Dataset Information

Association of Rare Coding Mutations With Alzheimer Disease and Other Dementias Among Adults of European Ancestry.

ABSTRACT: Importance:Some of the unexplained heritability of Alzheimer disease (AD) may be due to rare variants whose effects are not captured in genome-wide association studies because very large samples are needed to observe statistically significant associations. Objective:To identify genetic variants associated with AD risk using a nonstatistical approach. Design, Setting, and Participants:Genetic association study in which rare variants were identified by whole-exome sequencing in unrelated individuals of European ancestry from the Alzheimer's Disease Sequencing Project (ADSP). Data were analyzed between March 2017 and September 2018. Main Outcomes and Measures:Minor alleles genome-wide and in 95 genes previously associated with AD, AD-related traits, or other dementias were tabulated and filtered for predicted functional impact and occurrence in participants with AD but not controls. Support for several findings was sought in a whole-exome sequencing data set comprising 19 affected relative pairs from Utah high-risk pedigrees and whole-genome sequencing data sets from the ADSP and Alzheimer's Disease Neuroimaging Initiative. Results:Among 5617 participants with AD (3202 [57.0%] women; mean [SD] age, 76.4 [9.3] years) and 4594 controls (2719 [59.0%] women; mean [SD] age, 86.5 [4.5] years), a total of 24 variants with moderate or high functional impact from 19 genes were observed in 10 or more participants with AD but not in controls. These variants included a missense mutation (rs149307620 [p.A284T], n?=?10) in NOTCH3, a gene in which coding mutations are associated with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), that was also identified in 1 participant with AD and 1 participant with mild cognitive impairment in the whole genome sequencing data sets. Four participants with AD carried the TREM2 rs104894002 (p.Q33X) high-impact mutation that, in homozygous form, causes Nasu-Hakola disease, a rare disorder characterized by early-onset dementia and multifocal bone cysts, suggesting an intermediate inheritance model for the mutation. Compared with controls, participants with AD had a significantly higher burden of deleterious rare coding variants in dementia-associated genes (2314 vs 3354 cumulative variants, respectively; P?=?.006). Conclusions and Relevance:Different mutations in the same gene or variable dose of a mutation may be associated with result in distinct dementias. These findings suggest that minor differences in the structure or amount of protein may be associated with in different clinical outcomes. Understanding these genotype-phenotype associations may provide further insight into the pathogenic nature of the mutations, as well as offer clues for developing new therapeutic targets.

SUBMITTER: Patel D

PROVIDER: S-EPMC6450321 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Association of Rare Coding Mutations With Alzheimer Disease and Other Dementias Among Adults of European Ancestry.

Patel Devanshi D Mez Jesse J Vardarajan Badri N BN Staley Lyndsay L Chung Jaeyoon J Zhang Xiaoling X Farrell John J JJ Rynkiewicz Michael J MJ Cannon-Albright Lisa A LA Teerlink Craig C CC Stevens Jeffery J Corcoran Christopher C Gonzalez Murcia Josue D JD Lopez Oscar L OL Mayeux Richard R Haines Jonathan L JL Pericak-Vance Margaret A MA Schellenberg Gerard G Kauwe John S K JSK Lunetta Kathryn L KL Farrer Lindsay A LA

JAMA network open 20190301 3

<h4>Importance</h4>Some of the unexplained heritability of Alzheimer disease (AD) may be due to rare variants whose effects are not captured in genome-wide association studies because very large samples are needed to observe statistically significant associations.<h4>Objective</h4>To identify genetic variants associated with AD risk using a nonstatistical approach.<h4>Design, setting, and participants</h4>Genetic association study in which rare variants were identified by whole-exome sequencing ...[more]

PMID: 30924900

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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:ImportanceAlzheimer disease and related dementias (ADRD), currently incurable neurodegenerative diseases, can threaten patients' financial status owing to memory deficits and changes in risk perception. Deteriorating financial capabilities are among the earliest signs of cognitive decline, but the frequency and extent of adverse financial events before and after diagnosis have not been characterized.ObjectivesTo describe the financial presentation of ADRD using administrative credit data.Design, setting, and participantsThis retrospective secondary data analysis of consumer credit report outcomes from 1999 to 2018 linked to Medicare claims data included 81 364 Medicare beneficiaries living in single-person households.ExposuresOccurrence of adverse financial events in those with vs without ADRD diagnosis and time of adverse financial event from ADRD diagnosis.Main outcomes and measuresMissed payments on credit accounts (30 or more days late) and subprime credit scores.ResultsOverall, 54 062 (17 890 [33.1%] men; mean [SD] age, 74 [7.3] years) were never diagnosed with ADRD during the sample period and 27 302 had ADRD for at least 1 quarter of observation (8573 [31.4%] men; mean [SD] age, 79.4 [7.5] years). Single Medicare beneficiaries diagnosed with ADRD were more likely to miss payments on credit accounts as early as 6 years prior to diagnosis compared with demographically similar beneficiaries without ADRD (7.7% vs 7.3%; absolute difference, 0.4 percentage points [pp]; 95% CI, 0.07-0.70:) and to develop subprime credit scores 2.5 years prior to diagnosis (8.5% vs 8.1%; absolute difference, 0.38 pp; 95% CI, 0.04-0.72). By the quarter after diagnosis, patients with ADRD remained more likely to miss payments than similar beneficiaries who did not develop ADRD (7.9% vs 6.9%; absolute difference, 1.0 pp; 95% CI, 0.67-1.40) and more likely to have subprime credit scores than those without ADRD (8.2% vs 7.5%; absolute difference, 0.70 pp; 95% CI, 0.34-1.1). Adverse financial events were more common among patients with ADRD in lower-education census tracts. The patterns of adverse events associated with ADRD were unique compared with other medical conditions (eg, glaucoma, hip fracture).Conclusions and relevanceAlzheimer disease and related dementias were associated with adverse financial events years prior to clinical diagnosis that become more prevalent after diagnosis and were most common in lower-education census tracts.

Project description:ImportanceEarly-onset Alzheimer disease (EOAD) is a rare form of Alzheimer disease (AD) with a large genetic basis that is only partially understood. In late-onset AD, elevated circulating cholesterol levels increase AD risk even after adjusting for the apolipoprotein E ε4 (APOE E4) allele, a major genetic factor for AD and elevated cholesterol levels; however, the role of circulating cholesterol levels in EOAD is unclear.ObjectivesTo investigate the association between circulating cholesterol levels and EOAD and to identify genetic variants underlying this possible association.Design, setting, and participantsIn this case series, plasma cholesterol levels were directly measured in 267 samples from the AD research centers (ADRCs) of Emory University and University of California, San Francisco, collected from January 21, 2009, through August 21, 2014. The association between cholesterol and EOAD was examined using multiple linear regression. To determine the underlying genetic variants, APOB, APP, PSEN1, and PSEN2 were sequenced in samples from 2125 EOAD cases and controls recruited from 29 ADRCs from January 1, 1984, through December 31, 2015. Data were analyzed from November 23, 2016, through April 10, 2018.ExposuresClinical diagnosis, age at clinical diagnosis, plasma cholesterol measures (total cholesterol, low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol, triglycerides, and apolipoprotein B), and genetic variants in APOE, APP, PSEN1, PSEN2, and APOB.Main outcomes and measuresThe primary outcome was the association between EOAD and plasma cholesterol measures. The secondary outcome was the association between EOAD and the burden of genetic variants in APOB.ResultsOf the 2125 samples that underwent genetic sequencing, 1276 were from women (60.0%) and 654 (30.8%) were from patients with EOAD (mean [SD] ages, 55.6 [4.3] years for cases and 72.0 [9.6] years for controls). APOE E4 explained 10.1% of the variance of EOAD. After controlling for APOE E4, EOAD cases had higher levels of total cholesterol (mean difference [SE], 21.9 [5.2] mg/dL; P = 2.9 × 10-5), LDL-C (mean difference [SE], 22.0 [4.5] mg/dL; P = 1.8 × 10-6), and ApoB (mean difference [SE], 12.0 [2.4] mg/dL; P = 2.0 × 10-6) than controls in 267 frozen samples. Approximately 3% of EOAD cases carried known AD-causing mutations. Gene-based rare variant burden testing in 2066 samples showed that rare APOB coding variants were significantly more abundant in EOAD cases after adjusting for sex, APOE E4, genetic principal components, ADRC center, and batch (effect size, 0.20; P = 4.20 × 10-4).Conclusions and relevanceElevated LDL-C levels were associated with higher probability of having EOAD, and EOAD cases were enriched for rare coding variants in APOB, which codes for the major protein of LDL-C. Collectively, these novel findings highlight the important role of LDL-C in EOAD pathogenesis and suggest a direct link of APOB variants to AD risk.

Project description:ImportanceThe 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.ObjectiveTo determine whether rare missense variants on APOE are associated with AD risk.Design, setting, and participantsAssociation 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 measuresIn 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.ResultsA 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 relevanceIn 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.

Dataset Information

Association of Rare Coding Mutations With Alzheimer Disease and Other Dementias Among Adults of European Ancestry.

Publications

Association of Rare Coding Mutations With Alzheimer Disease and Other Dementias Among Adults of European Ancestry.

Similar Datasets

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