Late-onset Alzheimer disease risk variants mark brain regulatory loci.
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ABSTRACT:
SUBMITTER: Allen M
PROVIDER: S-EPMC4807909 | biostudies-literature | 2015 Aug
REPOSITORIES: biostudies-literature
Publications
Late-onset Alzheimer disease risk variants mark brain regulatory loci.
Allen Mariet M Kachadoorian Michaela M Carrasquillo Minerva M MM Karhade Aditya A Manly Lester L Burgess Jeremy D JD Wang Chen C Serie Daniel D Wang Xue X Siuda Joanna J Zou Fanggeng F Chai High Seng HS Younkin Curtis C Crook Julia J Medway Christopher C Nguyen Thuy T Ma Li L Malphrus Kimberly K Lincoln Sarah S Petersen Ronald C RC Graff-Radford Neill R NR Asmann Yan W YW Dickson Dennis W DW Younkin Steven G SG Ertekin-Taner Nilüfer N
Neurology. Genetics 20150723 2
<h4>Objective</h4>To investigate the top late-onset Alzheimer disease (LOAD) risk loci detected or confirmed by the International Genomics of Alzheimer's Project for association with brain gene expression levels to identify variants that influence Alzheimer disease (AD) risk through gene expression regulation.<h4>Methods</h4>Expression levels from the cerebellum (CER) and temporal cortex (TCX) were obtained using Illumina whole-genome cDNA-mediated annealing, selection, extension, and ligation a ...[more]
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Project description:ObjectiveRecent genome-wide association studies (GWAS) of late-onset Alzheimer disease (LOAD) identified 9 novel risk loci. Discovery of functional variants within genes at these loci is required to confirm their role in Alzheimer disease (AD). Single nucleotide polymorphisms that influence gene expression (eSNPs) constitute an important class of functional variants. We therefore investigated the influence of the novel LOAD risk loci on human brain gene expression.MethodsWe measured gene expression levels in the cerebellum and temporal cortex of autopsied AD subjects and those with other brain pathologies (∼400 total subjects). To determine whether any of the novel LOAD risk variants are eSNPs, we tested their cis-association with expression of 6 nearby LOAD candidate genes detectable in human brain (ABCA7, BIN1, CLU, MS4A4A, MS4A6A, PICALM) and an additional 13 genes ±100 kb of these SNPs. To identify additional eSNPs that influence brain gene expression levels of the novel candidate LOAD genes, we identified SNPs ±100 kb of their location and tested for cis-associations.ResultsCLU rs11136000 (p = 7.81 × 10(-4)) and MS4A4A rs2304933/rs2304935 (p = 1.48 × 10(-4)-1.86 × 10(-4)) significantly influence temporal cortex expression levels of these genes. The LOAD-protective CLU and risky MS4A4A locus alleles associate with higher brain levels of these genes. There are other cis-variants that significantly influence brain expression of CLU and ABCA7 (p = 4.01 × 10(-5)-9.09 × 10(-9)), some of which also associate with AD risk (p = 2.64 × 10(-2)-6.25 × 10(-5)).ConclusionsCLU and MS4A4A eSNPs may at least partly explain the LOAD risk association at these loci. CLU and ABCA7 may harbor additional strong eSNPs. These results have implications in the search for functional variants at the novel LOAD risk loci.
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Project description:Although it is clear that apoE plays an important role in the genetics of late-onset Alzheimer disease (AD), evidence exists that additional genes may play a role in AD, and estimates of the total contribution of apoE to the variance in onset of AD vary widely. Unfortunately, little information is available on the number and contribution of additional genes. We estimated the number of additional quantitative-trait loci and their contribution to the variance in age at onset of AD, as well as the contribution of apoE and sex, in an oligogenic segregation analysis of 75 families (742 individuals) ascertained for members with late-onset AD. We found evidence that four additional loci make a contribution to the variance in age at onset of late-onset AD that is similar to or greater in magnitude than that made by apoE, with one locus making a contribution several times greater than that of apoE. Additionally, we confirmed previous findings of a dose effect for the apoE varepsilon4 allele, a protective effect for the varepsilon2 allele, evidence for allelic interactions at the apoE locus, and a small protective effect for males. Furthermore, although we estimate that the apoE genotype can make a difference of </=17 years in age at onset of AD, our estimate of the contribution of apoE (7%-9%) to total variation in onset of AD is somewhat smaller than that which has previously been reported. Our results suggest that several genes that have not yet been localized may play a larger role than does apoE in late-onset AD.
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Project description:Brain development in the early stages of life has been suggested to be one of the factors that may influence an individual's risk of Alzheimer disease (AD) later in life. Four microcephaly genes, which regulate brain development in utero and have been suggested to play a role in the evolution of the human brain, were selected as candidate genes that may modulate the risk of AD. We examined the association between single nucleotide polymorphisms tagging common sequence variations in these genes and risk of AD in two case-control samples. We found that the G allele of rs2442607 in microcephalin 1 was associated with an increased risk of AD (under an additive genetic model, P=0.01; odds ratio=3.41; confidence interval, 1.77-6.57). However, this association was not replicated using another case-control sample research participants from the Alzheimer Disease Neuroimaging Initiative. We conclude that the common variations we measured in the 4 microcephaly genes do not affect the risk of AD or that their effect size is small.
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Project description:ImportanceGenetic causes of late-onset Alzheimer disease (LOAD) are not completely explained by known genetic loci. Whole-exome and whole-genome sequencing can improve the understanding of the causes of LOAD and provide initial steps required to identify potential therapeutic targets.ObjectiveTo identify the genetic loci for LOAD across different ethnic groups.Design, setting, and participantsThis multicenter cohort study was designed to analyze whole-exome sequencing data from a multiethnic cohort using a transethnic gene-kernel association test meta-analysis, adjusted for sex, age, and principal components, to identify genetic variants associated with LOAD. A meta-analysis was conducted on the results of 2 independent studies of whole-exome and whole-genome sequence data from individuals of European ancestry. This group of European American, African American, and Caribbean Hispanic individuals participating in an urban population-based study were the discovery cohort; the additional cohorts included affected individuals and control participants from 2 publicly available data sets. Replication was achieved using independent data sets from Caribbean Hispanic families with multiple family members affected by LOAD and the International Genetics of Alzheimer Project.Main outcomes and measuresLate-onset Alzheimer disease.ResultsThe discovery cohort included 3595 affected individuals, while the additional cohorts included 5931 individuals with LOAD and 5504 control participants. Of 3916 individuals in the discovery cohort, we included 3595 individuals (1397 with LOAD and 2198 cognitively healthy controls; 2451 [68.2%] women; mean [SD] age, 80.3 [6.83] years). Another 321 individuals (8.2%) were excluded because of non-LOAD diagnosis, age younger than 60 years, missing covariates, duplicate data, or genetic outlier status. Gene-based tests that compared affected individuals (n = 7328) and control participants (n = 7702) and included only rare and uncommon variants annotated as having moderate-high functional effect supported PINX1 (8p23.1) as a locus with gene-wide significance (P = 2.81 × 10-6) after meta-analysis across the 3 studies. The PINX1 finding was replicated using data from the family-based study and the International Genetics of Alzheimer Project. Full meta-analysis of discovery and replication cohorts reached a P value of 6.16 × 10-7 for PINX1 (in 7620 affected individuals vs 7768 control participants). We also identified TREM2 in an annotation model that prioritized highly deleterious variants with a combined annotation dependent depletion greater than 20 (P= 1.0 × 10-7).Conclusions and relevanceThis gene-based, transethnic approach identified PINX1, a gene involved in telomere integrity, and TREM2, a gene with a product of an immune receptor found in microglia, as associated with LOAD. Both genes have well-established roles in aging and neurodegeneration.
| S-EPMC6503572 | biostudies-literature
Project description:ObjectiveTo investigate association of genetic risk factors for late-onset Alzheimer disease (LOAD) with risk of posterior cortical atrophy (PCA), a syndrome of visual impairment with predominant Alzheimer disease (AD) pathology in posterior cortical regions, and with risk of "posterior AD" neuropathology.MethodsWe assessed 81 participants with PCA diagnosed clinically and 54 with neuropathologic diagnosis of posterior AD vs 2,523 controls for association with 11 significant single nucleotide polymorphisms (SNPs) from published LOAD risk genome-wide association studies.ResultsThere was highly significant association with APOE ε4 and increased risk of PCA (p = 0.0003, odds ratio [OR] = 3.17) and posterior AD (p = 1.11 × 10(-17), OR = 6.43). No other locus was significant after corrections for multiple testing, although rs11136000 near CLU (p = 0.019, OR = 0.60) and rs744373 near BIN1 (p = 0.025, OR = 1. 63) associated nominally significantly with posterior AD, and rs3851179 at the PICALM locus had significant association with PCA (p = 0.0003, OR = 2.84). ABCA7 locus SNP rs3764650, which was also tested under the recessive model because of Hardy-Weinberg disequilibrium, also had nominally significant association with PCA risk. The direction of association at APOE, CLU, and BIN1 loci was the same for participants with PCA and posterior AD. The effects for all SNPs, except rs3851179, were consistent with those for LOAD risk.ConclusionsWe identified a significant effect for APOE and nominate CLU, BIN1, and ABCA7 as additional risk loci for PCA and posterior AD. Our findings suggest that at least some of the genetic risk factors for LOAD are shared with these atypical conditions and provide effect-size estimates for their future genetic studies.
| S-EPMC4001196 | biostudies-literature
Project description:A recent study reported significant association of late-onset Alzheimer's disease (LOAD) with multiple single nucleotide polymorphisms (SNPs) and haplotypes in SORL1, a neuronal sortilin-related receptor protein known to be involved in the trafficking and processing of amyloid precursor protein. Here we attempted to validate this finding in three large, well characterized case-control series. Approximately 2000 samples from the three series were individually genotyped for 12 SNPs, including the 10 reported significant SNPs and 2 that constitute the reported significant haplotypes. A total of 25 allelic and haplotypic association tests were performed. One SNP rs2070045 was marginally replicated in the three sample sets combined (nominal P=0.035); however, this result does not remain significant when accounting for multiple comparisons. Further validation in other sample sets will be required to assess the true effects of SORL1 variants in LOAD.
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Project description:IMPORTANCE:Because APOE locus variants contribute to risk of late-onset Alzheimer disease (LOAD) and to differences in age at onset (AAO), it is important to know whether other established LOAD risk loci also affect AAO in affected participants. OBJECTIVES:To investigate the effects of known Alzheimer disease risk loci in modifying AAO and to estimate their cumulative effect on AAO variation using data from genome-wide association studies in the Alzheimer Disease Genetics Consortium. DESIGN, SETTING, AND PARTICIPANTS:The Alzheimer Disease Genetics Consortium comprises 14 case-control, prospective, and family-based data sets with data on 9162 participants of white race/ethnicity with Alzheimer disease occurring after age 60 years who also had complete AAO information, gathered between 1989 and 2011 at multiple sites by participating studies. Data on genotyped or imputed single-nucleotide polymorphisms most significantly associated with risk at 10 confirmed LOAD loci were examined in linear modeling of AAO, and individual data set results were combined using a random-effects, inverse variance-weighted meta-analysis approach to determine whether they contribute to variation in AAO. Aggregate effects of all risk loci on AAO were examined in a burden analysis using genotype scores weighted by risk effect sizes. MAIN OUTCOMES AND MEASURES:Age at disease onset abstracted from medical records among participants with LOAD diagnosed per standard criteria. RESULTS:Analysis confirmed the association of APOE with earlier AAO (P = 3.3 × 10(-96)), with associations in CR1 (rs6701713, P = 7.2 × 10(-4)), BIN1 (rs7561528, P = 4.8 × 10(-4)), and PICALM (rs561655, P = 2.2 × 10(-3)) reaching statistical significance (P <?.005). Risk alleles individually reduced AAO by 3 to 6 months. Burden analyses demonstrated that APOE contributes to 3.7% of the variation in AAO (R(2) = 0.256) over baseline (R(2) = 0.221), whereas the other 9 loci together contribute to 2.2% of the variation (R(2) = 0.242). CONCLUSIONS AND RELEVANCE:We confirmed an association of APOE (OMIM 107741) variants with AAO among affected participants with LOAD and observed novel associations of CR1 (OMIM 120620), BIN1 (OMIM 601248), and PICALM (OMIM 603025) with AAO. In contrast to earlier hypothetical modeling, we show that the combined effects of Alzheimer disease risk variants on AAO are on the scale of, but do not exceed, the APOE effect. While the aggregate effects of risk loci on AAO may be significant, additional genetic contributions to AAO are individually likely to be small.
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Project description:ObjectiveIn African Americans, we sought to systematically identify coding Alzheimer disease (AD) risk variants at the previously reported AD genome-wide association study (GWAS) loci genes.MethodsWe identified coding variants within genes at the 20 published AD GWAS loci by whole-exome sequencing of 238 African American participants, validated these in 300 additional participants, and tested their association with AD risk in the combined cohort of 538 and with memory endophenotypes in 319 participants.ResultsTwo ABCA7 missense variants (rs3764647 and rs3752239) demonstrated significant association with AD risk. Variants in MS4A6A, PTK2B, and ZCWPW1 showed significant gene-based association. In addition, coding variants in ZCWPW1 (rs6465770) and NME8 (rs10250905 and rs62001869) showed association with memory endophenotypes.ConclusionsOur findings support a role for ABCA7 missense variants in conferring AD risk in African Americans, highlight allelic heterogeneity at this locus, suggest the presence of AD-risk variants in MS4A6A, PTK2B, and ZCWPW1, nominate additional variants that may modulate cognition, and importantly provide a thorough screen of coding variants at AD GWAS loci that can guide future studies in this population.
| S-EPMC5406839 | biostudies-literature
Project description:ImportanceIdentifying the youngest age when Alzheimer disease (AD) influences cognition and the earliest affected cognitive domains will improve understanding of the natural history of AD and approaches to early diagnosis.ObjectiveTo evaluate the age at which cognitive differences between individuals with higher compared with lower genetic risk of AD are first apparent and which cognitive assessments show the earliest difference.Design, setting, and participantsThis cross-sectional study used data from UK Biobank participants of European genetic ancestry, aged 40 years or older, who contributed genotypic and cognitive test data from January 1, 2006, to December 31, 2015. Data analysis was performed from March 10, 2020, to January 4, 2022.ExposureThe AD genetic risk score (GRS), which is a weighted sum of 23 single-nucleotide variations.Main outcomes and measuresSeven cognitive tests were administered via touchscreen at in-person visits or online. Cognitive domains assessed included fluid intelligence, episodic memory, processing speed, executive functioning, and prospective memory. Multiple cognitive measures were derived from some tests, yielding 32 separate measures. Interactions between age and AD-GRS for each of the 32 cognitive measures were tested with linear regression using a Bonferroni-corrected P value threshold. For cognitive measures with significant evidence of age by AD-GRS interaction, the youngest age of interaction was assessed with new regression models, with nonlinear specification of age terms. Models with youngest age of interaction from 40 to 70 years, in 1-year increments, were compared, and the best-fitting model for each cognitive measure was chosen. Results across cognitive measures were compared to determine which cognitive indicators showed earliest AD-related change.ResultsA total of 405 050 participants (mean [SD] age, 57.1 [7.9] years; 54.1% female) were included. Sample sizes differed across cognitive tests (from 12 455 to 404 682 participants). The AD-GRS significantly modified the association with age on 13 measures derived from the pairs matching (range in difference in mean cognition per decade increase in age for 1-SD higher AD-GRS, 2.5%-11.5%), symbol digit substitution (range in difference in mean cognition per decade increase in age for 1-SD higher AD-GRS, 2.0%-5.8%), and numeric memory tests (difference in mean cognition per decade increase in age for 1-SD higher AD-GRS, 8.8%) (P = 1.56 × 10-3). Best-fitting models suggested that cognitive scores of individuals with a high vs low AD-GRS began to diverge by 56 years of age for all 13 measures and by 47 years of age for 9 measures.Conclusions and relevanceIn this cross-sectional study, by early midlife, subtle differences in memory and attention were detectable among individuals with higher genetic risk of AD.
| S-EPMC8980909 | biostudies-literature
Project description:ImportanceGenetic variants associated with susceptibility to late-onset Alzheimer disease are known for individuals of European ancestry, but whether the same or different variants account for the genetic risk of Alzheimer disease in African American individuals is unknown. Identification of disease-associated variants helps identify targets for genetic testing, prevention, and treatment.ObjectiveTo identify genetic loci associated with late-onset Alzheimer disease in African Americans.Design, setting, and participantsThe Alzheimer Disease Genetics Consortium (ADGC) assembled multiple data sets representing a total of 5896 African Americans (1968 case participants, 3928 control participants) 60 years or older that were collected between 1989 and 2011 at multiple sites. The association of Alzheimer disease with genotyped and imputed single-nucleotide polymorphisms (SNPs) was assessed in case-control and in family-based data sets. Results from individual data sets were combined to perform an inverse variance-weighted meta-analysis, first with genome-wide analyses and subsequently with gene-based tests for previously reported loci.Main outcomes and measuresPresence of Alzheimer disease according to standardized criteria.ResultsGenome-wide significance in fully adjusted models (sex, age, APOE genotype, population stratification) was observed for a SNP in ABCA7 (rs115550680, allele = G; frequency, 0.09 cases and 0.06 controls; odds ratio [OR], 1.79 [95% CI, 1.47-2.12]; P = 2.2 × 10(-9)), which is in linkage disequilibrium with SNPs previously associated with Alzheimer disease in Europeans (0.8 < D' < 0.9). The effect size for the SNP in ABCA7 was comparable with that of the APOE ϵ4-determining SNP rs429358 (allele = C; frequency, 0.30 cases and 0.18 controls; OR, 2.31 [95% CI, 2.19-2.42]; P = 5.5 × 10(-47)). Several loci previously associated with Alzheimer disease but not reaching significance in genome-wide analyses were replicated in gene-based analyses accounting for linkage disequilibrium between markers and correcting for number of tests performed per gene (CR1, BIN1, EPHA1, CD33; 0.0005 < empirical P < .001).Conclusions and relevanceIn this meta-analysis of data from African American participants, Alzheimer disease was significantly associated with variants in ABCA7 and with other genes that have been associated with Alzheimer disease in individuals of European ancestry. Replication and functional validation of this finding is needed before this information is used in clinical settings.
| S-EPMC3667653 | biostudies-literature