Meta-analysis confirms CR1, CLU, and PICALM as Alzheimer disease risk loci and reveals interactions with APOE genotypes

Gyungah Jun, Adam C. Naj, Gary W Beecham, Li San Wang, Jacqueline Buros, Paul J. Gallins, Joseph D. Buxbaum, Nilufer Ertekin-Taner, M. Daniele Fallin, Robert Friedland, Rivka Inzelberg, Patricia Kramer, Ekaterina Rogaeva, Peter St George-Hyslop, Laura B. Cantwell, Beth A. Dombroski, Andrew J. Saykin, Eric M. Reiman, David A. Bennett, John C. Morris & 16 others Kathryn L. Lunetta, Eden R Martin, Thomas J. Montine, Alison M. Goate, Deborah Blacker, Debby W. Tsuang, Duane Beekly, L. Adrienne Cupples, Hakon Hakonarson, Walter Kukull, Tatiana M. Foroud, Jonathan Haines, Richard Mayeux, Lindsay A. Farrer, Margaret A Pericak-Vance, Gerard D. Schellenberg

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Abstract

Objectives: To determine whether genotypes at CLU, PICALM, and CR1 confer risk for Alzheimer disease (AD) and whether risk for AD associated with these genes is influenced by apolipoprotein E (APOE) genotypes. Design: Association study ofADand CLU, PICALM, CR1, and APOE genotypes. Setting: Academic research institutions in the United States, Canada, and Israel. Participants: Seven thousand seventy cases with AD, 3055 with autopsies, and 8169 elderly cognitively normal controls, 1092 with autopsies, from 12 different studies, including white, African American, Israeli-Arab, and Caribbean Hispanic individuals. Results: Unadjusted, CLU (odds ratio [OR], 0.91; 95% confidence interval [CI], 0.85-0.96 for single-nucleotide polymorphism [SNP] rs11136000), CR1 (OR, 1.14; 95% CI, 1.07-1.22; SNP rs3818361), and PICALM (OR, 0.89; 95% CI, 0.84-0.94, SNP rs3851179) were associated with AD in white individuals. None were significantly associated with AD in the other ethnic groups. APOEε4 was significantly associated with AD (ORs, 1.80-9.05) in all but 1 small white cohort and in the Arab cohort. Adjusting for age, sex, and the presence of at least 1 APOEε4 allele greatly reduced evidence for association with PICALM but not CR1 or CLU. Models with the main SNP effect, presence or absence of APOEε4, and an interaction term showed significant interaction between presence or absence of APOEε4 and PICALM. Conclusions: We confirm in a completely independent data set that CR1, CLU, and PICALM are AD susceptibility loci in European ancestry populations. Genotypes at PICALM confer risk predominantly in APOE ε4-positive subjects. Thus, APOE and PICALM synergistically interact.

Original languageEnglish
Pages (from-to)1473-1484
Number of pages12
JournalArchives of Neurology
Volume67
Issue number12
DOIs
StatePublished - Dec 1 2010

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Apolipoproteins E
Meta-Analysis
Alzheimer Disease
Genotype
Single Nucleotide Polymorphism
Odds Ratio
Confidence Intervals
Autopsy
Apolipoprotein E4
Disease Susceptibility
Israel
Alzheimer's Disease
Interaction
Locus
Meta-analysis
Hispanic Americans
Ethnic Groups
African Americans
Canada
Alleles

ASJC Scopus subject areas

  • Clinical Neurology

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Meta-analysis confirms CR1, CLU, and PICALM as Alzheimer disease risk loci and reveals interactions with APOE genotypes. / Jun, Gyungah; Naj, Adam C.; Beecham, Gary W; Wang, Li San; Buros, Jacqueline; Gallins, Paul J.; Buxbaum, Joseph D.; Ertekin-Taner, Nilufer; Fallin, M. Daniele; Friedland, Robert; Inzelberg, Rivka; Kramer, Patricia; Rogaeva, Ekaterina; St George-Hyslop, Peter; Cantwell, Laura B.; Dombroski, Beth A.; Saykin, Andrew J.; Reiman, Eric M.; Bennett, David A.; Morris, John C.; Lunetta, Kathryn L.; Martin, Eden R; Montine, Thomas J.; Goate, Alison M.; Blacker, Deborah; Tsuang, Debby W.; Beekly, Duane; Cupples, L. Adrienne; Hakonarson, Hakon; Kukull, Walter; Foroud, Tatiana M.; Haines, Jonathan; Mayeux, Richard; Farrer, Lindsay A.; Pericak-Vance, Margaret A; Schellenberg, Gerard D.

In: Archives of Neurology, Vol. 67, No. 12, 01.12.2010, p. 1473-1484.

Research output: Contribution to journalArticle

Jun, G, Naj, AC, Beecham, GW, Wang, LS, Buros, J, Gallins, PJ, Buxbaum, JD, Ertekin-Taner, N, Fallin, MD, Friedland, R, Inzelberg, R, Kramer, P, Rogaeva, E, St George-Hyslop, P, Cantwell, LB, Dombroski, BA, Saykin, AJ, Reiman, EM, Bennett, DA, Morris, JC, Lunetta, KL, Martin, ER, Montine, TJ, Goate, AM, Blacker, D, Tsuang, DW, Beekly, D, Cupples, LA, Hakonarson, H, Kukull, W, Foroud, TM, Haines, J, Mayeux, R, Farrer, LA, Pericak-Vance, MA & Schellenberg, GD 2010, 'Meta-analysis confirms CR1, CLU, and PICALM as Alzheimer disease risk loci and reveals interactions with APOE genotypes', Archives of Neurology, vol. 67, no. 12, pp. 1473-1484. https://doi.org/10.1001/archneurol.2010.201
Jun, Gyungah ; Naj, Adam C. ; Beecham, Gary W ; Wang, Li San ; Buros, Jacqueline ; Gallins, Paul J. ; Buxbaum, Joseph D. ; Ertekin-Taner, Nilufer ; Fallin, M. Daniele ; Friedland, Robert ; Inzelberg, Rivka ; Kramer, Patricia ; Rogaeva, Ekaterina ; St George-Hyslop, Peter ; Cantwell, Laura B. ; Dombroski, Beth A. ; Saykin, Andrew J. ; Reiman, Eric M. ; Bennett, David A. ; Morris, John C. ; Lunetta, Kathryn L. ; Martin, Eden R ; Montine, Thomas J. ; Goate, Alison M. ; Blacker, Deborah ; Tsuang, Debby W. ; Beekly, Duane ; Cupples, L. Adrienne ; Hakonarson, Hakon ; Kukull, Walter ; Foroud, Tatiana M. ; Haines, Jonathan ; Mayeux, Richard ; Farrer, Lindsay A. ; Pericak-Vance, Margaret A ; Schellenberg, Gerard D. / Meta-analysis confirms CR1, CLU, and PICALM as Alzheimer disease risk loci and reveals interactions with APOE genotypes. In: Archives of Neurology. 2010 ; Vol. 67, No. 12. pp. 1473-1484.
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abstract = "Objectives: To determine whether genotypes at CLU, PICALM, and CR1 confer risk for Alzheimer disease (AD) and whether risk for AD associated with these genes is influenced by apolipoprotein E (APOE) genotypes. Design: Association study ofADand CLU, PICALM, CR1, and APOE genotypes. Setting: Academic research institutions in the United States, Canada, and Israel. Participants: Seven thousand seventy cases with AD, 3055 with autopsies, and 8169 elderly cognitively normal controls, 1092 with autopsies, from 12 different studies, including white, African American, Israeli-Arab, and Caribbean Hispanic individuals. Results: Unadjusted, CLU (odds ratio [OR], 0.91; 95{\%} confidence interval [CI], 0.85-0.96 for single-nucleotide polymorphism [SNP] rs11136000), CR1 (OR, 1.14; 95{\%} CI, 1.07-1.22; SNP rs3818361), and PICALM (OR, 0.89; 95{\%} CI, 0.84-0.94, SNP rs3851179) were associated with AD in white individuals. None were significantly associated with AD in the other ethnic groups. APOEε4 was significantly associated with AD (ORs, 1.80-9.05) in all but 1 small white cohort and in the Arab cohort. Adjusting for age, sex, and the presence of at least 1 APOEε4 allele greatly reduced evidence for association with PICALM but not CR1 or CLU. Models with the main SNP effect, presence or absence of APOEε4, and an interaction term showed significant interaction between presence or absence of APOEε4 and PICALM. Conclusions: We confirm in a completely independent data set that CR1, CLU, and PICALM are AD susceptibility loci in European ancestry populations. Genotypes at PICALM confer risk predominantly in APOE ε4-positive subjects. Thus, APOE and PICALM synergistically interact.",
author = "Gyungah Jun and Naj, {Adam C.} and Beecham, {Gary W} and Wang, {Li San} and Jacqueline Buros and Gallins, {Paul J.} and Buxbaum, {Joseph D.} and Nilufer Ertekin-Taner and Fallin, {M. Daniele} and Robert Friedland and Rivka Inzelberg and Patricia Kramer and Ekaterina Rogaeva and {St George-Hyslop}, Peter and Cantwell, {Laura B.} and Dombroski, {Beth A.} and Saykin, {Andrew J.} and Reiman, {Eric M.} and Bennett, {David A.} and Morris, {John C.} and Lunetta, {Kathryn L.} and Martin, {Eden R} and Montine, {Thomas J.} and Goate, {Alison M.} and Deborah Blacker and Tsuang, {Debby W.} and Duane Beekly and Cupples, {L. Adrienne} and Hakon Hakonarson and Walter Kukull and Foroud, {Tatiana M.} and Jonathan Haines and Richard Mayeux and Farrer, {Lindsay A.} and Pericak-Vance, {Margaret A} and Schellenberg, {Gerard D.}",
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TY - JOUR

T1 - Meta-analysis confirms CR1, CLU, and PICALM as Alzheimer disease risk loci and reveals interactions with APOE genotypes

AU - Jun, Gyungah

AU - Naj, Adam C.

AU - Beecham, Gary W

AU - Wang, Li San

AU - Buros, Jacqueline

AU - Gallins, Paul J.

AU - Buxbaum, Joseph D.

AU - Ertekin-Taner, Nilufer

AU - Fallin, M. Daniele

AU - Friedland, Robert

AU - Inzelberg, Rivka

AU - Kramer, Patricia

AU - Rogaeva, Ekaterina

AU - St George-Hyslop, Peter

AU - Cantwell, Laura B.

AU - Dombroski, Beth A.

AU - Saykin, Andrew J.

AU - Reiman, Eric M.

AU - Bennett, David A.

AU - Morris, John C.

AU - Lunetta, Kathryn L.

AU - Martin, Eden R

AU - Montine, Thomas J.

AU - Goate, Alison M.

AU - Blacker, Deborah

AU - Tsuang, Debby W.

AU - Beekly, Duane

AU - Cupples, L. Adrienne

AU - Hakonarson, Hakon

AU - Kukull, Walter

AU - Foroud, Tatiana M.

AU - Haines, Jonathan

AU - Mayeux, Richard

AU - Farrer, Lindsay A.

AU - Pericak-Vance, Margaret A

AU - Schellenberg, Gerard D.

PY - 2010/12/1

Y1 - 2010/12/1

N2 - Objectives: To determine whether genotypes at CLU, PICALM, and CR1 confer risk for Alzheimer disease (AD) and whether risk for AD associated with these genes is influenced by apolipoprotein E (APOE) genotypes. Design: Association study ofADand CLU, PICALM, CR1, and APOE genotypes. Setting: Academic research institutions in the United States, Canada, and Israel. Participants: Seven thousand seventy cases with AD, 3055 with autopsies, and 8169 elderly cognitively normal controls, 1092 with autopsies, from 12 different studies, including white, African American, Israeli-Arab, and Caribbean Hispanic individuals. Results: Unadjusted, CLU (odds ratio [OR], 0.91; 95% confidence interval [CI], 0.85-0.96 for single-nucleotide polymorphism [SNP] rs11136000), CR1 (OR, 1.14; 95% CI, 1.07-1.22; SNP rs3818361), and PICALM (OR, 0.89; 95% CI, 0.84-0.94, SNP rs3851179) were associated with AD in white individuals. None were significantly associated with AD in the other ethnic groups. APOEε4 was significantly associated with AD (ORs, 1.80-9.05) in all but 1 small white cohort and in the Arab cohort. Adjusting for age, sex, and the presence of at least 1 APOEε4 allele greatly reduced evidence for association with PICALM but not CR1 or CLU. Models with the main SNP effect, presence or absence of APOEε4, and an interaction term showed significant interaction between presence or absence of APOEε4 and PICALM. Conclusions: We confirm in a completely independent data set that CR1, CLU, and PICALM are AD susceptibility loci in European ancestry populations. Genotypes at PICALM confer risk predominantly in APOE ε4-positive subjects. Thus, APOE and PICALM synergistically interact.

AB - Objectives: To determine whether genotypes at CLU, PICALM, and CR1 confer risk for Alzheimer disease (AD) and whether risk for AD associated with these genes is influenced by apolipoprotein E (APOE) genotypes. Design: Association study ofADand CLU, PICALM, CR1, and APOE genotypes. Setting: Academic research institutions in the United States, Canada, and Israel. Participants: Seven thousand seventy cases with AD, 3055 with autopsies, and 8169 elderly cognitively normal controls, 1092 with autopsies, from 12 different studies, including white, African American, Israeli-Arab, and Caribbean Hispanic individuals. Results: Unadjusted, CLU (odds ratio [OR], 0.91; 95% confidence interval [CI], 0.85-0.96 for single-nucleotide polymorphism [SNP] rs11136000), CR1 (OR, 1.14; 95% CI, 1.07-1.22; SNP rs3818361), and PICALM (OR, 0.89; 95% CI, 0.84-0.94, SNP rs3851179) were associated with AD in white individuals. None were significantly associated with AD in the other ethnic groups. APOEε4 was significantly associated with AD (ORs, 1.80-9.05) in all but 1 small white cohort and in the Arab cohort. Adjusting for age, sex, and the presence of at least 1 APOEε4 allele greatly reduced evidence for association with PICALM but not CR1 or CLU. Models with the main SNP effect, presence or absence of APOEε4, and an interaction term showed significant interaction between presence or absence of APOEε4 and PICALM. Conclusions: We confirm in a completely independent data set that CR1, CLU, and PICALM are AD susceptibility loci in European ancestry populations. Genotypes at PICALM confer risk predominantly in APOE ε4-positive subjects. Thus, APOE and PICALM synergistically interact.

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