GenoRisk: A polygenic risk score for Alzheimer's disease

Dickson, Samuel P.; Hendrix, Suzanne; Brown, Bruce L.; Ridge, Perry G.; Nicodemus‐Johnson, Jessie; Hardy, Marci; McKeany, Allison M; Booth, Steven B; Fortna, Ryan R.; Kauwe, John; Niagads,

doi:10.1002/trc2.12211

Cited by 9 publications

(6 citation statements)

References 45 publications

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“…Females were underrepresented here, so the results may not be generalizable to them. We studied only individuals with HIV infection; it is possible that PERK genetic variations also associate with depression in people without HIV or in other neurodegenerative diseases where there is evidence that the unfolded protein response is activated [ 84 , 85 ].…”

Section: Discussionmentioning

confidence: 99%

PKR-like ER kinase (PERK) Haplotypes Are Associated with Depressive Symptoms in People with HIV

Ellis¹

2023

J Neurol Psychol

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Background: Depression is a debilitating and difficult-to-treat condition in people with HIV (PWH) despite viral suppression on antiretroviral therapy (ART). Depression is associated with activation of the PKR-like ER kinase (PERK) pathway, which regulates protein synthesis in response to metabolic stress. We evaluated common PERK haplotypes that influence PERK expression in relation to depressed mood in PWH.Methods: PWH from 6 research centers were enrolled in the study. Genotyping was conducted using targeted sequencing with TaqMan. The major PERK haplotypes A, B, and D were identified. Depressive symptom severity was assessed using the Beck Depression Inventory-II (BDI-II). Covariates including genetically-defined ancestry, demographics, HIV disease/treatment parameters and antidepressant treatments were assessed. Data were analyzed using multivariable regression models.Results: A total of 287 PWH with a mean (SD) age of 57.1±7.8 years were enrolled. Although the largest ethnic group was non-Hispanic white (n=129, 45.3%), African-American (n=124, 43.5%) and Hispanic (n=30, 10.5%) made up over half the sample. 20.3% were female and 96.5% were virally suppressed. Mean BDI-II was 9.6±9.5, and 28.9% scored above the cutoff for mild depression (BDI-II>13). PERK haplotype frequencies were AA57.8%, AB25.8%, AD 10.1%, and BB4.88%. PERK haplotypes were differentially represented according to genetic ancestry (p=6.84e-6). BDI-II scores were significantly higher in participants with the AB haplotype (F=4.45, p=0.0007).This finding was robust to consideration of potential confounds. Conclusion:PERK haplotypes were associated with depressed mood in PWH.Consequently, pharmacological targeting of PERKrelated pathways might amelioratedepression in PWH.

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Section: Discussionmentioning

confidence: 99%

PKR-like ER kinase (PERK) Haplotypes Are Associated with Depressive Symptoms in People with HIV

Ellis¹

2023

J Neurol Psychol

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“…Currently, PRS seems most applicable to estimate risk in late-onset forms of AD [ 28 , 64 ] and has proven useful to stratify patients for clinical trials to reduce variability [ 65 , 66 ], and for genes that show reduced penetrance (e.g., PSEN2 ), PRS might influence clinical expression, as has been shown for other diseases such as hereditary breast cancer [ 67 ]. Additional work is required to support these potential applications of PRS in a clinical setting.…”

Section: Discussionmentioning

confidence: 99%

Mapping the genetic landscape of early-onset Alzheimer’s disease in a cohort of 36 families

et al. 2022

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Background Many families with clinical early-onset Alzheimer’s disease (EOAD) remain genetically unexplained. A combination of genetic factors is not standardly investigated. In addition to monogenic causes, we evaluated the possible polygenic architecture in a large series of families, to assess if genetic testing of familial EOAD could be expanded. Methods Thirty-six pedigrees (77 patients) were ascertained from a larger cohort of patients, with relationships determined by genetic data (exome sequencing data and/or SNP arrays). All families included at least one AD patient with symptom onset <70 years. We evaluated segregating rare variants in known dementia-related genes, and other genes or variants if shared by multiple families. APOE was genotyped and duplications in APP were assessed by targeted test or using SNP array data. We computed polygenic risk scores (PRS) compared with a reference population-based dataset, by imputing SNP arrays or exome sequencing data. Results In eight families, we identified a pathogenic variant, including the genes APP, PSEN1, SORL1, and an unexpected GRN frameshift variant. APOE-ε4 homozygosity was present in eighteen families, showing full segregation with disease in seven families. Eight families harbored a variant of uncertain significance (VUS), of which six included APOE-ε4 homozygous carriers. PRS was not higher in the families combined compared with the population mean (beta 0.05, P = 0.21), with a maximum increase of 0.61 (OR = 1.84) in the GRN family. Subgroup analyses indicated lower PRS in six APP/PSEN1 families compared with the rest (beta −0.22 vs. 0.10; P = 0.009) and lower APOE burden in all eight families with monogenic cause (beta 0.29 vs. 1.15, P = 0.010). Nine families remained without a genetic cause or risk factor identified. Conclusion Besides monogenic causes, we suspect a polygenic disease architecture in multiple families based on APOE and rare VUS. The risk conveyed by PRS is modest across the studied families. Families without any identified risk factor render suitable candidates for further in-depth genetic evaluation.

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“…The risk conferred by the APOE4 gene appears to be attenuated in Black individuals [ 19 ]. Polygenic risk scores (containing single nucleotide polymorphisms (SNPs) identified as increasing the risk of AD in genome-wide association studies (GWAS)) explain up to 20% of additional risk beyond that associated with APOE4 [ 20 ].…”

Section: Biomarker Definition and Classificationmentioning

confidence: 99%

Biomarkers for Alzheimer’s Disease: Context of Use, Qualification, and Roadmap for Clinical Implementation

Cummings

Kinney

2022

Medicina

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Background and Objectives: The US Food and Drug Administration (FDA) defines a biomarker as a characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or responses to an exposure or intervention. Biomarkers may be used in clinical care or as drug development tools (DDTs) in clinical trials. The goal of this review and perspective is to provide insight into the regulatory guidance for the use of biomarkers in clinical trials and clinical care. Materials and Methods: We reviewed FDA guidances relevant to biomarker use in clinical trials and their transition to use in clinical care. We identified instructive examples of these biomarkers in Alzheimer’s disease (AD) drug development and their application in clinical practice. Results: For use in clinical trials, biomarkers must have a defined context of use (COU) as a risk/susceptibility, diagnostic, monitoring, predictive, prognostic, pharmacodynamic, or safety biomarker. A four-stage process defines the pathway to establish the regulatory acceptance of the COU for a biomarker including submission of a letter of intent, description of the qualification plan, submission of a full qualification package, and acceptance through a qualification recommendation. Biomarkers used in clinical care may be companion biomarkers, in vitro diagnostic devices (IVDs), or laboratory developed tests (LDTs). A five-phase biomarker development process has been proposed to structure the biomarker development process. Conclusions: Biomarkers are increasingly important in drug development and clinical care. Adherence to regulatory guidance for biomarkers used in clinical trials and patient care is required to advance these important drug development and clinical tools.

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GenoRisk: A polygenic risk score for Alzheimer's disease

Cited by 9 publications

References 45 publications

PKR-like ER kinase (PERK) Haplotypes Are Associated with Depressive Symptoms in People with HIV

PKR-like ER kinase (PERK) Haplotypes Are Associated with Depressive Symptoms in People with HIV

Mapping the genetic landscape of early-onset Alzheimer’s disease in a cohort of 36 families

Biomarkers for Alzheimer’s Disease: Context of Use, Qualification, and Roadmap for Clinical Implementation

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