Genome-wide analysis of genetic loci associated with Alzheimer disease

Sudha Seshadri, Annette L. Fitzpatrick, M. Arfan Ikram, Anita L. DeStefano, Vilmundur Gudnason, Merce Boada, Joshua C. Bis, Albert V. Smith, Minerva M. Carassquillo, Jean Charles Lambert, Denise Harold, Elisabeth M C Schrijvers, Reposo Ramirez-Lorca, Stephanie Debette, W. T. Longstreth, A. Cecile J W Janssens, V. Shane Pankratz, Jean François Dartigues, Paul Hollingworth, Thor AspelundIsabel Hernandez, Alexa Beiser, Lewis H. Kuller, Peter J. Koudstaal, Dennis W Dickson, Christophe Tzourio, Richard Abraham, Carmen Antunez, Yangchun Du, Jerome I. Rotter, Yurii S. Aulchenko, Tamara B. Harris, Ronald Carl Petersen, Claudine Berr, Michael J. Owen, Jesus Lopez-Arrieta, Badri N. Varadarajan, James T. Becker, Fernando Rivadeneira, Michael A. Nalls, Neill R Graff Radford, Dominique Campion, Sanford Auerbach, Kenneth Rice, Albert Hofman, Palmi V. Jonsson, Helena Schmidt, Mark Lathrop, Thomas H. Mosley, Rhoda Au, Bruce M. Psaty, Andre G. Uitterlinden, Lindsay A. Farrer, Thomas Lumley, Agustin Ruiz, Julie Williams, Philippe Amouyel, Steven G Younkin, Philip A. Wolf, Lenore J. Launer, Oscar L. Lopez, Cornelia M. Van Duijn, Monique M B Breteler

Research output: Contribution to journalArticle

784 Citations (Scopus)

Abstract

Context: Genome-wide association studies (GWAS) have recently identified CLU, PICALM, and CR1 as novel genes for late-onset Alzheimer disease (AD). Objectives: To identify and strengthen additional loci associated with AD and confirm these in an independent sample and to examine the contribution of recently identified genes to AD risk prediction in a 3-stage analysis of new and previously published GWAS on more than 35 000 persons (8371 AD cases). Design, Setting, and Participants: In stage 1, we identified strong genetic associations (P<10-3) in a sample of 3006 AD cases and 14 642 controls by combining new data from the population-based Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (1367 AD cases [973 incident]) with previously reported results from the Translational Genomics Research Institute and the Mayo AD GWAS. We identified 2708 single-nucleotide polymorphisms (SNPs) with P<10-3. In stage 2, we pooled results for these SNPs with the European AD Initiative (2032 cases and 5328 controls) to identify 38 SNPs (10 loci) with P<10-5. In stage 3, we combined data for these 10 loci with data from the Genetic and Environmental Risk in AD consortium (3333 cases and 6995 controls) to identify 4 SNPs with P<1.7 × 10-8. These 4 SNPs were replicated in an independent Spanish sample (1140 AD cases and 1209 controls). Genome-wide association analyses were completed in 2007-2008 and the meta-analyses and replication in 2009. Main Outcome Measure: Presence of Alzheimer disease. Results: Two loci were identified to have genome-wide significance for the first time: rs744373 near BIN1 (odds ratio [OR],1.13; 95% confidence interval [CI],1.06-1.21 per copy of the minor allele; P=1.59×10-11) and rs597668 near EXOC3L2/BLOC1S3/ MARK4 (OR, 1.18; 95% CI, 1.07-1.29; P=6.45×10-9). Associations of these 2 loci plus the previously identified loci CLU and PICALM with AD were confirmed in the Spanish sample (P<.05). However, although CLU and PICALM were confirmed to be associated with AD in this independent sample, they did not improve the ability of a model that included age, sex, and APOE to predict incident AD (improvement in area under the receiver operating characteristic curve from 0.847 to 0.849 in the Rotterdam Study and 0.702 to 0.705 in the Cardiovascular Health Study). Conclusions: Two genetic loci for AD were found for the first time to reach genome-wide statistical significance. These findings were replicated in an independent population. Two recently reported associations were also confirmed. These loci did not improve AD risk prediction. While not clinically useful, they may implicate biological pathways useful for future research.

Original languageEnglish (US)
Pages (from-to)1832-1840
Number of pages9
JournalJAMA - Journal of the American Medical Association
Volume303
Issue number18
DOIs
StatePublished - May 12 2010

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Genetic Loci
Alzheimer Disease
Genome
Genome-Wide Association Study
Single Nucleotide Polymorphism
Odds Ratio
Confidence Intervals
Aptitude
Translational Medical Research
Genomics
ROC Curve
Population
Genes

ASJC Scopus subject areas

  • Medicine(all)

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Seshadri, S., Fitzpatrick, A. L., Ikram, M. A., DeStefano, A. L., Gudnason, V., Boada, M., ... Breteler, M. M. B. (2010). Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA - Journal of the American Medical Association, 303(18), 1832-1840. https://doi.org/10.1001/jama.2010.574

Genome-wide analysis of genetic loci associated with Alzheimer disease. / Seshadri, Sudha; Fitzpatrick, Annette L.; Ikram, M. Arfan; DeStefano, Anita L.; Gudnason, Vilmundur; Boada, Merce; Bis, Joshua C.; Smith, Albert V.; Carassquillo, Minerva M.; Lambert, Jean Charles; Harold, Denise; Schrijvers, Elisabeth M C; Ramirez-Lorca, Reposo; Debette, Stephanie; Longstreth, W. T.; Janssens, A. Cecile J W; Pankratz, V. Shane; Dartigues, Jean François; Hollingworth, Paul; Aspelund, Thor; Hernandez, Isabel; Beiser, Alexa; Kuller, Lewis H.; Koudstaal, Peter J.; Dickson, Dennis W; Tzourio, Christophe; Abraham, Richard; Antunez, Carmen; Du, Yangchun; Rotter, Jerome I.; Aulchenko, Yurii S.; Harris, Tamara B.; Petersen, Ronald Carl; Berr, Claudine; Owen, Michael J.; Lopez-Arrieta, Jesus; Varadarajan, Badri N.; Becker, James T.; Rivadeneira, Fernando; Nalls, Michael A.; Graff Radford, Neill R; Campion, Dominique; Auerbach, Sanford; Rice, Kenneth; Hofman, Albert; Jonsson, Palmi V.; Schmidt, Helena; Lathrop, Mark; Mosley, Thomas H.; Au, Rhoda; Psaty, Bruce M.; Uitterlinden, Andre G.; Farrer, Lindsay A.; Lumley, Thomas; Ruiz, Agustin; Williams, Julie; Amouyel, Philippe; Younkin, Steven G; Wolf, Philip A.; Launer, Lenore J.; Lopez, Oscar L.; Van Duijn, Cornelia M.; Breteler, Monique M B.

In: JAMA - Journal of the American Medical Association, Vol. 303, No. 18, 12.05.2010, p. 1832-1840.

Research output: Contribution to journalArticle

Seshadri, S, Fitzpatrick, AL, Ikram, MA, DeStefano, AL, Gudnason, V, Boada, M, Bis, JC, Smith, AV, Carassquillo, MM, Lambert, JC, Harold, D, Schrijvers, EMC, Ramirez-Lorca, R, Debette, S, Longstreth, WT, Janssens, ACJW, Pankratz, VS, Dartigues, JF, Hollingworth, P, Aspelund, T, Hernandez, I, Beiser, A, Kuller, LH, Koudstaal, PJ, Dickson, DW, Tzourio, C, Abraham, R, Antunez, C, Du, Y, Rotter, JI, Aulchenko, YS, Harris, TB, Petersen, RC, Berr, C, Owen, MJ, Lopez-Arrieta, J, Varadarajan, BN, Becker, JT, Rivadeneira, F, Nalls, MA, Graff Radford, NR, Campion, D, Auerbach, S, Rice, K, Hofman, A, Jonsson, PV, Schmidt, H, Lathrop, M, Mosley, TH, Au, R, Psaty, BM, Uitterlinden, AG, Farrer, LA, Lumley, T, Ruiz, A, Williams, J, Amouyel, P, Younkin, SG, Wolf, PA, Launer, LJ, Lopez, OL, Van Duijn, CM & Breteler, MMB 2010, 'Genome-wide analysis of genetic loci associated with Alzheimer disease', JAMA - Journal of the American Medical Association, vol. 303, no. 18, pp. 1832-1840. https://doi.org/10.1001/jama.2010.574
Seshadri S, Fitzpatrick AL, Ikram MA, DeStefano AL, Gudnason V, Boada M et al. Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA - Journal of the American Medical Association. 2010 May 12;303(18):1832-1840. https://doi.org/10.1001/jama.2010.574
Seshadri, Sudha ; Fitzpatrick, Annette L. ; Ikram, M. Arfan ; DeStefano, Anita L. ; Gudnason, Vilmundur ; Boada, Merce ; Bis, Joshua C. ; Smith, Albert V. ; Carassquillo, Minerva M. ; Lambert, Jean Charles ; Harold, Denise ; Schrijvers, Elisabeth M C ; Ramirez-Lorca, Reposo ; Debette, Stephanie ; Longstreth, W. T. ; Janssens, A. Cecile J W ; Pankratz, V. Shane ; Dartigues, Jean François ; Hollingworth, Paul ; Aspelund, Thor ; Hernandez, Isabel ; Beiser, Alexa ; Kuller, Lewis H. ; Koudstaal, Peter J. ; Dickson, Dennis W ; Tzourio, Christophe ; Abraham, Richard ; Antunez, Carmen ; Du, Yangchun ; Rotter, Jerome I. ; Aulchenko, Yurii S. ; Harris, Tamara B. ; Petersen, Ronald Carl ; Berr, Claudine ; Owen, Michael J. ; Lopez-Arrieta, Jesus ; Varadarajan, Badri N. ; Becker, James T. ; Rivadeneira, Fernando ; Nalls, Michael A. ; Graff Radford, Neill R ; Campion, Dominique ; Auerbach, Sanford ; Rice, Kenneth ; Hofman, Albert ; Jonsson, Palmi V. ; Schmidt, Helena ; Lathrop, Mark ; Mosley, Thomas H. ; Au, Rhoda ; Psaty, Bruce M. ; Uitterlinden, Andre G. ; Farrer, Lindsay A. ; Lumley, Thomas ; Ruiz, Agustin ; Williams, Julie ; Amouyel, Philippe ; Younkin, Steven G ; Wolf, Philip A. ; Launer, Lenore J. ; Lopez, Oscar L. ; Van Duijn, Cornelia M. ; Breteler, Monique M B. / Genome-wide analysis of genetic loci associated with Alzheimer disease. In: JAMA - Journal of the American Medical Association. 2010 ; Vol. 303, No. 18. pp. 1832-1840.
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title = "Genome-wide analysis of genetic loci associated with Alzheimer disease",
abstract = "Context: Genome-wide association studies (GWAS) have recently identified CLU, PICALM, and CR1 as novel genes for late-onset Alzheimer disease (AD). Objectives: To identify and strengthen additional loci associated with AD and confirm these in an independent sample and to examine the contribution of recently identified genes to AD risk prediction in a 3-stage analysis of new and previously published GWAS on more than 35 000 persons (8371 AD cases). Design, Setting, and Participants: In stage 1, we identified strong genetic associations (P<10-3) in a sample of 3006 AD cases and 14 642 controls by combining new data from the population-based Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (1367 AD cases [973 incident]) with previously reported results from the Translational Genomics Research Institute and the Mayo AD GWAS. We identified 2708 single-nucleotide polymorphisms (SNPs) with P<10-3. In stage 2, we pooled results for these SNPs with the European AD Initiative (2032 cases and 5328 controls) to identify 38 SNPs (10 loci) with P<10-5. In stage 3, we combined data for these 10 loci with data from the Genetic and Environmental Risk in AD consortium (3333 cases and 6995 controls) to identify 4 SNPs with P<1.7 × 10-8. These 4 SNPs were replicated in an independent Spanish sample (1140 AD cases and 1209 controls). Genome-wide association analyses were completed in 2007-2008 and the meta-analyses and replication in 2009. Main Outcome Measure: Presence of Alzheimer disease. Results: Two loci were identified to have genome-wide significance for the first time: rs744373 near BIN1 (odds ratio [OR],1.13; 95{\%} confidence interval [CI],1.06-1.21 per copy of the minor allele; P=1.59×10-11) and rs597668 near EXOC3L2/BLOC1S3/ MARK4 (OR, 1.18; 95{\%} CI, 1.07-1.29; P=6.45×10-9). Associations of these 2 loci plus the previously identified loci CLU and PICALM with AD were confirmed in the Spanish sample (P<.05). However, although CLU and PICALM were confirmed to be associated with AD in this independent sample, they did not improve the ability of a model that included age, sex, and APOE to predict incident AD (improvement in area under the receiver operating characteristic curve from 0.847 to 0.849 in the Rotterdam Study and 0.702 to 0.705 in the Cardiovascular Health Study). Conclusions: Two genetic loci for AD were found for the first time to reach genome-wide statistical significance. These findings were replicated in an independent population. Two recently reported associations were also confirmed. These loci did not improve AD risk prediction. While not clinically useful, they may implicate biological pathways useful for future research.",
author = "Sudha Seshadri and Fitzpatrick, {Annette L.} and Ikram, {M. Arfan} and DeStefano, {Anita L.} and Vilmundur Gudnason and Merce Boada and Bis, {Joshua C.} and Smith, {Albert V.} and Carassquillo, {Minerva M.} and Lambert, {Jean Charles} and Denise Harold and Schrijvers, {Elisabeth M C} and Reposo Ramirez-Lorca and Stephanie Debette and Longstreth, {W. T.} and Janssens, {A. Cecile J W} and Pankratz, {V. Shane} and Dartigues, {Jean Fran{\cc}ois} and Paul Hollingworth and Thor Aspelund and Isabel Hernandez and Alexa Beiser and Kuller, {Lewis H.} and Koudstaal, {Peter J.} and Dickson, {Dennis W} and Christophe Tzourio and Richard Abraham and Carmen Antunez and Yangchun Du and Rotter, {Jerome I.} and Aulchenko, {Yurii S.} and Harris, {Tamara B.} and Petersen, {Ronald Carl} and Claudine Berr and Owen, {Michael J.} and Jesus Lopez-Arrieta and Varadarajan, {Badri N.} and Becker, {James T.} and Fernando Rivadeneira and Nalls, {Michael A.} and {Graff Radford}, {Neill R} and Dominique Campion and Sanford Auerbach and Kenneth Rice and Albert Hofman and Jonsson, {Palmi V.} and Helena Schmidt and Mark Lathrop and Mosley, {Thomas H.} and Rhoda Au and Psaty, {Bruce M.} and Uitterlinden, {Andre G.} and Farrer, {Lindsay A.} and Thomas Lumley and Agustin Ruiz and Julie Williams and Philippe Amouyel and Younkin, {Steven G} and Wolf, {Philip A.} and Launer, {Lenore J.} and Lopez, {Oscar L.} and {Van Duijn}, {Cornelia M.} and Breteler, {Monique M B}",
year = "2010",
month = "5",
day = "12",
doi = "10.1001/jama.2010.574",
language = "English (US)",
volume = "303",
pages = "1832--1840",
journal = "JAMA - Journal of the American Medical Association",
issn = "0002-9955",
publisher = "American Medical Association",
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TY - JOUR

T1 - Genome-wide analysis of genetic loci associated with Alzheimer disease

AU - Seshadri, Sudha

AU - Fitzpatrick, Annette L.

AU - Ikram, M. Arfan

AU - DeStefano, Anita L.

AU - Gudnason, Vilmundur

AU - Boada, Merce

AU - Bis, Joshua C.

AU - Smith, Albert V.

AU - Carassquillo, Minerva M.

AU - Lambert, Jean Charles

AU - Harold, Denise

AU - Schrijvers, Elisabeth M C

AU - Ramirez-Lorca, Reposo

AU - Debette, Stephanie

AU - Longstreth, W. T.

AU - Janssens, A. Cecile J W

AU - Pankratz, V. Shane

AU - Dartigues, Jean François

AU - Hollingworth, Paul

AU - Aspelund, Thor

AU - Hernandez, Isabel

AU - Beiser, Alexa

AU - Kuller, Lewis H.

AU - Koudstaal, Peter J.

AU - Dickson, Dennis W

AU - Tzourio, Christophe

AU - Abraham, Richard

AU - Antunez, Carmen

AU - Du, Yangchun

AU - Rotter, Jerome I.

AU - Aulchenko, Yurii S.

AU - Harris, Tamara B.

AU - Petersen, Ronald Carl

AU - Berr, Claudine

AU - Owen, Michael J.

AU - Lopez-Arrieta, Jesus

AU - Varadarajan, Badri N.

AU - Becker, James T.

AU - Rivadeneira, Fernando

AU - Nalls, Michael A.

AU - Graff Radford, Neill R

AU - Campion, Dominique

AU - Auerbach, Sanford

AU - Rice, Kenneth

AU - Hofman, Albert

AU - Jonsson, Palmi V.

AU - Schmidt, Helena

AU - Lathrop, Mark

AU - Mosley, Thomas H.

AU - Au, Rhoda

AU - Psaty, Bruce M.

AU - Uitterlinden, Andre G.

AU - Farrer, Lindsay A.

AU - Lumley, Thomas

AU - Ruiz, Agustin

AU - Williams, Julie

AU - Amouyel, Philippe

AU - Younkin, Steven G

AU - Wolf, Philip A.

AU - Launer, Lenore J.

AU - Lopez, Oscar L.

AU - Van Duijn, Cornelia M.

AU - Breteler, Monique M B

PY - 2010/5/12

Y1 - 2010/5/12

N2 - Context: Genome-wide association studies (GWAS) have recently identified CLU, PICALM, and CR1 as novel genes for late-onset Alzheimer disease (AD). Objectives: To identify and strengthen additional loci associated with AD and confirm these in an independent sample and to examine the contribution of recently identified genes to AD risk prediction in a 3-stage analysis of new and previously published GWAS on more than 35 000 persons (8371 AD cases). Design, Setting, and Participants: In stage 1, we identified strong genetic associations (P<10-3) in a sample of 3006 AD cases and 14 642 controls by combining new data from the population-based Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (1367 AD cases [973 incident]) with previously reported results from the Translational Genomics Research Institute and the Mayo AD GWAS. We identified 2708 single-nucleotide polymorphisms (SNPs) with P<10-3. In stage 2, we pooled results for these SNPs with the European AD Initiative (2032 cases and 5328 controls) to identify 38 SNPs (10 loci) with P<10-5. In stage 3, we combined data for these 10 loci with data from the Genetic and Environmental Risk in AD consortium (3333 cases and 6995 controls) to identify 4 SNPs with P<1.7 × 10-8. These 4 SNPs were replicated in an independent Spanish sample (1140 AD cases and 1209 controls). Genome-wide association analyses were completed in 2007-2008 and the meta-analyses and replication in 2009. Main Outcome Measure: Presence of Alzheimer disease. Results: Two loci were identified to have genome-wide significance for the first time: rs744373 near BIN1 (odds ratio [OR],1.13; 95% confidence interval [CI],1.06-1.21 per copy of the minor allele; P=1.59×10-11) and rs597668 near EXOC3L2/BLOC1S3/ MARK4 (OR, 1.18; 95% CI, 1.07-1.29; P=6.45×10-9). Associations of these 2 loci plus the previously identified loci CLU and PICALM with AD were confirmed in the Spanish sample (P<.05). However, although CLU and PICALM were confirmed to be associated with AD in this independent sample, they did not improve the ability of a model that included age, sex, and APOE to predict incident AD (improvement in area under the receiver operating characteristic curve from 0.847 to 0.849 in the Rotterdam Study and 0.702 to 0.705 in the Cardiovascular Health Study). Conclusions: Two genetic loci for AD were found for the first time to reach genome-wide statistical significance. These findings were replicated in an independent population. Two recently reported associations were also confirmed. These loci did not improve AD risk prediction. While not clinically useful, they may implicate biological pathways useful for future research.

AB - Context: Genome-wide association studies (GWAS) have recently identified CLU, PICALM, and CR1 as novel genes for late-onset Alzheimer disease (AD). Objectives: To identify and strengthen additional loci associated with AD and confirm these in an independent sample and to examine the contribution of recently identified genes to AD risk prediction in a 3-stage analysis of new and previously published GWAS on more than 35 000 persons (8371 AD cases). Design, Setting, and Participants: In stage 1, we identified strong genetic associations (P<10-3) in a sample of 3006 AD cases and 14 642 controls by combining new data from the population-based Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (1367 AD cases [973 incident]) with previously reported results from the Translational Genomics Research Institute and the Mayo AD GWAS. We identified 2708 single-nucleotide polymorphisms (SNPs) with P<10-3. In stage 2, we pooled results for these SNPs with the European AD Initiative (2032 cases and 5328 controls) to identify 38 SNPs (10 loci) with P<10-5. In stage 3, we combined data for these 10 loci with data from the Genetic and Environmental Risk in AD consortium (3333 cases and 6995 controls) to identify 4 SNPs with P<1.7 × 10-8. These 4 SNPs were replicated in an independent Spanish sample (1140 AD cases and 1209 controls). Genome-wide association analyses were completed in 2007-2008 and the meta-analyses and replication in 2009. Main Outcome Measure: Presence of Alzheimer disease. Results: Two loci were identified to have genome-wide significance for the first time: rs744373 near BIN1 (odds ratio [OR],1.13; 95% confidence interval [CI],1.06-1.21 per copy of the minor allele; P=1.59×10-11) and rs597668 near EXOC3L2/BLOC1S3/ MARK4 (OR, 1.18; 95% CI, 1.07-1.29; P=6.45×10-9). Associations of these 2 loci plus the previously identified loci CLU and PICALM with AD were confirmed in the Spanish sample (P<.05). However, although CLU and PICALM were confirmed to be associated with AD in this independent sample, they did not improve the ability of a model that included age, sex, and APOE to predict incident AD (improvement in area under the receiver operating characteristic curve from 0.847 to 0.849 in the Rotterdam Study and 0.702 to 0.705 in the Cardiovascular Health Study). Conclusions: Two genetic loci for AD were found for the first time to reach genome-wide statistical significance. These findings were replicated in an independent population. Two recently reported associations were also confirmed. These loci did not improve AD risk prediction. While not clinically useful, they may implicate biological pathways useful for future research.

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U2 - 10.1001/jama.2010.574

DO - 10.1001/jama.2010.574

M3 - Article

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VL - 303

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EP - 1840

JO - JAMA - Journal of the American Medical Association

JF - JAMA - Journal of the American Medical Association

SN - 0002-9955

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