Dataset Information

GenoRisk: A polygenic risk score for Alzheimer's disease.

ABSTRACT:

Introduction

Recent clinical trials are considering inclusion of more than just apolipoprotein E (APOE) ε4 genotype as a way of reducing variability in analysis of outcomes.

Methods

Case-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.

Results

The 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.

Discussion

GenoRisk could improve the risk assessment of individuals identified for prevention studies.

SUBMITTER: Dickson SP

PROVIDER: S-EPMC8485054 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Publications

GenoRisk: A polygenic risk score for Alzheimer's disease.

Dickson Samuel P SP Hendrix Suzanne B SB Brown Bruce L BL Ridge Perry G PG Nicodemus-Johnson Jessie J Hardy Marci L ML McKeany Allison M AM Booth Steven B SB Fortna Ryan R RR Kauwe John S K JSK

Alzheimer's & dementia (New York, N. Y.) 20210930 1

<h4>Introduction</h4>Recent clinical trials are considering inclusion of more than just apolipoprotein E (<i>APOE</i>) ε4 genotype as a way of reducing variability in analysis of outcomes.<h4>Methods</h4>Case-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 se ...[more]

PMID: 34621978

Similar Datasets

Project description:The heritability of Alzheimer's disease estimated from twin studies is greater than the heritability derived from genome-based studies, for reasons that remain unclear. We apply both approaches to the same twin sample, considering both Alzheimer's disease polygenic risk scores and heritability from twin models, to provide insight into the role of measured genetic variants and to quantify uncaptured genetic risk. A population-based heritability and polygenic association study of Alzheimer's disease was conducted between 1986 and 2016 and is the first study to incorporate polygenic risk scores into biometrical twin models of Alzheimer's disease. The sample included 1586 twins drawn from the Swedish Twin Registry which were nested within 1137 twin pairs (449 complete pairs and 688 incomplete pairs) with clinically based diagnoses and registry follow-up (M age = 85.28, SD = 7.02; 44% male; 431 cases and 1155 controls). We report contributions of polygenic risk scores at P < 1 × 10-5, considering a full polygenic risk score (PRS), PRS without the APOE region (PRS.no.APOE) and PRS.no.APOE plus directly measured APOE alleles. Biometric twin models estimated the contribution of environmental influences and measured (PRS) and unmeasured genes to Alzheimer's disease risk. The full PRS and PRS.no.APOE contributed 10.1 and 2.4% to Alzheimer's disease risk, respectively. When APOE ɛ4 alleles were added to the model with the PRS.no.APOE, the total contribution was 11.4% to Alzheimer's disease risk, where APOE ɛ4 explained 9.3% and PRS.no.APOE dropped from 2.4 to 2.1%. The total genetic contribution to Alzheimer's disease risk, measured and unmeasured, was 71% while environmental influences unique to each twin accounted for 29% of the risk. The APOE region accounts for much of the measurable genetic contribution to Alzheimer's disease, with a smaller contribution from other measured polygenic influences. Importantly, substantial background genetic influences remain to be understood.

Dataset Information

GenoRisk: A polygenic risk score for Alzheimer's disease.

Introduction

Methods

Results

Discussion

Publications

GenoRisk: A polygenic risk score for Alzheimer's disease.

Similar Datasets

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