scholarly journals Considering the APOE locus in polygenic scores for Alzheimer’s disease

2019 ◽  
Author(s):  
Erin B. Ware ◽  
Jessica D. Faul ◽  
Colter M. Mitchell ◽  
Kelly M. Bakulski
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cumulative Effect ◽  
Carrier Status ◽  
Nucleotide Polymorphisms ◽  
Genomic Locus ◽  
Single Nucleotide ◽  
Polygenic Score ◽  
Polygenic Scores ◽  
Small Additive

AbstractPolygenic scores are a strategy to aggregate the small, additive effects of single nucleotide polymorphisms across the genome. With phenotypes like Alzheimer’s disease, which have a strong and well established genomic locus (APOE), the cumulative effect of genetic variants outside of this area has not been well established in a population-representative sample. Here we examine the association between polygenic scores both with and without the APOE region at different P value thresholds. We also investigate the addition of APOE-ε4 carrier status and its effect on the polygenic score – dementia association. We found that including the APOE region through weighted variants in a polygenic score was insufficient to capture the large amount of risk attributed to this region. We recommend removing this region from polygenic score calculation and treating the APOE locus as an independent covariate.

scholarly journals Considering the APOE locus in Alzheimer’s disease polygenic scores in the Health and Retirement Study: a longitudinal panel study

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Erin B. Ware ◽  
Jessica D. Faul ◽  
Colter M. Mitchell ◽  
Kelly M. Bakulski
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Repeated Measures ◽  
Panel Study ◽  
European Ancestry ◽  
Health And Retirement Study ◽  
Carrier Status ◽  
Polygenic Score ◽  
Polygenic Scores ◽  
Retirement Study

Abstract Background Polygenic scores are a strategy to aggregate the small, additive effects of single nucleotide polymorphisms across the genome. With phenotypes like Alzheimer’s disease, which have a strong and well-established genomic locus (APOE), the cumulative effect of genetic variants outside of this area has not been well established in a population-representative sample. Methods Here we examine the association between polygenic scores for Alzheimer’s disease both with and without the APOE region (chr19: 45,384,477 to 45,432,606, build 37/hg 19) at different P value thresholds and dementia. We also investigate the addition of APOE-ε4 carrier status and its effect on the polygenic score—dementia association in the Health and Retirement Study using generalized linear models accounting for repeated measures by individual and use a binomial distribution, logit link, and unstructured correlation structure. Results In a large sample of European ancestry participants of the Health and Retirement Study (n = 9872) with an average of 5.2 (standard deviation 1.8) visit spaced two years apart, we found that including the APOE region through weighted variants in a polygenic score was insufficient to capture the large amount of risk attributed to this region. We also found that a polygenic score with a P value threshold of 0.01 had the strongest association with the odds of dementia in this sample (odds ratio = 1.10 95%CI 1.0 to 1.2). Conclusion We recommend removing the APOE region from polygenic score calculation and treating the APOE locus as an independent covariate when modeling dementia. We also recommend using a moderately conservative P value threshold (e.g. 0.01) when creating polygenic scores for Alzheimer’s disease on dementia. These recommendations may help elucidate relationships between polygenic scores and regions of strong significance for phenotypes similar to Alzheimer’s disease.

IL-1β, IL-6, IL-10, and TNFα Single Nucleotide Polymorphisms in Human Influence the Susceptibility to Alzheimer’s Disease Pathology

2020 ◽  
Vol 75 (3) ◽  
pp. 1029-1047 ◽  
Author(s):  
Mirjana Babić Leko ◽  
Matea Nikolac Perković ◽  
Nataša Klepac ◽  
Dubravka Švob Štrac ◽  
Fran Borovečki ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Single Nucleotide Polymorphisms ◽  
Nucleotide Polymorphisms ◽  
Human Influence ◽  
Single Nucleotide

scholarly journals Relationships of Cerebrospinal Fluid Alzheimer’s Disease Biomarkers and COMT, DBH, and MAOB Single Nucleotide Polymorphisms

2020 ◽  
Vol 73 (1) ◽  
pp. 135-145
Author(s):  
Mirjana Babić Leko ◽  
Matea Nikolac Perković ◽  
Nataša Klepac ◽  
Dubravka Švob Štrac ◽  
Fran Borovečki ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Single Nucleotide Polymorphisms ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Disease Biomarkers

Identification of Biological Pathways to Alzheimer's Disease Using Polygenic Scores

2017 ◽  
Vol 41 (S1) ◽  
pp. S166-S167
Author(s):  
J. Harrison ◽  
E. Baker ◽  
L. Hubbard ◽  
D. Linden ◽  
J. Williams ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Folding ◽  
Late Onset ◽  
Cell Lineage ◽  
Biological Pathways ◽  
Risk Scores ◽  
Nucleotide Polymorphisms ◽  
Discovery Sample ◽  
Polygenic Scores

IntroductionSingle nucleotide polymorphisms (SNPs) contribute small increases in risk for late-onset Alzheimer's disease (LOAD). LOAD SNPs cluster around genes with similar biological functions (pathways). Polygenic risk scores (PRS) aggregate the effect of SNPs genome-wide. However, this approach has not been widely used for SNPs within specific pathways.ObjectivesWe investigated whether pathway-specific PRS were significant predictors of LOAD case/control status.MethodsWe mapped SNPs to genes within 8 pathways implicated in LOAD. For our polygenic analysis, the discovery sample comprised 13,831 LOAD cases and 29,877 controls. LOAD risk alleles for SNPs in our 8 pathways were identified at a P-value threshold of 0.5. Pathway-specific PRS were calculated in a target sample of 3332 cases and 9832 controls. The genetic data were pruned with R2 > 0.2 while retaining the SNPs most significantly associated with AD. We tested whether pathway-specific PRS were associated with LOAD using logistic regression, adjusting for age, sex, country, and principal components. We report the proportion of variance in liability explained by each pathway.ResultsThe most strongly associated pathways were the immune response (NSNPs = 9304, = 5.63 × 10−19, R2 = 0.04) and hemostasis (NSNPs = 7832, P = 5.47 × 10−7, R2 = 0.015). Regulation of endocytosis, hematopoietic cell lineage, cholesterol transport, clathrin and protein folding were also significantly associated but accounted for less than 1% of the variance. With APOE excluded, all pathways remained significant except proteasome-ubiquitin activity and protein folding.ConclusionsGenetic risk for LOAD can be split into contributions from different biological pathways. These offer a means to explore disease mechanisms and to stratify patients.Disclosure of interestThe authors have not supplied their declaration of competing interest.

scholarly journals Impact of SORL1 Single Nucleotide Polymorphisms on Alzheimer’s Disease Cerebrospinal Fluid Markers

2011 ◽  
Vol 32 (3) ◽  
pp. 164-170 ◽  
Author(s):  
Panagiotis Alexopoulos ◽  
Liang-Hao Guo ◽  
Martina Kratzer ◽  
Christine Westerteicher ◽  
Alexander Kurz ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Single Nucleotide Polymorphisms ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide

Association between Single-Nucleotide Polymorphisms of the hOGG1,NEIL1,APEX1, FEN1,LIG1, and LIG3 Genes and Alzheimer's Disease Risk

2016 ◽  
Vol 73 (2) ◽  
pp. 98-107 ◽  
Author(s):  
Dominik Kwiatkowski ◽  
Piotr Czarny ◽  
Monika Toma ◽  
Anna Korycinska ◽  
Katarzyna Sowinska ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Single Nucleotide Polymorphisms ◽  
Disease Risk ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide
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