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 language | English (US) |
|---|---|
| Pages (from-to) | 1832-1840 |
| Number of pages | 9 |
| Journal | JAMA - Journal of the American Medical Association |
| Volume | 303 |
| Issue number | 18 |
| DOIs | |
| State | Published - May 12 2010 |
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ASJC Scopus subject areas
- Medicine(all)
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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 journal › Article
}
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.
UR - http://www.scopus.com/inward/record.url?scp=77952307991&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77952307991&partnerID=8YFLogxK
U2 - 10.1001/jama.2010.574
DO - 10.1001/jama.2010.574
M3 - Article
C2 - 20460622
AN - SCOPUS:77952307991
VL - 303
SP - 1832
EP - 1840
JO - JAMA - Journal of the American Medical Association
JF - JAMA - Journal of the American Medical Association
SN - 0002-9955
IS - 18
ER -