Association of a Total Cholesterol Polygenic Score with Cholesterol Levels and Pathological Biomarkers across the Alzheimer's Disease Spectrum.
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SUBMITTER: Nilsson NIV
PROVIDER: S-EPMC8623969 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:To evaluate whether the polygenic profile modifies the development of sporadic Alzheimer's disease (sAD) and pathological biomarkers in cerebrospinal fluid (CSF), 462 sAD patients and 463 age-matched cognitively normal (CN) controls were genotyped for 35 single-nucleotide polymorphisms (SNPs) that are significantly associated with sAD. Then, the alleles found to be associated with sAD were used to build polygenic risk score (PRS) models to represent the genetic risk. Receiver operating characteristic (ROC) analyses and the Cox proportional hazards model were used to evaluate the predictive value of PRS for the sAD risk and age at onset. We measured the CSF levels of Aβ42, Aβ42/Aβ40, total tau (T-tau), and phosphorylated tau (P-tau) in a subgroup (60 sAD and 200 CN participants), and analyzed their relationships with the PRSs. We found that 14 SNPs, including SNPs in the APOE, BIN1, CD33, EPHA1, SORL1, and TOMM40 genes, were associated with sAD risk in our cohort. The PRS models built with these SNPs showed potential for discriminating sAD patients from CN controls, and were able to predict the incidence rate of sAD and age at onset. Furthermore, the PRSs were correlated with the CSF levels of Aβ42, Aβ42/Aβ40, T-tau, and P-tau. Our study suggests that PRS models hold promise for assessing the genetic risk and development of AD. As genetic risk profiles vary among populations, large-scale genome-wide sequencing studies are urgently needed to identify the genetic risk loci of sAD in Chinese populations to build accurate PRS models for clinical practice.
| S-EPMC7340696 | biostudies-literature
Project description:IntroductionRecent clinical trials are considering inclusion of more than just apolipoprotein E (APOE) ε4 genotype as a way of reducing variability in analysis of outcomes.MethodsCase-control data were used to compare the capacity of age, sex, and 58 Alzheimer's disease (AD)-associated single nucleotide polymorphisms (SNPs) to predict AD status using several statistical models. Model performance was assessed with Brier scores and tenfold cross-validation. Genotype and sex × age estimates from the best performing model were combined with age and intercept estimates from the general population to develop a personalized genetic risk score, termed age, and sex-adjusted GenoRisk.ResultsThe elastic net model that included age, age x sex interaction, allelic APOE terms, and 29 additional SNPs performed the best. This model explained an additional 19% of the heritable risk compared to APOE genotype alone and achieved an area under the curve of 0.747.DiscussionGenoRisk could improve the risk assessment of individuals identified for prevention studies.
| S-EPMC8485054 | biostudies-literature
Project description:Mounting evidence indicates that the polygenic basis of late-onset Alzheimer's disease can be harnessed to identify individuals at greatest risk for cognitive decline. We have previously developed and validated a polygenic hazard score comprising of 31 single nucleotide polymorphisms for predicting Alzheimer's disease dementia age of onset. In this study, we examined whether polygenic hazard scores are associated with: (i) regional tracer uptake using amyloid PET; (ii) regional volume loss using longitudinal MRI; (iii) post-mortem regional amyloid-β protein and tau associated neurofibrillary tangles; and (iv) four common non-Alzheimer's pathologies. Even after accounting for APOE, we found a strong association between polygenic hazard scores and amyloid PET standard uptake volume ratio with the largest effects within frontal cortical regions in 980 older individuals across the disease spectrum, and longitudinal MRI volume loss within the entorhinal cortex in 607 older individuals across the disease spectrum. We also found that higher polygenic hazard scores were associated with greater rates of cognitive and clinical decline in 632 non-demented older individuals, even after controlling for APOE status, frontal amyloid PET and entorhinal cortex volume. In addition, the combined model that included polygenic hazard scores, frontal amyloid PET and entorhinal cortex volume resulted in a better fit compared to a model with only imaging markers. Neuropathologically, we found that polygenic hazard scores were associated with regional post-mortem amyloid load and neuronal neurofibrillary tangles, even after accounting for APOE, validating our imaging findings. Lastly, polygenic hazard scores were associated with Lewy body and cerebrovascular pathology. Beyond APOE, we show that in living subjects, polygenic hazard scores were associated with amyloid deposition and neurodegeneration in susceptible brain regions. Polygenic hazard scores may also be useful for the identification of individuals at the highest risk for developing multi-aetiological dementia.
| S-EPMC6351776 | biostudies-literature
Project description:BackgroundParathyroid hormone-related protein (PTHrP) is involved in intracellular calcium regulation, neural cell proliferation and synaptic transmission. To date, no studies have been performed to evaluate the potential of PTHrP concentrations in cerebrospinal fluid (CSF) as a biomarker of brain pathophysiology. In this study we evaluated the association between CSF concentrations of PTHrP with the core CSF biomarkers of Alzheimer's disease (AD).MethodsPTHrP and calcium were analysed using validated mass spectrometry based methods in a set of CSF samples that tested positive (n = 45) and negative (n = 45) for the AD biomarkers, including total tau protein (T-tau), phosphorylated tau protein (P-tau) and amyloid-β 42 (Aβ42). The measured CSF concentrations of PTHrP and calcium (Ca) were evaluated for association with AD CSF biomarkers.ResultsPTHrP and Ca concentrations in CSF samples ranged between 25 and 137 pmol/L and 0.92-1.53 mmol/L, respectively. Higher concentrations of PTHrP were observed in association with increased concentrations of T-tau and P-tau in the AD and the control group; while a stronger correlation was observed in the control group (ρ = 0.6, p < 0.0001; and ρ = 0.72, p < 0.0001, for T-tau and P-tau, respectively). Negative correlation was observed between concentrations of PTHrP and Aβ42 in the AD group (ρ = 0.27, p = 0.015). A statistically significantly lower ratio Aβ42/PTHrP was observed in the AD group (p < 0.0001).ConclusionIn the current study, we observed an association of PTHrP concentrations with concentrations of clinically used CSF biomarkers of AD. Concentrations of PTHrP were positively correlated with concentrations of T-tau and P-tau, suggesting an association with neuronal secretion and function, which is reduced upon progression to AD pathology. Our data suggest potential utility of the Aβ42/PTHrP ratio in assessment of AD progression.
| S-EPMC8669458 | biostudies-literature
Project description:BackgroundRecent studies suggest that plasma phosphorylated tau181 (p-tau181) is a highly specific biomarker for Alzheimer's disease (AD)-related tau pathology. It has great potential for the diagnostic and prognostic evaluation of AD, since it identifies AD with the same accuracy as tau PET and CSF p-tau181 and predicts the development of AD dementia in cognitively unimpaired (CU) individuals and in those with mild cognitive impairment (MCI). Plasma p-tau181 may also be used as a biomarker in studies exploring disease pathogenesis, such as genetic or environmental risk factors for AD-type tau pathology. The aim of the present study was to investigate the relation between polygenic risk scores (PRSs) for AD and plasma p-tau181.MethodsData from the Alzheimer's Disease Neuroimaging Initiative (ADNI) was used to examine the relation between AD PRSs, constructed based on findings in recent genome-wide association studies, and plasma p-tau181, using linear regression models. Analyses were performed in the total sample (n = 818), after stratification on diagnostic status (CU (n = 236), MCI (n = 434), AD dementia (n = 148)), and after stratification on Aβ pathology status (Aβ positives (n = 322), Aβ negatives (n = 409)).ResultsAssociations between plasma p-tau181 and APOE PRSs (p = 3e-18-7e-15) and non-APOE PRSs (p = 3e-4-0.03) were seen in the total sample. The APOE PRSs were associated with plasma p-tau181 in all diagnostic groups (CU, MCI, and AD dementia), while the non-APOE PRSs were associated only in the MCI group. The APOE PRSs showed similar results in amyloid-β (Aβ)-positive and negative individuals (p = 5e-5-1e-3), while the non-APOE PRSs were associated with plasma p-tau181 in Aβ positives only (p = 0.02).ConclusionsPolygenic risk for AD including APOE was found to associate with plasma p-tau181 independent of diagnostic and Aβ pathology status, while polygenic risk for AD beyond APOE was associated with plasma p-tau181 only in MCI and Aβ-positive individuals. These results extend the knowledge about the relation between genetic risk for AD and p-tau181, and further support the usefulness of plasma p-tau181 as a biomarker of AD.
| S-EPMC7792087 | biostudies-literature
Project description:Study objectivesAge-related changes in sleep include a reduction in total sleep time and a greater incidence of sleep disorders, and are also an integral part of neurodegenerations. In the present study, we aimed to: a) identify common genetic variants that may influence self-reported sleep duration, and b) examine the association between the identified genetic variants and performance in different cognitive domains.MethodsA sample of 197 cognitively healthy participants, aged 20-80 years, mostly non-Hispanic Whites (69%), were selected from the Reference Abilities Neural Network and the Cognitive Reserve study. Each participant underwent an evaluation of sleep function and assessment of neuropsychological performance on global cognition and four different domains (memory, speed of processing, fluid reasoning, language). Published GWAS summary statistics from a Polygenic Score (PS) for sleep duration in a large European ancestry cohort (N = 30,251) were used to derive a PS in our study sample. Multivariate linear models were used to test the associations between the PS and sleep duration and cognitive performance. Age, sex, and education were used as covariates. Secondary analyses were conducted in three age-groups (young, middle, old).ResultsHigher PS was linked to longer sleep duration and was also associated with better performance in global cognition, fluid reasoning, speed of processing, and language, but not memory. Results especially for fluid reasoning, language, and global cognition were driven mostly by the young group.ConclusionsOur study replicated the previously reported association between sleep-PS and longer sleep duration. We additionally found a significant association between the sleep-PS and cognitive function. Our results suggest that common genetic variants may influence the link between sleep duration and cognitive health.
| S-EPMC7541541 | biostudies-literature
Project description:Sporadic early-onset Alzheimer's disease (sEOAD) exhibits the symptoms of late-onset Alzheimer's disease but lacks the familial aspect of the early-onset familial form. The genetics of Alzheimer's disease (AD) identifies APOE?4 to be the greatest risk factor; however, it is a complex disease involving both environmental risk factors and multiple genetic loci. Polygenic risk scores (PRSs) accumulate the total risk of a phenotype in an individual based on variants present in their genome. We determined whether sEOAD cases had a higher PRS compared to controls. A cohort of sEOAD cases was genotyped on the NeuroX array, and PRSs were generated using PRSice. The target data set consisted of 408 sEOAD cases and 436 controls. The base data set was collated by the International Genomics of Alzheimer's Project consortium, with association data from 17,008 late-onset Alzheimer's disease cases and 37,154 controls, which can be used for identifying sEOAD cases due to having shared phenotype. PRSs were generated using all common single nucleotide polymorphisms between the base and target data set, PRS were also generated using only single nucleotide polymorphisms within a 500 kb region surrounding the APOE gene. Sex and number of APOE ?2 or ?4 alleles were used as variables for logistic regression and combined with PRS. The results show that PRS is higher on average in sEOAD cases than controls, although there is still overlap among the whole cohort. Predictive ability of identifying cases and controls using PRSice was calculated with 72.9% accuracy, greater than the APOE locus alone (65.2%). Predictive ability was further improved with logistic regression, identifying cases and controls with 75.5% accuracy.
| S-EPMC5995122 | biostudies-literature
Project description:BackgroundOur understanding of the pathophysiology underlying Alzheimer's disease (AD) has benefited from genomic analyses, including those that leverage polygenic risk score (PRS) models of disease. The use of functional annotation has been able to improve the power of genomic models.ObjectiveWe sought to leverage genomic functional annotations to build tissue-specific AD PRS models and study their relationship with AD and its biomarkers.MethodsWe built 13 tissue-specific AD PRS and studied the scores' relationships with AD diagnosis, cerebrospinal fluid (CSF) amyloid, CSF tau, and other CSF biomarkers in two longitudinal cohort studies of AD.ResultsThe AD PRS model that was most predictive of AD diagnosis (even without APOE) was the liver AD PRS: n = 1,115; odds ratio = 2.15 (1.67-2.78), p = 3.62×10-9. The liver AD PRS was also statistically significantly associated with cerebrospinal fluid biomarker evidence of amyloid-β (Aβ42:Aβ40 ratio, p = 3.53×10-6) and the phosphorylated tau:amyloid-β ratio (p = 1.45×10-5).ConclusionThese findings provide further evidence of the role of the liver-functional genome in AD and the benefits of incorporating functional annotation into genomic research.
| S-EPMC10050104 | biostudies-literature
Project description:BACKGROUND: Cholesterol concentrations in blood are related to cardiovascular diseases. Recent genome-wide association studies (GWAS) of cholesterol levels identified a number of single-locus effects on total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C) levels. Here, we report single-locus and epistasis SNP effects on TC and HDL-C using the Framingham Heart Study (FHS) data. RESULTS: Single-locus effects and pairwise epistasis effects of 432,096 SNP markers were tested for their significance on log-transformed TC and HDL-C levels. Twenty nine additive SNP effects reached single-locus genome-wide significance (p < 7.2 x 10-8) and no dominance effect reached genome-wide significance. Two new gene regions were detected, the RAB3GAP1-R3HDM1-LCT-MCM6 region of chr02 for TC identified by six new SNPs, and the OSBPL8-ZDHHC17 region (chr12) for HDL-C identified by one new SNP. The remaining 22 single-locus SNP effects confirmed previously reported genes or gene regions. For TC, three SNPs identified two gene regions that were tightly linked with previously reported genes associated with TC, including rs599839 that was 10 bases downstream PSRC1 and 3.498 kb downstream CELSR2, rs4970834 in CELSR2, and rs4245791 in ABCG8 that slightly overlapped with ABCG5. For HDL-C, LPL was confirmed by 12 SNPs 8-45 kb downstream, CETP by two SNPs 0.5-11 kb upstream, and the LIPG-ACAA2 region by five SNPs inside this region. Two epistasis effects on TC and thirteen epistasis effects on HDL-C reached the significance of "suggestive linkage". The most significant epistasis effect (p = 5.72 x 10-13) was close to reaching "significant linkage" and was a dominance x dominance effect of HDL-C between LMBRD1 (chr06) and the LRIG3 region (chr12), and this pair of gene regions had six other D x D effects with "suggestive linkage". CONCLUSIONS: Genome-wide association analysis of the FHS data detected two new gene regions with genome-wide significance, detected epistatic SNP effects on TC and HDL-C with the significance of suggestive linkage in seven pairs of gene regions, and confirmed some previously reported gene regions associated with TC and HDL-C.
| S-EPMC2867786 | biostudies-literature
Project description:Importance:Myopia is a leading cause of untreatable visual impairment and is increasing in prevalence worldwide. Interventions for slowing childhood myopia progression have shown success in randomized clinical trials; hence, there is a need to identify which children would benefit most from treatment intervention. Objectives:To examine whether genetic information alone can identify children at risk of myopia development and whether including a child's genetic predisposition to educational attainment is associated with improved genetic prediction of the risk of myopia. Design, Setting, and Participants:Meta-analysis of 3 genome-wide association studies (GWAS) including a total of 711 984 individuals. These were a published GWAS for educational attainment and 2 GWAS for refractive error in the UK Biobank, which is a multisite cohort study that recruited participants between January 2006 and October 2010. A polygenic risk score was applied in a population-based validation sample examined between September 1998 and September 2000 (Avon Longitudinal Study of Parents and Children [ALSPAC] mothers). Data analysis was performed from February 2018 to May 2019. Main Outcomes and Measures:The primary outcome was the area under the receiver operating characteristic curve (AUROC) in analyses for predicting myopia, using noncycloplegic autorefraction measurements for myopia severity levels of less than or equal to -0.75 diopter (D) (any), less than or equal to -3.00 D (moderate), or less than or equal to -5.00 D (high). The predictor variable was a polygenic risk score (PRS) derived from genome-wide association study data for refractive error (n?=?95?619), age of onset of spectacle wear (n?=?287?448), and educational attainment (n?=?328?917). Results:A total of 383 067 adults aged 40 to 69 years from the UK Biobank were included in the new GWAS analyses. The PRS was evaluated in 1516 adults aged 24 to 51 years from the ALSPAC mothers cohort. The PRS had an AUROC of 0.67 (95% CI, 0.65-0.70) for myopia, 0.75 (95% CI, 0.70-0.79) for moderate myopia, and 0.73 (95% CI, 0.66-0.80) for high myopia. Inclusion in the PRS of information associated with genetic predisposition to educational attainment marginally improved the AUROC for myopia (AUROC, 0.674 vs 0.668; P?=?.02), but not those for moderate and high myopia. Individuals with a PRS in the top 10% were at 6.1-fold higher risk (95% CI, 3.4-10.9) of high myopia. Conclusions and Relevance:A personalized medicine approach may be feasible for detecting very young children at risk of myopia. However, accuracy must improve further to merit uptake in clinical practice; currently, cycloplegic autorefraction remains a better indicator of myopia risk (AUROC, 0.87).
| S-EPMC6824229 | biostudies-literature