Dataset Information

Genome-Wide Association Study of Incident Dementia in a Community-Based Sample of Older Subjects.

ABSTRACT:

Background

Alzheimer's disease (AD) is a complex disease influenced by the environment and genetics; however, much of the genetic component remains unaccounted for.

Objective

The purpose of this work was to use genome-wide association analyses to detect genetic associations with incident AD in a sample of older adults aged 75 and above.

Methods

We performed a genome-wide association study (GWAS) on genome-wide genotyped and imputed data (14,072,053 variants) on the Gingko Evaluation of Memory (GEM) study sample consisting of 424 incident dementia (mean age = 84.46±3.91) and 2,206 non-demented (mean age = 84.55±3.23) subjects.

Results

The established association of APOE*4 carriers with AD was confirmed in this community-based sample of older subjects (odds ratio (OR) = 2.22; p = 9.36E-14) and was stronger in females (OR = 2.72; p = 1.74E-10) than in males (OR = 1.88; p = 2.43E-05). We observed a novel genome-wide significant (GWS) locus on chromosome 12 near ncRNA LOC105369711/rs148377161 (OR = 3.31; p = 1.66E-08). In addition, sex-stratified analyses identified two novel associations in males: one near ncRNA LOC729987/rs140076909 on chromosome 1 (OR = 4.51; p = 3.72E-08) and the other approaching GWS near ncRNA LOC105375138/rs117803234 on chromosome 7 (OR = 3.76; p = 6.93E-08).

Conclusion

The use of community-based samples of older individuals and incident dementia as a phenotype may be a helpful approach for the identification of novel genes for AD, which may not be detected in standard case-control studies. Replication of these signals and further studies of these regions and genes will help to provide a clearer picture for their role in AD.

SUBMITTER: Harper JD

PROVIDER: S-EPMC9359180 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Genome-Wide Association Study of Incident Dementia in a Community-Based Sample of Older Subjects.

Harper Jordan D JD Fan Kang-Hsien KH Aslam M Muaaz MM Snitz Beth E BE DeKosky Steven T ST Lopez Oscar L OL Feingold Eleanor E Kamboh M Ilyas MI

Journal of Alzheimer's disease : JAD 20220101 2

<h4>Background</h4>Alzheimer's disease (AD) is a complex disease influenced by the environment and genetics; however, much of the genetic component remains unaccounted for.<h4>Objective</h4>The purpose of this work was to use genome-wide association analyses to detect genetic associations with incident AD in a sample of older adults aged 75 and above.<h4>Methods</h4>We performed a genome-wide association study (GWAS) on genome-wide genotyped and imputed data (14,072,053 variants) on the Gingko E ...[more]

PMID: 35694926

Similar Datasets

Project description:BackgroundSome observational studies had found that shift work would increase risks of metabolic disorders, cancers, and cardiovascular diseases, but there was no homogeneous evidence of such an association between shift work and incident dementia. This study aimed to investigate whether shift work would increase the risk of dementia in a general population.MethodsOne hundred seventy thousand seven hundred twenty-two employed participants without cognitive impairment or dementia at baseline recruited between 2006 and 2010 were selected from the UK Biobank cohort study. Follow-up occurred through June 2021. Shift work status at baseline was self-reported by participants and they were categorized as non-shift workers or shift workers. Among shift workers, participants were further categorized as night shift workers or shift but non-night shift workers. The primary outcome was all-cause dementia in a time-to-event analysis, and the secondary outcomes were subtypes of dementia, including Alzheimer's disease, vascular dementia, and other types of dementia.ResultsIn total, 716 dementia cases were observed among 170,722 participants over a median follow-up period of 12.4 years. Shift workers had an increased risk of all-cause dementia as compared with non-shift workers after multivariable adjustment (hazard ratio [HR], 1.30, 95% confidence interval [CI], 1.08-1.58); however, among shift workers, night shift work was not associated with the risk of dementia (HR, 1.04, 95% CI, 0.73-1.47). We found no significant interaction between shift work and genetic predisposition to dementia on the primary outcome (P for interaction = 0.77).ConclusionsShift work at baseline was associated with an increased risk of all-cause dementia. Among shift workers, there was no significant association between night shift work and the risk of dementia. The increased incidence of dementia in shift workers did not differ between participants in different genetic risk strata for dementia.

Project description:A true understanding of the distribution and functional correlates of Alzheimer's disease pathology in dementia-free older adults requires a population-based perspective. Here we report initial findings from a sample of 102 cognitively unimpaired participants (average age 77.2 years, 54.9% women, 13.7% APOE*4 carriers) recruited for neuroimaging from a larger representative population-based cohort participating in an ongoing longitudinal study of aging, the Monongahela-Youghiogheny Healthy Aging Team (MYHAT). All participants scored < 1.0 on the Clinical Dementia Rating (CDR) Scale, with 8 participants (7.8%) scoring CDR = 0.5. Participants completed a positron emission tomography scan using the tracers [C-11]Pittsburgh Compound-B (PiB) and [F-18]AV-1451 to estimate amyloid and tau deposition. PiB positivity was defined on a regional basis using established standardized uptake value ratio cutoffs (SUVR; cerebellar gray matter reference), with 39 participants (38.2%) determined to be PiB(+). Health history, lifestyle, and cognitive abilities were assessed cross-sectionally at the nearest annual parent MYHAT study visit. A series of adjusted regression analyses modeled cognitive performance as a function of global PiB SUVR and [F-18]AV-1451 SUVR in Braak associated regions 1, 3/4, and 5/6. In comparison to PiB(-) participants (n = 63), PiB(+) participants were older, less educated, and were more likely to be APOE*4 carriers. Global PiB SUVR was significantly correlated with [F-18]AV-1451 SUVR in all Braak-associated regions (r = .38-0.53, p < .05). In independent models, higher Global PiB SUVR and Braak 1 [F-18]AV-1451 SUVR were associated with worse performance on a semantic interference verbal memory test. Our findings suggest that brain amyloid is common in a community-based setting, and is associated with tau deposition, but both pathologies show few associations with concurrent cognitive performance in a dementia-free sample.

Project description:Dementia incidence increases steadily with age at rates that may vary across racial groups. This racial disparity may be attributable to polygenic risk, as well as lifestyle and behavioural factors. We examined whether Alzheimer's disease polygenic score and race predict Alzheimer's disease and other related dementia incidence differentially by sex and mediation through polygenic scores for other health and behavioural conditions. We used longitudinal data from the nationally representative Health and Retirement Study. We restricted participants to those with complete data on 31 polygenic scores, including Alzheimer's disease polygenic score (2006-2012). Among participants aged 55 years and older in 2008, we excluded those with any memory problems between 2006 and 2008 and included those with complete follow-up on incident Alzheimer's disease and all-cause dementia, between 2010 and 2018 (N = 9683), based on self- or proxy-diagnosis every 2 years (2010, 2012, 2014, 2016 and 2018). Cox proportional hazards and 4-way decomposition models were conducted. Analyses were also stratified by sex and by race. There were racial differences in all-cause dementia incidence (age and sex-adjusted model, per standard deviation: hazard ratio, HR = 1.34, 95% confidence interval, CI: 1.09-1.65, P = 0.007), partially driven by educational attainment and income. We also found independent associations of race (age and sex-adjusted model, African American versus White adults: HR = 2.07, 95% CI: 1.52-2.83, P < 0.001) and Alzheimer's disease polygenic score (age and sex-adjusted model, per SD: HR = 1.37, 95% CI: 1.00-1.87, P < 0.001) with Alzheimer's disease incidence, including sex differences whereby women had a stronger effect of Alzheimer's disease polygenic score on Alzheimer's disease incidence compared with men (P < 0.05 for sex by Alzheimer's disease polygenic score interaction) adjusting for race and other covariates. The total impact of Alzheimer's disease polygenic scores on Alzheimer's disease incidence was mostly direct, while the effect of race on all-cause dementia incidence was mediated through socio-economic, lifestyle and health-related factors. Finally, among the 30 polygenic scores we examined, the total effects on the pathway Alzheimer's disease polygenic score --> Other polygenic score --> Incident Alzheimer's or all-cause dementia, were statistically significant for all, driven primarily by the controlled direct effect (P< 0. 001). In conclusion, both race and Alzheimer's disease polygenic scores were associated independently with Alzheimer's disease and all-cause dementia incidence. Alzheimer's disease polygenic score was more strongly linked to incident Alzheimer's disease among women, while racial difference in all-cause dementia was explained by other factors including socio-economic status.

Dataset Information

Genome-Wide Association Study of Incident Dementia in a Community-Based Sample of Older Subjects.

Background

Objective

Methods

Results

Conclusion

Publications

Genome-Wide Association Study of Incident Dementia in a Community-Based Sample of Older Subjects.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets