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 L.; Gallins, Paul J.; Buxbaum, Joseph D.; Ertekin-Taner, Nilüfer; Fallin, M. Daniele; Friedland, Robert P.; Inzelberg, Rivka; Kramer, Patricia L.; Rogaeva, Ekaterina; George-Hyslop, Peter St; 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; Hákonarson, Hákon; Kukull, Walter A.; Foroud, Tatiana; Haines, Jonathan L.; Mayeux, Richard; Farrer, Lindsay A.; Pericak‐Vance, Margaret A.; Schellenberg, Gerard D.

doi:10.1001/archneurol.2010.201

Cited by 388 publications

(323 citation statements)

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“…Years later, GWAS studies identified variants at other genes such as CLU, PICALM and CR1 as risk factors for Alzheimer's disease (Lambert et al 2009;Harold et al 2009). These results have been confirmed in a meta-analysis (Jun et al 2010). More recently, some of these risk gene variants have been associated with cognitive decline, more concretely with poor memory performance in population-based studies (Barral et al 2012;Pedraza et al 2013).…”

Section: Discussionmentioning

confidence: 53%

Genotype patterns at CLU, CR1, PICALM and APOE, cognition and Mediterranean diet: the PREDIMED-NAVARRA trial

et al. 2014

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The traditional Mediterranean diet (MedDiet) has shown beneficial effects on cognitive decline. Nevertheless, diet-gene interactions have been poorly evaluated. We aimed to investigate diet-gene interaction in the PREDIMED-NAVARRA randomized trial. A total of 522 participants (67 ± 6 years at baseline) enrolled in the PREDIMED-NAVARRA trial were randomly allocated to one of three diets: two MedDiets (supplemented with either extra-virgin olive oil or nuts) or a low-fat diet. They were evaluated with the Mini-Mental State Examination (MMSE) and the Clock Drawing Test (CDT) after 6.5 years of intervention. Subjects were genotyped for CR1-rs3818361, CLU-rs11136000, PICALM-rs3851179 and Apolipoprotein E (ApoE) genes. We studied MedDietgene interactions for cognition and assessed the effect of the MedDiet on cognition across different genetic profiles. A significant interaction (p = 0.041) between CLUrs11136000 and the MedDiet intervention on the MMSE was found with a beneficial effect of MedDiet among carriers of the T minor allele (B = 0.97, 95 % CI 0.45-1.49). Similar effect was observed for CR1-rs3818361, but no significant interaction was observed (p = 0.335). For PICALM-rs3851179, the MedDiet intervention showed a beneficial effect in both genotype groups. No apparent interaction was found for the CDT between intervention and gene variants. Similarly, participants randomly allocated to MedDiet groups, with favorable 123Genes Nutr (2014) 9:393 DOI 10.1007/s12263-014-0393-7 profiles of CR1, CLU and PICALM genes, significantly improved CDT scores compared to controls with the same genetic profile. Cognitive performance was better for nonApoE4 and for ApoE4 carriers of MedDiet groups compared to controls, but for CDT performance, we only found statistical significant differences for non-ApoE4 carriers. A MedDiet intervention modulates the effect of genetic factors on cognition. The effect of MedDiet might be greater for subjects with a more favorable genetic profile.

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Section: Discussionmentioning

confidence: 53%

Genotype patterns at CLU, CR1, PICALM and APOE, cognition and Mediterranean diet: the PREDIMED-NAVARRA trial

et al. 2014

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“…Our findings appear to be independent of the individual APOE status, as our results remain significant when including APOE as a covariate and no interaction between CLU variant and APOE status was observed. Interestingly, although CLU and APOE have similar functionality, no significant interaction of CLU with presence or absence of APOE4 alleles has been observed in population genetics (Harold et al, 2009;Jun et al, 2010). Only in one study was a more strongly significant association between CLU and AD in APOE4 carriers reported, although the association was significant in both groups (Lambert et al, 2009).…”

Section: Discussionmentioning

confidence: 89%

“…In 2009, through genome-wide association study, a single nucleotide polymorphism (SNP) within clusterine (CLU, also called APOJ ) on chromosome 8p21.1, rs11136000 was discovered to be significantly associated with AD in two independent studies (Harold et al, 2009;Lambert et al, 2009). This finding has since been replicated by several groups (Carrasquillo et al, 2010;Corneveaux et al, 2010;Jun et al, 2010;Kamboh et al, 2010;Seshadri et al, 2010), leading to CLU being the third top-ranking locus associated with Alzheimer's disease in the AlzGene database (http://www.alzgene.org). Carrying the minor allele T is assumed to establish a protective effect and reduces the risk to develop AD by 16% (Bertram and Tanzi, 2010); conversely, carrying the C-allele could be interpreted as an AD risk factor.…”

Section: Introductionmentioning

confidence: 82%

“…Recent genome-wide association studies have identified a SNP (11136000) within the Clusterin gene as strongly associated with risk for Alzheimers disease (Harold et al, 2009;Lambert et al, 2009;Carrasquillo et al, 2010;Corneveaux et al, 2010;Jun et al, 2010;Kamboh et al, 2010;Seshadri et al, 2010). CLU appears to be a biologically plausible candidate for AD as it binds amyloid beta peptide (A␤) and critically modifies A␤ Figure 1.…”

Section: Discussionmentioning

confidence: 99%

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Hippocampal Function in Healthy Carriers of theCLUAlzheimer's Disease Risk Variant

Erk¹,

Meyer‐Lindenberg²,

Boberfeld³

et al. 2011

J. Neurosci.

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Alzheimer's disease is a devastating, common, progressive dementia with considerable heritability. Recently, a genetic variant associated with the disease was discovered at CLU (rs11136000) with genome-wide support. Here we show, using an imaging genetics approach in a large genotyped sample, that healthy carriers of the variant exhibit altered coupling between hippocampus and prefrontal cortex during memory processing, mirroring clinical evidence of disturbed connectivity in patients and providing a neurogenetic mechanism for CLU-associated risk and protection.

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“…The first large‐scale genome‐wide association studies (GWAS) using common single nucleotide polymorphisms (SNPs) identified CLU , PICALM , CR1, and BIN1 as late onset Alzheimer disease (LOAD) susceptibility loci,1, 2, 3 which were widely confirmed by others 4, 5. The effect sizes of these genetic associations were much smaller than for APOE ,2, 6 with odds ratios ranging from 1.16 to 1.20.…”

mentioning

confidence: 99%

Rare coding mutations identified by sequencing of Alzheimer disease genome‐wide association studies loci

Vardarajan

Ghani

Kahn

et al. 2015

Annals of Neurology

135

117

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ObjectiveTo detect rare coding variants underlying loci detected by genome‐wide association studies (GWAS) of late onset Alzheimer disease (LOAD).MethodsWe conducted targeted sequencing of ABCA7, BIN1, CD2AP, CLU, CR1, EPHA1, MS4A4A/MS4A6A, and PICALM in 3 independent LOAD cohorts: 176 patients from 124 Caribbean Hispanics families, 120 patients and 33 unaffected individuals from the 129 National Institute on Aging LOAD Family Study; and 263 unrelated Canadian individuals of European ancestry (210 sporadic patients and 53 controls). Rare coding variants found in at least 2 data sets were genotyped in independent groups of ancestry‐matched controls. Additionally, the Exome Aggregation Consortium was used as a reference data set for population‐based allele frequencies.ResultsOverall we detected a statistically significant 3.1‐fold enrichment of the nonsynonymous mutations in the Caucasian LOAD cases compared with controls (p = 0.002) and no difference in synonymous variants. A stop‐gain mutation in ABCA7 (E1679X) and missense mutation in CD2AP (K633R) were highly significant in Caucasian LOAD cases, and mutations in EPHA1 (P460L) and BIN1 (K358R) were significant in Caribbean Hispanic families with LOAD. The EPHA1 variant segregated completely in an extended Caribbean Hispanic family and was also nominally significant in the Caucasians. Additionally, BIN1 (K358R) segregated in 2 of the 6 Caribbean Hispanic families where the mutations were discovered.InterpretationTargeted sequencing of confirmed GWAS loci revealed an excess burden of deleterious coding mutations in LOAD, with the greatest burden observed in ABCA7 and BIN1. Identifying coding variants in LOAD will facilitate the creation of tractable models for investigation of disease‐related mechanisms and potential therapies. Ann Neurol 2015;78:487–498

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Meta-analysis Confirms CR1, CLU, and PICALM as Alzheimer Disease Risk Loci and Reveals Interactions With APOE Genotypes

Cited by 388 publications

References 52 publications

Genotype patterns at CLU, CR1, PICALM and APOE, cognition and Mediterranean diet: the PREDIMED-NAVARRA trial

Genotype patterns at CLU, CR1, PICALM and APOE, cognition and Mediterranean diet: the PREDIMED-NAVARRA trial

Hippocampal Function in Healthy Carriers of theCLUAlzheimer's Disease Risk Variant

Rare coding mutations identified by sequencing of Alzheimer disease genome‐wide association studies loci

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