Dataset Information

Association of Rare APOE Missense Variants V236E and R251G With Risk of Alzheimer Disease.

ABSTRACT:

Importance

The APOE ε2 and APOE ε4 alleles are the strongest protective and risk-increasing, respectively, genetic variants for late-onset Alzheimer disease (AD). However, the mechanisms linking APOE to AD-particularly the apoE protein's role in AD pathogenesis and how this is affected by APOE variants-remain poorly understood. Identifying missense variants in addition to APOE ε2 and APOE ε4 could provide critical new insights, but given the low frequency of additional missense variants, AD genetic cohorts have previously been too small to interrogate this question robustly.

Objective

To determine whether rare missense variants on APOE are associated with AD risk.

Design, setting, and participants

Association with case-control status was tested in a sequenced discovery sample (stage 1) and followed up in several microarray imputed cohorts as well as the UK Biobank whole-exome sequencing resource using a proxy-AD phenotype (stages 2 and 3). This study combined case-control, family-based, population-based, and longitudinal AD-related cohorts that recruited referred and volunteer participants. Stage 1 included 37 409 nonunique participants of European or admixed European ancestry, with 11 868 individuals with AD and 11 934 controls passing analysis inclusion criteria. In stages 2 and 3, 475 473 participants were considered across 8 cohorts, of which 84 513 individuals with AD and proxy-AD and 328 372 controls passed inclusion criteria. Selection criteria were cohort specific, and this study was performed a posteriori on individuals who were genotyped. Among the available genotypes, 76 195 were excluded. All data were retrieved between September 2015 and November 2021 and analyzed between April and November 2021.

Main outcomes and measures

In primary analyses, the AD risk associated with each missense variant was estimated, as appropriate, with either linear mixed-model regression or logistic regression. In secondary analyses, associations were estimated with age at onset using linear mixed-model regression and risk of conversion to AD using competing-risk regression.

Results

A total of 544 384 participants were analyzed in the primary case-control analysis; 312 476 (57.4%) were female, and the mean (SD; range) age was 64.9 (15.2; 40-110) years. Two missense variants were associated with a 2-fold to 3-fold decreased AD risk: APOE ε4 (R251G) (odds ratio, 0.44; 95% CI, 0.33-0.59; P = 4.7 × 10-8) and APOE ε3 (V236E) (odds ratio, 0.37; 95% CI, 0.25-0.56; P = 1.9 × 10-6). Additionally, the cumulative incidence of AD in carriers of these variants was found to grow more slowly with age compared with noncarriers.

Conclusions and relevance

In this genetic association study, a novel variant associated with AD was identified: R251G always coinherited with ε4 on the APOE gene, which mitigates the ε4-associated AD risk. The protective effect of the V236E variant, which is always coinherited with ε3 on the APOE gene, was also confirmed. The location of these variants confirms that the carboxyl-terminal portion of apoE plays an important role in AD pathogenesis. The large risk reductions reported here suggest that protein chemistry and functional assays of these variants should be pursued, as they have the potential to guide drug development targeting APOE.

SUBMITTER: Le Guen Y

PROVIDER: S-EPMC9157381 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Association of Rare APOE Missense Variants V236E and R251G With Risk of Alzheimer Disease.

Le Guen Yann Y Belloy Michael E ME Grenier-Boley Benjamin B de Rojas Itziar I Castillo-Morales Atahualpa A Jansen Iris I Nicolas Aude A Bellenguez Céline C Dalmasso Carolina C Küçükali Fahri F Eger Sarah J SJ Rasmussen Katrine Laura KL Thomassen Jesper Qvist JQ Deleuze Jean-François JF He Zihuai Z Napolioni Valerio V Amouyel Philippe P Jessen Frank F Kehoe Patrick G PG van Duijn Cornelia C Tsolaki Magda M Sánchez-Juan Pascual P Sleegers Kristel K Ingelsson Martin M Rossi Giacomina G Hiltunen Mikko M Sims Rebecca R van der Flier Wiesje M WM Ramirez Alfredo A Andreassen Ole A OA Frikke-Schmidt Ruth R Williams Julie J Ruiz Agustín A Lambert Jean-Charles JC Greicius Michael D MD Arosio Beatrice B Benussi Luisa L Boland Anne A Borroni Barbara B Caffarra Paolo P Daian Delphine D Daniele Antonio A Debette Stéphanie S Dufouil Carole C Düzel Emrah E Galimberti Daniela D Giedraitis Vilmantas V Grimmer Timo T Graff Caroline C Grünblatt Edna E Hanon Olivier O Hausner Lucrezia L Heilmann-Heimbach Stefanie S Holstege Henne H Hort Jakub J Jürgen Deckert D Kuulasmaa Teemu T van der Lugt Aad A Masullo Carlo C Mecocci Patrizia P Mehrabian Shima S de Mendonça Alexandre A Moebus Susanne S Nacmias Benedetta B Nicolas Gael G Olaso Robert R Papenberg Goran G Parnetti Lucilla L Pasquier Florence F Peters Oliver O Pijnenburg Yolande A L YAL Popp Julius J Rainero Innocenzo I Ramakers Inez I Riedel-Heller Steffi S Scarmeas Nikolaos N Scheltens Philip P Scherbaum Norbert N Schneider Anja A Seripa Davide D Soininen Hilkka H Solfrizzi Vincenzo V Spalletta Gianfranco G Squassina Alessio A van Swieten John J Tegos Thomas J TJ Tremolizzo Lucio L Verhey Frans F Vyhnalek Martin M Wiltfang Jens J Boada Mercè M García-González Pablo P Puerta Raquel R Real Luis M LM Álvarez Victoria V Bullido María J MJ Clarimon Jordi J García-Alberca José María JM Mir Pablo P Moreno Fermin F Pastor Pau P Piñol-Ripoll Gerard G Molina-Porcel Laura L Pérez-Tur Jordi J Rodríguez-Rodríguez Eloy E Royo Jose Luís JL Sánchez-Valle Raquel R Dichgans Martin M Rujescu Dan D

JAMA neurology 20220701 7

<h4>Importance</h4>The APOE ε2 and APOE ε4 alleles are the strongest protective and risk-increasing, respectively, genetic variants for late-onset Alzheimer disease (AD). However, the mechanisms linking APOE to AD-particularly the apoE protein's role in AD pathogenesis and how this is affected by APOE variants-remain poorly understood. Identifying missense variants in addition to APOE ε2 and APOE ε4 could provide critical new insights, but given the low frequency of additional missense variants, ...[more]

PMID: 35639372

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Project description:ImportanceNumerous studies have established the association of the common APOE ε2 and APOE ε4 alleles with Alzheimer disease (AD) risk across ancestries. Studies of the interaction of these alleles with other amino acid changes on APOE in non-European ancestries are lacking and may improve ancestry-specific risk prediction.ObjectiveTo determine whether APOE amino acid changes specific to individuals of African ancestry modulate AD risk.Design, setting, and participantsCase-control study including 31 929 participants and using a sequenced discovery sample (Alzheimer Disease Sequencing Project; stage 1) followed by 2 microarray imputed data sets derived from the Alzheimer Disease Genetic Consortium (stage 2, internal replication) and the Million Veteran Program (stage 3, external validation). This study combined case-control, family-based, population-based, and longitudinal AD cohorts, which recruited participants (1991-2022) in primarily US-based studies with 1 US/Nigerian study. Across all stages, individuals included in this study were of African ancestry.ExposuresTwo APOE missense variants (R145C and R150H) were assessed, stratified by APOE genotype.Main outcomes and measuresThe primary outcome was AD case-control status, and secondary outcomes included age at AD onset.ResultsStage 1 included 2888 cases (median age, 77 [IQR, 71-83] years; 31.3% male) and 4957 controls (median age, 77 [IQR, 71-83] years; 28.0% male). In stage 2, across multiple cohorts, 1201 cases (median age, 75 [IQR, 69-81] years; 30.8% male) and 2744 controls (median age, 80 [IQR, 75-84] years; 31.4% male) were included. In stage 3, 733 cases (median age, 79.4 [IQR, 73.8-86.5] years; 97.0% male) and 19 406 controls (median age, 71.9 [IQR, 68.4-75.8] years; 94.5% male) were included. In ε3/ε4-stratified analyses of stage 1, R145C was present in 52 individuals with AD (4.8%) and 19 controls (1.5%); R145C was associated with an increased risk of AD (odds ratio [OR], 3.01; 95% CI, 1.87-4.85; P = 6.0 × 10-6) and was associated with a reported younger age at AD onset (β, -5.87 years; 95% CI, -8.35 to -3.4 years; P = 3.4 × 10-6). Association with increased AD risk was replicated in stage 2 (R145C was present in 23 individuals with AD [4.7%] and 21 controls [2.7%]; OR, 2.20; 95% CI, 1.04-4.65; P = .04) and was concordant in stage 3 (R145C was present in 11 individuals with AD [3.8%] and 149 controls [2.7%]; OR, 1.90; 95% CI, 0.99-3.64; P = .051). Association with earlier AD onset was replicated in stage 2 (β, -5.23 years; 95% CI, -9.58 to -0.87 years; P = .02) and stage 3 (β, -10.15 years; 95% CI, -15.66 to -4.64 years; P = 4.0 × 10-4). No significant associations were observed in other APOE strata for R145C or in any APOE strata for R150H.Conclusions and relevanceIn this exploratory analysis, the APOE ε3[R145C] missense variant was associated with an increased risk of AD among individuals of African ancestry with the ε3/ε4 genotype. With additional external validation, these findings may inform AD genetic risk assessment in individuals of African ancestry.

Project description:Importance:The ?2 and ?4 alleles of the apolipoprotein E (APOE) gene are associated with Alzheimer disease (AD) risk. Although nearby genetic variants have also been shown to be associated with AD, including rs2075650 in the TOMM40 gene and rs4420638 near the APOC1 gene, it is unknown whether these associations are independent of the ?2 and ?4 alleles. Objective:To assess whether variants near APOE are associated with AD independently of the ?2/?3/?4 genotype. Design, Setting, and Participants:In this genetic association study of the Alzheimer's Disease Genetics Consortium imputed genotype at data, 14?415 variants near APOE (±500 kilobase) for 18?795 individuals with European ancestry were tested for association with AD using 4 logistic mixed models adjusting for sex, cohort, population structure, and relatedness. Model 1 had no APOE adjustment, and model 2 adjusted for the count of ?2 and ?4 alleles. Model 3 was restricted to ?3 homozygotes, and model 4 was restricted to ?4 homozygotes. Data were downloaded from May 31, 2018, to June 3, 2018, and analyzed from November 1, 2018, to June 24, 2020. Main Outcomes and Measures:Alzheimer disease affectation status was defined by clinicians using standard National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer Disease and Related Disorders Association criteria. Association was evaluated using Score tests; results with P?<?.05 divided by the number of independent tests per model were considered statistically significant. Results:Among the 18?795 individuals in the study, 9704 were affected by AD and 9066 were control individuals; the median age at onset/evaluation was 76 (interquartile range, 70-82) years; and 11 167 were female (59.4%). Associations with AD were found for rs2075650 (odds ratio [OR], 2.59; 95% CI, 2.45-2.75; P?=?3.19?×?10-228) and rs4420638 (OR, 2.77; 95% CI, 2.62-2.94; P?=?2.99?×?10-254) without APOE adjustment. Although rs2075650 was nominally associated with AD among the ?4 homozygotes (OR, 1.33; 95% CI, 1.00-1.77; P?=?.047), the association between rs4420638 and AD was eliminated by APOE adjustment (model 2 OR, 1.06 [95% CI, 0.96-1.18; P?=?.24]; model 3 OR, 1.13 [95% CI, 0.95-1.34; P?=?.18]; model 4 OR, 0.90 [95% CI, 0.56-1.45; P?=?.66]). There was a significant association between rs192879175 and AD among ?3 homozygotes (OR, 0.50; 95% CI, 0.37-0.68; P?=?8.30?×?10-6). Conclusions and Relevance:The results of this genetic association study suggest that ?2/?3/?4 alleles are not the only variants in the APOE region that are associated with AD risk. Additional work with independent data is needed to replicate these results.

Project description:ImportanceThe association of major lipid genes with and their potential as drug targets for age-related macular degeneration (AMD) is unknown. These associations are important to study because AMD is the leading cause of irreversible late-onset blindness in high-income countries.ObjectiveTo determine whether the full range of structural genetic variation in apolipoprotein E (APOE), a master gene in peripheral and cerebral lipid metabolism, is associated with risk of AMD.Design, setting, and participantsThis cohort study used data from the Copenhagen City Heart Study (CCHS) and the Copenhagen General Population Study (CGPS) cohorts. Participants were followed from study inclusion at the time of blood sampling to occurrence of event, death, emigration, or December 7, 2018, whichever came first. For participants in CCHS, the APOE gene was sequenced, and 9 variants with a heterozygote frequency of at least 0.0002 were genotyped in the CGPS. Observers were masked to patient groupings. Data were analyzed from March to September 2021.ExposuresThe exposure was APOE status, and the direct gene product in plasma, apoE levels, was measured in all participants.Main outcomes and measuresCox regression was applied to estimate risk of AMD associated with APOE genotype.ResultsA total of 105 546 participants (mean [SD] age, 57.7 [13.4] years; 58 140 [55%] female participants) were included. Compared with participants with the common ɛ33 genotype, risk of AMD was lower in participants with ε44 (multifactorially adjusted hazard ratio [aHR], 0.66; 95% CI, 0.45-0.96) and ε43 (aHR, 0.80; 95% CI, 0.71-0.90) genotypes and higher in the ε32 (aHR, 1.15; 95% CI, 1.00-1.31) genotype. Compared with noncarriers, risk of AMD was higher for participants with Gly145Asp (aHR, 3.53; 95% CI, 1.14-10.96) and Arg154Cys (aHR, 4.52; 95% CI, 1-13-18.13) heterozygotes. Results were similar after further adjustment for lipid traits and after adjustment for the APOE ε2/ε3/ε4 variant. Combining all common and rare structural variants in a weighted allele score, risk of AMD per 1-mg/dL genetically higher plasma apoE was increased in the adjusted model (aHR, 1.12; 95% CI, 1.05-1.19), the adjusted model plus APOE ɛ2/ɛ3/ɛ4 status (aHR, 1.82; 95% CI, 1.20-2.76), and the adjusted model in individuals with the ε33 genotype only (aHR, 1.77; 95% CI, 1.14-2.75).Conclusions and relevanceThese findings highlight that structural variation in APOE beyond the ε2/ε3/ε4 variants may be important for risk of AMD in a population of European ancestry. Rare functional ɛ2-like variants in APOE have previously been reported to have protective associations for Alzheimer disease but the present findings suggest a simultaneous high risk of AMD. This would limit the drug target potential of mechanisms resembling these variants.

Project description:Background and objectivesBrain amyloid deposition, a major risk factor for Alzheimer's disease (AD), is currently estimated by measuring cerebrospinal fluid or plasma amyloid peptide levels, or by positron-emission tomography imaging. Assessing genetic risks relating to amyloid deposition before any accumulation has occurred would allow for earlier intervention in persons at increased risk for developing AD. Previous work linking amyloid burden and genetic risk relied almost exclusively on APOE, a major AD genetic risk factor. Here, we ask whether a polygenic risk score (PRS) that incorporates an optimized list of common variants linked to AD and excludes APOE is associated with brain amyloid load in cognitively unimpaired elderly adults.MethodsWe included 291 elderly asymptomatic participants from the INveStIGation of AlzHeimer's PredicTors (INSIGHT-preAD) cohort who underwent amyloid imaging, including 83 amyloid-positive (+) participants. We used an Alzheimer's (A) PRS composed of 33 AD risk variants excluding APOE, and selected the 17 variants that showed the strongest association with amyloid positivity to define an optimized (oA) PRS. Participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study [228 participants, 90 amyloid (+)] were tested as a validation cohort. Finally, 2,300 AD patients and 6,994 controls from the European Alzheimer's Disease Initiative (EADI) were evaluated.ResultsA-PRS was not significantly associated with amyloid burden in the INSIGHT or ADNI cohorts with or without correction for APOE genotype. However, oA-PRS was significantly associated with amyloid status independently of APOE adjustment (INSIGHT OR: 5.26 [1.71-16.88]; ADNI OR: 3.38 [1.02-11.63]). Interestingly, oA-PRS accurately discriminated amyloid (+) and (-) APOE ε4 carriers (INSIGHT OR: 181.6 [7.53-10,674.6]; ADNI OR: 44.94 [3.03-1,277]). A-PRS and oA-PRS showed a significant association with disease status in the EADI cohort (OR: 1.68 [1.53-1.85] and 2.06 [1.73-2.45] respectively). Genes assigned to oA-PRS variants were enriched in ontologies related to Aβ metabolism and deposition.DiscussionPRSs relying on AD genetic risk factors excluding APOE may improve risk prediction for brain amyloid, allowing stratification of cognitively unimpaired individuals at risk of AD independent of their APOE status.

Project description:BackgroundThe APOE ε4 allele is the most significant common genetic risk factor for late-onset Alzheimer's disease (LOAD). The region surrounding APOE on chromosome 19 has also shown consistent association with LOAD. However, no common variants in the region remain significant after adjusting for APOE genotype. We report a rare variant association analysis of genes in the vicinity of APOE with cerebrospinal fluid (CSF) and neuroimaging biomarkers of LOAD.MethodsWhole genome sequencing (WGS) was performed on 817 blood DNA samples from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Sequence data from 757 non-Hispanic Caucasian participants was used in the present analysis. We extracted all rare variants (MAF (minor allele frequency) < 0.05) within a 312 kb window in APOE's vicinity encompassing 12 genes. We assessed CSF and neuroimaging (MRI and PET) biomarkers as LOAD-related quantitative endophenotypes. Gene-based analyses of rare variants were performed using the optimal Sequence Kernel Association Test (SKAT-O).ResultsA total of 3,334 rare variants (MAF < 0.05) were found within the APOE region. Among them, 72 rare non-synonymous variants were observed. Eight genes spanning the APOE region were significantly associated with CSF Aβ1-42 (p < 1.0 × 10-3). After controlling for APOE genotype and adjusting for multiple comparisons, 4 genes (CBLC, BCAM, APOE, and RELB) remained significant. Whole-brain surface-based analysis identified highly significant clusters associated with rare variants of CBLC in the temporal lobe region including the entorhinal cortex, as well as frontal lobe regions. Whole-brain voxel-wise analysis of amyloid PET identified significant clusters in the bilateral frontal and parietal lobes showing associations of rare variants of RELB with cortical amyloid burden.ConclusionsRare variants within genes spanning the APOE region are significantly associated with LOAD-related CSF Aβ1-42 and neuroimaging biomarkers after adjusting for APOE genotype. These findings warrant further investigation and illustrate the role of next generation sequencing and quantitative endophenotypes in assessing rare variants which may help explain missing heritability in AD and other complex diseases.

Dataset Information

Association of Rare APOE Missense Variants V236E and R251G With Risk of Alzheimer Disease.

Importance

Objective

Design, setting, and participants

Main outcomes and measures

Results

Conclusions and relevance

Publications

Association of Rare APOE Missense Variants V236E and R251G With Risk of Alzheimer Disease.

Similar Datasets

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