Cognitive Decline in Alzheimer's Disease: Limited Clinical Utility for GWAS or Polygenic Risk Scores in a Clinical Trial Setting.
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ABSTRACT:
SUBMITTER: Euesden J
PROVIDER: S-EPMC7290959 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The genetic protective factors for cognitive decline in aging remain unknown. Predicting an individual's rate of cognitive decline-or with better cognitive resilience-using genetics will allow personalized intervention for cognitive enhancement and the optimal selection of target samples in clinical trials. Here, using genome-wide polygenic scores (GPS) of cognitive capacity as the genomic indicators for variations of human intelligence, we analyzed the 18-year records of cognitive and behavioral data of 8511 European-ancestry adults from the Wisconsin Longitudinal Study (WLS), specifically focusing on the cognitive assessments that were repeatedly administered to the participants with their average ages of 64.5 and 71.5. We identified a significant interaction effect between age and cognitive capacity GPS, which indicated that a higher cognitive capacity GPS significantly correlated with a slower cognitive decline in the domain of immediate memory recall (β = 1.86 × 10-1, p-value = 1.79 × 10-3). The additional phenome-wide analyses identified several associations between cognitive capacity GPSs and cognitive/behavioral phenotypes, such as similarities task (β = 1.36, 95% CI = (1.22, 1.51), p-value = 3.59 × 10-74), number series task (β = 0.94, 95% CI = (0.85, 1.04), p-value = 2.55 × 10-78), IQ scores (β = 1.42, 95% CI = (1.32, 1.51), p-value = 7.74 × 10-179), high school classrank (β = 1.86, 95% CI = (1.69, 2.02), p-value = 3.07 × 10-101), Openness from the BIG 5 personality factor (p-value = 2.19 × 10-14, β = 0.57, 95% CI = (0.42, 0.71)), and leisure activity of reading books (β = 0.50, 95% CI = (0.40, 0.60), p-value = 2.03 × 10-21), attending cultural events, such as concerts, plays, or museums (β = 0.60, 95% CI = (0.49, 0.72), p-value = 2.06 × 10-23), and watching TV (β = -0.48, 95% CI = (-0.59, -0.37), p-value = 4.16 × 10-18). As the first phenome-wide analysis of cognitive and behavioral phenotypes, this study presents the novel genetic protective effects of cognitive ability on the decline of memory recall in an aging population.
| S-EPMC9331374 | biostudies-literature
Project description:Since their first appearance in the context of schizophrenia and bipolar disorder in 2009, polygenic risk scores (PRSs) have been described for a large number of common complex diseases. However, the clinical utility of PRSs in disease risk assessment or therapeutic decision making is likely limited because PRSs usually only account for the heritable component of a trait and ignore the etiological role of environment and lifestyle. We surveyed the current state of PRSs for various diseases, including breast cancer, diabetes, prostate cancer, coronary artery disease, and Parkinson disease, with an extra focus upon the potential improvement of clinical scores by their combination with PRSs. We observed that the diagnostic and prognostic performance of PRSs alone is consistently low, as expected. Moreover, combining a PRS with a clinical score at best led to moderate improvement of the power of either risk marker. Despite the large number of PRSs reported in the scientific literature, prospective studies of their clinical utility, particularly of the PRS-associated improvement of standard screening or therapeutic procedures, are still rare. In conclusion, the benefit to individual patients or the health care system in general of PRS-based extensions of existing diagnostic or treatment regimens is still difficult to judge.
| S-EPMC10576695 | biostudies-literature
Project description:The treatment of complex and multifactorial diseases constitutes a big challenge in day-to-day clinical practice. As many parameters influence clinical phenotypes, accurate diagnosis and prompt therapeutic management is often difficult. Significant research and investment focuses on state-of-the-art genomic and metagenomic analyses in the burgeoning field of Precision (or Personalized) Medicine with genome-wide-association-studies (GWAS) helping in this direction by linking patient genotypes at specific polymorphic sites (single-nucleotide polymorphisms, SNPs) to the specific phenotype. The generation of polygenic risk scores (PRSs) is a relatively novel statistical method that associates the collective genotypes at many of a person's SNPs to a trait or disease. As GWAS sample sizes increase, PRSs may become a powerful tool for prevention, early diagnosis and treatment. However, the complexity and multidimensionality of genetic and environmental contributions to phenotypes continue to pose significant challenges for the clinical, broad-scale use of PRSs. To improve the value of PRS measures, we propose a novel pipeline which might better utilize GWAS results and improve the utility of PRS when applied to Alzheimer's Disease (AD), as a paradigm of multifactorial disease with existing large GWAS datasets that have not yet achieved significant clinical impact. We propose a refined approach for the construction of AD PRS improved by (1), taking into consideration the genetic loci where the SNPs are located, (2) evaluating the post-translational impact of SNPs on coding and non-coding regions by focusing on overlap with open chromatin data and SNPs that are expression quantitative trait loci (QTLs), and (3) scoring and annotating the severity of the associated clinical phenotype into the PRS. Open chromatin and eQTL data need to be carefully selected based on tissue/cell type of origin (e.g., brain, excitatory neurons). Applying such filters to traditional PRS on GWAS studies of complex diseases like AD, can produce a set of SNPs weighted according to our algorithm and a more useful PRS. Our proposed methodology may pave the way for new applications of genomic machine and deep learning pipelines to GWAS datasets in an effort to identify novel clinically useful genetic biomarkers for complex diseases like AD.
| S-EPMC8305482 | biostudies-literature
Project description:BackgroundPrior studies support a genetic basis for postoperative acute kidney injury (AKI). We conducted a genome-wide association study (GWAS), assessed the clinical utility of a polygenic risk score (PRS), and estimated the heritable component of AKI in patients who underwent noncardiac surgery.MethodsWe performed a retrospective large-scale genome-wide association study followed by a meta-analysis of patients who underwent noncardiac surgery at the Vanderbilt University Medical Center ("Vanderbilt" cohort) or Michigan Medicine, the academic medical center of the University of Michigan ("Michigan" cohort). In the Vanderbilt cohort, the relationship between polygenic risk score for estimated glomerular filtration rate and postoperative AKI was also tested to explore the predictive power of aggregating multiple common genetic variants associated with AKI risk. Similarly, in the Vanderbilt cohort genome-wide complex trait analysis was used to estimate the heritable component of AKI due to common genetic variants.ResultsThe study population included 8248 adults in the Vanderbilt cohort (mean [SD] 58.05 [15.23] years, 50.2% men) and 5998 adults in Michigan cohort (56.24 [14.76] years, 49% men). Incident postoperative AKI events occurred in 959 patients (11.6%) and in 277 patients (4.6%), respectively. No loci met genome-wide significance in the GWAS and meta-analysis. PRS for estimated glomerular filtration rate explained a very small percentage of variance in rates of postoperative AKI and was not significantly associated with AKI (odds ratio 1.050 per 1 SD increase in polygenic risk score [95% CI, 0.971-1.134]). The estimated heritability among common variants for AKI was 4.5% (SE = 4.5%) suggesting low heritability.ConclusionThe findings of this study indicate that common genetic variation minimally contributes to postoperative AKI after noncardiac surgery, and likely has little clinical utility for identifying high-risk patients.
| S-EPMC9587619 | biostudies-literature
Project description:The reconciliation between Mendelian inheritance of discrete traits and the genetically based correlation between relatives for quantitative traits was Fisher's infinitesimal model of a large number of genetic variants, each with very small effects, whose causal effects could not be individually identified. The development of genome-wide genetic association studies (GWAS) raised the hope that it would be possible to identify single polymorphic variants with identifiable functional effects on complex traits. It soon became clear that, with larger and larger GWAS on more and more complex traits, most of the significant associations had such small effects, that identifying their individual functional effects was essentially hopeless. Polygenic risk scores that provide an overall estimate of the genetic propensity to a trait at the individual level have been developed using GWAS data. These provide useful identification of groups of individuals with substantially increased risks, which can lead to recommendations of medical treatments or behavioral modifications to reduce risks. However, each such claim will require extensive investigation to justify its practical application. The challenge now is to use limited genetic association studies to find individually identifiable variants of significant functional effect that can help to understand the molecular basis of complex diseases and traits, and so lead to improved disease prevention and treatment. This can best be achieved by 1) the study of rare variants, often chosen by careful candidate assessment, and 2) the careful choice of phenotypes, often extremes of a quantitative variable, or traits with relatively high heritability.
| S-EPMC7431089 | biostudies-literature
Project description:Polygenic risk scores (PRSs) have wide applications in human genetics research, but often include tuning parameters which are difficult to optimize in practice due to limited access to individual-level data. Here, we introduce PUMAS, a novel method to fine-tune PRS models using summary statistics from genome-wide association studies (GWASs). Through extensive simulations, external validations, and analysis of 65 traits, we demonstrate that PUMAS can perform various model-tuning procedures using GWAS summary statistics and effectively benchmark and optimize PRS models under diverse genetic architecture. Furthermore, we show that fine-tuned PRSs will significantly improve statistical power in downstream association analysis.
| S-EPMC8419981 | biostudies-literature
Project description:Genomic medicine aims to improve health using the individual genomic data of people to inform care. While clinical utility of genomic medicine in many monogenic, Mendelian disorders is amply demonstrated, clinical utility is less evident in polygenic traits, e.g., coronary artery disease or breast cancer. Polygenic risk scores (PRS) are subsets of individual genotypes designed to capture heritability of common traits, and hence to allow the stratification of risk of the trait in a population. We systematically reviewed the PubMed database for unequivocal evidence of clinical utility of polygenic risk scores, using stringent inclusion and exclusion criteria. While we identified studies demonstrating clinical validity in conditions where medical intervention based on a PRS is likely to benefit patient outcome, we did not identify a single study demonstrating unequivocally such a benefit, i.e. clinical utility. We conclude that while the routine use of PRSs hold great promise, translational research is still needed before they should enter mainstream clinical practice.
| S-EPMC9055005 | biostudies-literature
Project description:Background: APOE is the largest genetic risk factor for sporadic Alzheimer's disease (AD), but there is a substantial polygenic component as well. Polygenic risk scores (PRS) can summarize small effects across the genome but may obscure differential risk associated with different molecular processes and pathways. Variability at the genetic level may contribute to the extensive phenotypic heterogeneity of Alzheimer's disease (AD). Here, we examine polygenic risk impacting specific pathways associated with AD and examined its relationship with clinical status and AD biomarkers of amyloid, tau, and neurodegeneration (A/T/N). Methods: A total of 1,411 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with genotyping data were included. Sets of variants identified from a pathway analysis of AD GWAS summary statistics were combined into clusters based on their assigned pathway. We constructed pathway-specific PRSs for each participant and tested their associations with diagnostic status (AD vs cognitively normal), abnormal levels of amyloid and ptau (positive vs negative), and hippocampal volume. The APOE region was excluded from all PRSs, and analyses controlled for APOE -ε4 carrier status. Results: Thirteen pathway clusters were identified relating to categories such as immune response, amyloid precursor processing, protein localization, lipid transport and binding, tyrosine kinase, and endocytosis. Eight pathway-specific PRSs were significantly associated with AD dementia diagnosis. Amyloid-positivity was associated with endocytosis and fibril formation, response misfolded protein, and regulation protein tyrosine PRSs. Ptau positivity and hippocampal volume were both related to protein localization and mitophagy PRS, and ptau positivity was additionally associated with an immune signaling PRS. A global AD PRS showed stronger associations with diagnosis and all biomarkers compared to pathway PRSs, suggesting a strong synergistic effect of all loci contributing to the global AD PRS. Conclusions: Pathway PRS may contribute to understanding separable disease processes, but do not appear to add significant power for predictive purposes. These findings demonstrate that, although genetic risk for AD is widely distributed, AD-phenotypes may be preferentially associated with risk in specific pathways. Defining genetic risk along multiple dimensions at the individual level may help clarify the etiological heterogeneity in AD.
| S-EPMC10002839 | biostudies-literature
Project description:The increasing proportion of variance in human complex traits explained by polygenic scores, along with progress in preimplantation genetic diagnosis, suggests the possibility of screening embryos for traits such as height or cognitive ability. However, the expected outcomes of embryo screening are unclear, which undermines discussion of associated ethical concerns. Here, we use theory, simulations, and real data to evaluate the potential gain of embryo screening, defined as the difference in trait value between the top-scoring embryo and the average embryo. The gain increases very slowly with the number of embryos but more rapidly with the variance explained by the score. Given current technology, the average gain due to screening would be ≈2.5 cm for height and ≈2.5 IQ points for cognitive ability. These mean values are accompanied by wide prediction intervals, and indeed, in large nuclear families, the majority of children top-scoring for height are not the tallest.
| S-EPMC6957074 | biostudies-literature
Project description:Most people's cognitive abilities decline with age, with significant and partly genetically driven, individual differences in rate of change. Although APOE ɛ4 and genetic scores for late-onset Alzheimer's disease (LOAD) have been related to cognitive decline during preclinical stages of dementia, there is limited knowledge concerning genetic factors implied in normal cognitive aging. In the present study, we examined three potential genetic predictors of age-related cognitive decline as follows: (1) the APOE ɛ4 allele, (2) a polygenic score for general cognitive ability (PGS-cog), and (3) a polygenic risk score for late-onset AD (PRS-LOAD). We examined up to six time points of cognitive measurements in the longitudinal population-based Betula study, covering a 25-year follow-up period. Only participants that remained alive and non-demented until the most recent dementia screening (1-3 years after the last test occasion) were included (n = 1087). Individual differences in rate of cognitive change (composite score) were predicted by the PRS-LOAD and APOE ɛ4, but not by PGS-cog. To control for the possibility that the results reflected a preclinical state of Alzheimer's disease in some participants, we re-ran the analyses excluding cognitive data from the last test occasion to model cognitive change up-until a minimum of 6 years before potential onset of clinical Alzheimers. Strikingly, the association of PRS-LOAD, but not APOE ɛ4, with cognitive change remained. The results indicate that PRS-LOAD predicts individual difference in rate of cognitive decline in normal aging, but it remains to be determined to what extent this reflects preclinical Alzheimer's disease brain pathophysiology and subsequent risk to develop the disease.
| S-EPMC7381667 | biostudies-literature