominique J F ; Srikanth, Velandai ; Lahti, Jari ; Grabe, Hans J. ; Smith, Jennifer A. ; Priebe, Lutz ; Yu, Lei ; Karbalai, Nazanin ; Hayward, Caroline ; Wilson, James F. ; Campbell, Harry ; Petrovic, Katja ; Fornage, Myriam ; Chauhan, Ganesh ; Yeo, Robin ; Boxall, Ruth ; Becker, James ; Stegle, Oliver ; Mather, Karen A. ; Chouraki, Vincent ; Sun, Qi ; Rose, Lynda M. ; Resnick, Susan ; Oldmeadow, Christopher ; Kirin, Mirna ; Wright, Alan F. ; Jonsdottir, Maria K. ; Au, Rhoda ; Becker, Albert ; Amin, Najaf ; Nalls, Mike A. ; Turner, Stephen T. ; Kardia, Sharon L R ; Oostra, Ben ; Windham, Gwen ; Coker, Laura H. ; Zhao, Wei ; Knopman, David S. ; Heiss, Gerardo ; Griswold, Michael E. ; Gottesman, Rebecca F. ; Vitart, Veronique ; Hastie, Nicholas D. ; Zgaga, Lina ; Rudan, Igor ; Polasek, Ozren ; Holliday, Elizabeth G. ; Schofield, Peter ; Choi, Seung Hoan ; Tanaka, Toshiko ; An, Yang ; Perry, Rodney T. ; Kennedy, Richard E. ; Sale, Michèle M. ; Wang, Jing ; Wadley, Virginia G. ; Liewald, David C. ; Ridker, Paul M. ; Gow, Alan J. ; Pattie, Alison ; Starr, John M. ; Porteous, David ; Liu, Xuan ; Thomson, Russell ; Armstrong, Nicola J. ; Eiriksdottir, Gudny ; Assareh, Arezoo A. ; Kochan, Nicole A. ; Widen, Elisabeth ; Palotie, Aarno ; Hsieh, Yi Chen ; Eriksson, Johan G. ; Vogler, Christian ; Van Swieten, John C. ; Shulman, Joshua M. ; Beiser, Alexa ; Rotter, Jerome ; Schmidt, Carsten O. ; Hoffmann, Wolfgang ; Nöthen, Markus M. ; Ferrucci, Luigi ; Attia, John ; Uitterlinden, Andre G. ; Amouyel, Philippe ; Dartigues, Jean François ; Amieva, Hélène ; Räikkönen, Katri ; Garcia, Melissa ; Wolf, Philip A. ; Hofman, Albert ; Longstreth, W. T. ; Psaty, Bruce M. ; Boerwinkle, Eric ; DeJager, Philip L. ; Sachdev, Perminder S. ; Schmidt, Reinhold ; Breteler, Monique ; Teumer, Alexander ; Lopez, Oscar L. ; Cichon, Sven ; Chasman, Daniel I. ; Grodstein, Francine ; Müller-Myhsok, Bertram ; Tzourio, Christophe ; Papassotiropoulos, Andreas ; Bennett, David A. ; Ikram, M. Arfan ; Deary, Ian J. ; Van Duijn, Cornelia M. ; Launer, Lenore ; Fitzpatrick, Annette L. ; Seshadri, Sudha ; Mosley, Thomas H. / Genome-wide studies of verbal declarative memory in nondemented older people : The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. In: Biological Psychiatry. 2015 ; Vol. 77, No. 8. pp. 749-763.
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abstract = "BACKGROUND: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting. METHODS: We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p <5 × 10-6) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults. RESULTS: rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10-10) and replication cohorts (p = 5.65 × 10-8). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10-8, and rs6813517 [SPOCK3], p = 2.58 × 10-8) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism. CONCLUSIONS: This largest study to date exploring the genetics of memory function in ∼40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.",
keywords = "Alzheimer disease, Dementia, Epidemiology, Genetics, Population-based, Verbal declarative memory",
author = "St{\'e}phanie Debette and {Ibrahim Verbaas}, {Carla A.} and Jan Bressler and Maaike Schuur and Albert Smith and Bis, {Joshua C.} and Gail Davies and Christiane Wolf and Vilmundur Gudnason and Chibnik, {Lori B.} and Qiong Yang and DeStefano, {Anita L.} and {De Quervain}, {Dominique J F} and Velandai Srikanth and Jari Lahti and Grabe, {Hans J.} and Smith, {Jennifer A.} and Lutz Priebe and Lei Yu and Nazanin Karbalai and Caroline Hayward and Wilson, {James F.} and Harry Campbell and Katja Petrovic and Myriam Fornage and Ganesh Chauhan and Robin Yeo and Ruth Boxall and James Becker and Oliver Stegle and Mather, {Karen A.} and Vincent Chouraki and Qi Sun and Rose, {Lynda M.} and Susan Resnick and Christopher Oldmeadow and Mirna Kirin and Wright, {Alan F.} and Jonsdottir, {Maria K.} and Rhoda Au and Albert Becker and Najaf Amin and Nalls, {Mike A.} and Turner, {Stephen T.} and Kardia, {Sharon L R} and Ben Oostra and Gwen Windham and Coker, {Laura H.} and Wei Zhao and Knopman, {David S.} and Gerardo Heiss and Griswold, {Michael E.} and Gottesman, {Rebecca F.} and Veronique Vitart and Hastie, {Nicholas D.} and Lina Zgaga and Igor Rudan and Ozren Polasek and Holliday, {Elizabeth G.} and Peter Schofield and Choi, {Seung Hoan} and Toshiko Tanaka and Yang An and Perry, {Rodney T.} and Kennedy, {Richard E.} and Sale, {Mich{\`e}le M.} and Jing Wang and Wadley, {Virginia G.} and Liewald, {David C.} and Ridker, {Paul M.} and Gow, {Alan J.} and Alison Pattie and Starr, {John M.} and David Porteous and Xuan Liu and Russell Thomson and Armstrong, {Nicola J.} and Gudny Eiriksdottir and Assareh, {Arezoo A.} and Kochan, {Nicole A.} and Elisabeth Widen and Aarno Palotie and Hsieh, {Yi Chen} and Eriksson, {Johan G.} and Christian Vogler and {Van Swieten}, {John C.} and Shulman, {Joshua M.} and Alexa Beiser and Jerome Rotter and Schmidt, {Carsten O.} and Wolfgang Hoffmann and N{\"o}then, {Markus M.} and Luigi Ferrucci and John Attia and Uitterlinden, {Andre G.} and Philippe Amouyel and Dartigues, {Jean Fran{\cc}ois} and H{\'e}l{\`e}ne Amieva and Katri R{\"a}ikk{\"o}nen and Melissa Garcia and Wolf, {Philip A.} and Albert Hofman and Longstreth, {W. T.} and Psaty, {Bruce M.} and Eric Boerwinkle and DeJager, {Philip L.} and Sachdev, {Perminder S.} and Reinhold Schmidt and Monique Breteler and Alexander Teumer and Lopez, {Oscar L.} and Sven Cichon and Chasman, {Daniel I.} and Francine Grodstein and Bertram M{\"u}ller-Myhsok and Christophe Tzourio and Andreas Papassotiropoulos and Bennett, {David A.} and Ikram, {M. Arfan} and Deary, {Ian J.} and {Van Duijn}, {Cornelia M.} and Lenore Launer and Fitzpatrick, {Annette L.} and Sudha Seshadri and Mosley, {Thomas H.}",
year = "2015",
doi = "10.1016/j.biopsych.2014.08.027",
language = "English",
volume = "77",
pages = "749--763",
journal = "Biological Psychiatry",
issn = "0006-3223",
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}

TY - JOUR

T1 - Genome-wide studies of verbal declarative memory in nondemented older people

T2 - The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium

AU - Debette, Stéphanie

AU - Ibrahim Verbaas, Carla A.

AU - Bressler, Jan

AU - Schuur, Maaike

AU - Smith, Albert

AU - Bis, Joshua C.

AU - Davies, Gail

AU - Wolf, Christiane

AU - Gudnason, Vilmundur

AU - Chibnik, Lori B.

AU - Yang, Qiong

AU - DeStefano, Anita L.

AU - De Quervain, Dominique J F

AU - Srikanth, Velandai

AU - Lahti, Jari

AU - Grabe, Hans J.

AU - Smith, Jennifer A.

AU - Priebe, Lutz

AU - Yu, Lei

AU - Karbalai, Nazanin

AU - Hayward, Caroline

AU - Wilson, James F.

AU - Campbell, Harry

AU - Petrovic, Katja

AU - Fornage, Myriam

AU - Chauhan, Ganesh

AU - Yeo, Robin

AU - Boxall, Ruth

AU - Becker, James

AU - Stegle, Oliver

AU - Mather, Karen A.

AU - Chouraki, Vincent

AU - Sun, Qi

AU - Rose, Lynda M.

AU - Resnick, Susan

AU - Oldmeadow, Christopher

AU - Kirin, Mirna

AU - Wright, Alan F.

AU - Jonsdottir, Maria K.

AU - Au, Rhoda

AU - Becker, Albert

AU - Amin, Najaf

AU - Nalls, Mike A.

AU - Turner, Stephen T.

AU - Kardia, Sharon L R

AU - Oostra, Ben

AU - Windham, Gwen

AU - Coker, Laura H.

AU - Zhao, Wei

AU - Knopman, David S.

AU - Heiss, Gerardo

AU - Griswold, Michael E.

AU - Gottesman, Rebecca F.

AU - Vitart, Veronique

AU - Hastie, Nicholas D.

AU - Zgaga, Lina

AU - Rudan, Igor

AU - Polasek, Ozren

AU - Holliday, Elizabeth G.

AU - Schofield, Peter

AU - Choi, Seung Hoan

AU - Tanaka, Toshiko

AU - An, Yang

AU - Perry, Rodney T.

AU - Kennedy, Richard E.

AU - Sale, Michèle M.

AU - Wang, Jing

AU - Wadley, Virginia G.

AU - Liewald, David C.

AU - Ridker, Paul M.

AU - Gow, Alan J.

AU - Pattie, Alison

AU - Starr, John M.

AU - Porteous, David

AU - Liu, Xuan

AU - Thomson, Russell

AU - Armstrong, Nicola J.

AU - Eiriksdottir, Gudny

AU - Assareh, Arezoo A.

AU - Kochan, Nicole A.

AU - Widen, Elisabeth

AU - Palotie, Aarno

AU - Hsieh, Yi Chen

AU - Eriksson, Johan G.

AU - Vogler, Christian

AU - Van Swieten, John C.

AU - Shulman, Joshua M.

AU - Beiser, Alexa

AU - Rotter, Jerome

AU - Schmidt, Carsten O.

AU - Hoffmann, Wolfgang

AU - Nöthen, Markus M.

AU - Ferrucci, Luigi

AU - Attia, John

AU - Uitterlinden, Andre G.

AU - Amouyel, Philippe

AU - Dartigues, Jean François

AU - Amieva, Hélène

AU - Räikkönen, Katri

AU - Garcia, Melissa

AU - Wolf, Philip A.

AU - Hofman, Albert

AU - Longstreth, W. T.

AU - Psaty, Bruce M.

AU - Boerwinkle, Eric

AU - DeJager, Philip L.

AU - Sachdev, Perminder S.

AU - Schmidt, Reinhold

AU - Breteler, Monique

AU - Teumer, Alexander

AU - Lopez, Oscar L.

AU - Cichon, Sven

AU - Chasman, Daniel I.

AU - Grodstein, Francine

AU - Müller-Myhsok, Bertram

AU - Tzourio, Christophe

AU - Papassotiropoulos, Andreas

AU - Bennett, David A.

AU - Ikram, M. Arfan

AU - Deary, Ian J.

AU - Van Duijn, Cornelia M.

AU - Launer, Lenore

AU - Fitzpatrick, Annette L.

AU - Seshadri, Sudha

AU - Mosley, Thomas H.

PY - 2015

Y1 - 2015

N2 - BACKGROUND: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting. METHODS: We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p <5 × 10-6) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults. RESULTS: rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10-10) and replication cohorts (p = 5.65 × 10-8). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10-8, and rs6813517 [SPOCK3], p = 2.58 × 10-8) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism. CONCLUSIONS: This largest study to date exploring the genetics of memory function in ∼40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.

AB - BACKGROUND: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting. METHODS: We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p <5 × 10-6) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults. RESULTS: rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10-10) and replication cohorts (p = 5.65 × 10-8). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10-8, and rs6813517 [SPOCK3], p = 2.58 × 10-8) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism. CONCLUSIONS: This largest study to date exploring the genetics of memory function in ∼40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.

KW - Alzheimer disease

KW - Dementia

KW - Epidemiology

KW - Genetics

KW - Population-based

KW - Verbal declarative memory

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U2 - 10.1016/j.biopsych.2014.08.027

DO - 10.1016/j.biopsych.2014.08.027

M3 - Article

C2 - 25648963

AN - SCOPUS:84928119304

VL - 77

SP - 749

EP - 763

JO - Biological Psychiatry

JF - Biological Psychiatry

SN - 0006-3223

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