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

Cohorts for Heart and Aging Research in Genomic Epidemiology consortium

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 (US)
Pages (from-to)749-763
Number of pages15
JournalBiological Psychiatry
Volume77
Issue number8
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

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. / Cohorts for Heart and Aging Research in Genomic Epidemiology consortium.

In: Biological Psychiatry, Vol. 77, No. 8, 01.01.2015, p. 749-763.

Research output: Contribution to journalArticle

Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. / 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.",
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author = "{Cohorts for Heart and Aging Research in Genomic Epidemiology consortium} and 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 Sudha Seshadri",
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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 - 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 - Seshadri, Sudha

PY - 2015/1/1

Y1 - 2015/1/1

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

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JO - Biological Psychiatry

JF - Biological Psychiatry

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