GAB2 Alleles Modify Alzheimer's Risk in APOE ɛ4 Carriers

Reiman, Eric M.; Webster, Jennifer; Myers, Amanda; Hardy, John; Dunckley, Travis; Zismann, Victoria; Joshipura, Keta; Pearson, John V.; Hu-Lince, Diane; Huentelman, Matthew J.; Craig, David W.; Coon, Keith D.; Liang, Winnie S.; Herbert, Ri Lee H.; Beach, Thomas G.; Rohrer, Kristen; Zhao, Alice; Leung, Doris G.; Bryden, Leslie; Marlowe, Lauren; Kaleem, Mona; Mastroeni, Diego; Grover, Andrew; Heward, Christopher B.; Ravid, Rivka; Rogers, Joseph; Hutton, Michael; Melquist, Stacey; Petersen, Ron; Alexander, Gene E.; Caselli, Richard J.; Kukull, Walter A.; Papassotiropoulos, Andreas; Stephan, Dietrich A.

doi:10.1016/j.neuron.2007.05.022

Cited by 437 publications

(447 citation statements)

References 34 publications

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“…Of note, our patient population is older on average than the original cohorts, which might be another explanation of the lack of association in our population. Our data however are supported by an absence of association between CALHM1 P86L and Alzheimer's disease risk in a recent study, which included family-based samples in which linkage to 10q24 was first reported , and reanalysis of publicly available genotype data of SNPs in the CALHM1 region, derived from two genome-wide association studies [Li et al, 2008;Reiman et al, 2007], was reported not to show evidence of association either . Meta-analysis of these and future replication studies will bear out whether CALHM1 can be considered an important risk gene for AD.…”

Section: Discussionsupporting

confidence: 73%

No association betweenCALHM1and risk for Alzheimer dementia in a Belgian population

et al. 2009

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A non-synonymous polymorphism, rs2986017 (p.P86L), in the newly characterized calcium homeostasis modulator 1 (CALHM1) gene located in the Alzheimer dementia (AD) linkage region on 10q24.33, was reported to increase risk of AD, and affect calcium homeostasis and amyloid β accumulation. We aimed to investigate the association between this functional polymorphism and AD in an independent study population. We genotyped rs2986017 in 362 Belgian AD patients and 519 ethnically matched control individuals. We found no evidence of association between rs2986017 and risk of disease, nor did we find an effect on onset age. Despite its functional properties, our study suggests the polymorphism does not contribute significantly to AD risk in the Belgian population.

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Section: Discussionsupporting

confidence: 73%

No association betweenCALHM1and risk for Alzheimer dementia in a Belgian population

et al. 2009

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“…However, the same large study that reported association in multiple groups [18] found no association in Caucasian American or African American families. Two groups examined SORL1 SNPs in publicly available data from the same genomewide association studies of AD [17] and found marginal associations with some variants in specific regions of SORL1. Meng et al [12] observed associated SNPs in the interval from exon 7 to exon 18;Webster et al [25], from intron 25 to intron 39 (SORL1 comprises 48 exons).…”

mentioning

confidence: 99%

No association of SORL1 SNPs with Alzheimer's disease

Minster¹,

DeKosky²,

Kamboh³

2008

Neuroscience Letters

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SORL1 is an element of the amyloid precursor protein processing pathway and is therefore a good candidate for affecting Alzheimer's disease (AD) risk. Indeed, there have been reports of associations between variation in SORL1 and AD risk. We examined six statistically significant single-nucleotide polymorphisms from the initial observation in a large Caucasian American case-controls cohort (1000 late-onset AD [LOAD] cases and 1000 older controls). Analysis of allele, genotype and haplotype frequencies revealed no association with LOAD risk in our cohort. KeywordsAlzheimer's disease; SORL1; genetics It is estimated that up to 79% of the risk for late-onset Alzheimer's disease (LOAD) is attributable to genetics [4]. Thus far, only variation in APOE has been definitively associated with LOAD [2], but only 20%-29% of risk is attributable to this variation [20,22]. Association between variation in an excellent biological candidate gene, sortilin-related receptor 1 (SORL1), and the risk of LOAD has been reported [18]. We genotyped and analyzed six of the single nucleotide polymorphisms (SNPs), listed in Table 1, that were reported to be associated with LOAD in a multiple case-control cohort or family-based samples [18] to verify this report.Case subjects were Caucasian Americans with LOAD (n = 1009; mean age-at-onset [AAO] 72.8 ± 6.2 [SD] years; 67.7% female; 7.3% autopsy-confirmed) recruited by the University of Pittsburgh Alzheimer's Disease Research Center. All cases were evaluated clinically and met criteria for probable or possible AD [11] or by autopsy and met neuropathological criteria for definite AD [13,14]. Controls were Caucasian Americans of age 60 or above with no psychiatric or neurological disorders (n = 1009; mean age-at-baseline 74.1 ± 6.2 [SD] years; 59.9% female; 1.3% autopsy-confirmed). All experiments on human subjects were conducted in accordance with the Declaration of Helsinki, and all procedures were carried out with the adequate understanding and written consent of the subjects. The genetic study was approved by the University of Pittsburgh Institutional Review Board.Genotypes for the six SORL1 SNPs were ascertained from genomic DNA using TaqMan SNP genotyping assays (Applied Biosystems, Foster City, California). Case and control samples were present on each 384-well plate used in genotyping. To estimate genotyping error rates, *Corresponding Author: University of Pittsburgh, Department of Human Genetics, Pittsburgh PA 15261, 412-624-3066, Fax: 412-383-7844, ikamboh@hgen.pitt.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. 10% of the s...

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“…This interaction was previously reported by the original authors. 34 The APOE group of SNPs obtained a higher weight than the GAB2 group. In the second stage, the stochastic search identified several SNPs that interact with rs7412 which is a well characterized SNP on the APOE gene that is associated with LOAD.…”

Section: Load Gwa Data Resultsmentioning

confidence: 93%

“…In the second stage, the stochastic search identified several SNPs that interact with rs7412 which is a well characterized SNP on the APOE gene that is associated with LOAD. [32][33][34] Table S1 (ESI †) gives the top 50 high scoring SNPs that interact with SNP rs7412. In particular, five previously reported SNPs namely rs901104, rs4291702, rs71158590, rs4945261, and rs2510038 in the GAB2 gene obtained low ranks and high interaction scores (see Table S1, ESI †).…”

Section: Load Gwa Data Resultsmentioning

confidence: 99%

Informative Bayesian Model Selection: a method for identifying interactions in genome-wide data

et al. 2014

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In high-dimensional genome-wide (GWA) data, a key challenge is to detect genomic variants that interact in a nonlinear fashion in their association with disease. Identifying such genomic interactions is important for elucidating the inheritance of complex phenotypes and diseases. In this paper, we introduce a new computational method called Informative Bayesian Model Selection (IBMS) that leverages correlation among variants in GWA data due to the linkage disequilibrium to identify interactions accurately in a computationally efficient manner. IBMS combines several statistical methods including canonical correlation analysis, logistic regression analysis, and a Bayesians statistical measure of evaluating interactions. Compared to BOOST and BEAM that are two widely used methods for detecting genomic interactions, IBMS had significantly higher power when evaluated on synthetic data. Furthermore, when applied to Alzheimer's disease GWA data, IBMS identified previously reported interactions. IBMS is a useful method for identifying variants in GWA data, and software that implements IBMS is freely available online from http://lbb.ut.ac.ir/Download/LBBsoft/IBMS.

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GAB2 Alleles Modify Alzheimer's Risk in APOE ɛ4 Carriers

Cited by 437 publications

References 34 publications

No association betweenCALHM1and risk for Alzheimer dementia in a Belgian population

No association betweenCALHM1and risk for Alzheimer dementia in a Belgian population

No association of SORL1 SNPs with Alzheimer's disease

Informative Bayesian Model Selection: a method for identifying interactions in genome-wide data

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