The DOI matches its Crossref record; 28 of the 29 references it cites were found in a registry or an index.
Common polygenic variation enhances risk prediction for Alzheimer’s disease
Open accessAbstract
The identification of subjects at high risk for Alzheimer's disease is important for prognosis and early intervention. We investigated the polygenic architecture of Alzheimer's disease and the accuracy of Alzheimer's disease prediction models, including and excluding the polygenic component in the model. This study used genotype data from the powerful dataset comprising 17 008 cases and 37 154 controls obtained from the International Genomics of Alzheimer's Project (IGAP). Polygenic score analysis tested whether the alleles identified to associate with disease in one sample set were significantly enriched in the cases relative to the controls in an independent sample. The disease prediction accuracy was investigated in a subset of the IGAP data, a sample of 3049 cases and 1554 controls (for whom APOE genotype data were available) by means of sensitivity, specificity, area under the receiver operating characteristic curve (AUC) and positive and negative predictive values. We observed significant evidence for a polygenic component enriched in Alzheimer's disease (P = 4.9 × 10(-26)). This enrichment remained significant after APOE and other genome-wide associated regions were excluded (P = 3.4 × 10(-19)). The best prediction accuracy AUC = 78.2% (95% confidence interval 77-80%) was achieved by a logistic regression model with APOE, the polygenic score, sex and age as predictors. In conclusion, Alzheimer's disease has a significant polygenic component, which has predictive utility for Alzheimer's disease risk and could be a valuable research tool complementing experimental designs, including preventative clinical trials, stem cell selection and high/low risk clinical studies. In modelling a range of sample disease prevalences, we found that polygenic scores almost doubles case prediction from chance with increased prediction at polygenic extremes.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“risk and seems to provide an improved method for risk prediction over more selective PRS or standard predictors such as APOEε4 alleles, age, and sex [118, 122, 123].”
From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [122]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
PLINK: a tool set for whole-genome association and population-based linkage analyses.
Purcell, S., Neale, B., Todd-Brown, K., Thomas, L., Ferreira, M. A. R., Bender, D., Maller, J., Sklar, P., de Bakker, P. I. W., Daly, M. J., et al. (2007) · The American Journal of Human Genetics · doi:10.1086/519795 · Cited by 34,089
Common polygenic variation contributes to risk of schizophrenia and bipolar disorder
The International Schizophrenia Consortium (2009) · Nature · doi:10.1038/nature08185 · Cited by 4,821
Meta-Analysis of 74,046 Individuals Identifies 11 New Susceptibility Loci for Alzheimer’s Disease
(EADI), E. A. D. I., Lambert, J.-C., (GERAD), G. A. E. R. I. A. D., Alzheimer's Disease Genetic Consortium (ADGC), (CHARGE), C. F. H. A. A. R. I. G. E., Ibrahim-Verbaas, C. A., Harold, D., Naj, A. C., Sims, R., Bellenguez, C., et al. (2013) · Nature Genetics · doi:10.1038/ng.2802 · Cited by 4,336
Self-citationHowie, B. N., Donnelly, P., & Marchini, J. (2009) · PLoS Genetics · doi:10.1371/journal.pgen.1000529 · Cited by 3,928
Harold, D., Abraham, R., Hollingworth, P., Sims, R., Gerrish, A., Hamshere, M. L., Pahwa, J. S., Moskvina, V., Dowzell, K., Williams, A., et al. (2009) · Nature Genetics · doi:10.1038/ng.440 · Cited by 3,326
Self-citationAlzheimer disease in the United States (2010–2050) estimated using the 2010 census
Hebert, L. E., Weuve, J., Scherr, P. A., & Evans, D. A. (2013) · Neurology · doi:10.1212/wnl.0b013e31828726f5 · Cited by 2,642
Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease
the European Alzheimer's Disease Initiative Investigators, Lambert, J.-C., Heath, S., Even, G., Campion, D., Sleegers, K., Hiltunen, M., Combarros, O., Zelenika, D., Bullido, M. J., et al. (2009) · Nature Genetics · doi:10.1038/ng.439 · Cited by 2,234
Self-citationThe clinical use of structural MRI in Alzheimer disease
Frisoni, G. B., Fox, N. C., Jack, C. R., Scheltens, P., & Thompson, P. M. (2010) · Nature Reviews Neurology · doi:10.1038/nrneurol.2009.215 · Cited by 2,113
Initiative, T. A. D. N., Hollingworth, P., CHARGE consortium, EADI1 consortium, Harold, D., Sims, R., Gerrish, A., Lambert, J.-C., Carrasquillo, M. M., Abraham, R., et al. (2011) · Nature Genetics · doi:10.1038/ng.803 · Cited by 1,997
Self-citationNaj, A. C., Jun, G., Beecham, G. W., Wang, L.-S., Vardarajan, B. N., Buros, J., Gallins, P. J., Buxbaum, J. D., Jarvik, G. P., Crane, P. K., et al. (2011) · Nature Genetics · doi:10.1038/ng.801 · Cited by 1,901
Self-citationMaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes
Li, Y., Willer, C. J., Ding, J., Scheet, P., & Abecasis, G. R. (2010) · Genetic Epidemiology · doi:10.1002/gepi.20533 · Cited by 1,843
Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease
Escott-Price, V., Bellenguez, C., Wang, L.-S., Choi, S.-H., Harold, D., Jones, L., Holmans, P., Gerrish, A., Vedernikov, A., Richards, A., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0094661 · Cited by 1,398
Self-citationA polygenic burden of rare disruptive mutations in schizophrenia
Purcell, S. M., Moran, J. L., Fromer, M., Ruderfer, D., Solovieff, N., Roussos, P., O’Dushlaine, C., Chambert, K., Bergen, S. E., Kähler, A., et al. (2014) · Nature · doi:10.1038/nature12975 · Cited by 1,385
Genome-wide Analysis of Genetic Loci Associated With Alzheimer Disease
Seshadri, S. (2010) · JAMA · doi:10.1001/jama.2010.574 · Cited by 1,219
Self-citationLarge-scale genotyping identifies 41 new loci associated with breast cancer risk
Michailidou, K., kConFab Investigators, Australian Ovarian Cancer Study Group, The GENICA (Gene Environment Interaction and Breast Cancer in Germany) Network, Hall, P. N., González‐Neira, A., Ghoussaini, M., Dennis, J., Milne, R. L., Schmidt, M. K., et al. (2013) · Nature Genetics · doi:10.1038/ng.2563 · Cited by 1,080
Rare Variants Create Synthetic Genome-Wide Associations
Dickson, S. P., Wang, K., Krantz, I., Hakonarson, H., & Goldstein, D. B. (2010) · PLoS Biology · doi:10.1371/journal.pbio.1000294 · Cited by 857
Weiner, M. W., Veitch, D. P., Aisen, P. S., Beckett, L. A., Cairns, N. J., Cedarbaum, J., Green, R. C., Harvey, D., Jack, C. R., Jagust, W., et al. (2015) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2014.11.001 · Cited by 348
Lee, S. H., Harold, D., Nyholt, D. R., ANZGene Consortium, International Endogene Consortium, the Genetic and Environmental Risk for Alzheimer's disease (GERAD1) Consortium, Goddard, M. E., Zondervan, K. T., Williams, J., Montgomery, G. W., et al. (2013) · Human Molecular Genetics · doi:10.1093/hmg/dds491 · Cited by 217
Self-citationInvestigating the Contribution of Common Genetic Variants to the Risk and Pathogenesis of ADHD
Stergiakouli, E., Hamshere, M. L., Holmans, P., Langley, K., Zaharieva, I. T., Genetics, D., Hawi, Z., Kent, L., Gill, M., Williams, N. M., et al. (2011) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2011.11040551 · Cited by 202
Self-citationConvergent genetic and expression data implicate immunity in Alzheimer's disease
International Genomics of Alzheimer's Disease Consortium (IGAP), Jones, L., Lambert, J., Wang, L., Choi, S., Harold, D., Vedernikov, A., Escott‐Price, V., Stone, T., Richards, A., et al. (2015) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2014.05.1757 · Cited by 199
Self-citationGenetic risk profiles for depression and anxiety in adult and elderly cohorts
Demirkan, A., Penninx, B. W. J. H., Hek, K., Wray, N. R., Amin, N., Aulchenko, Y. S., van Dyck, R., de Geus, E. J. C., Hofman, A., Uitterlinden, A. G., et al. (2010) · Molecular Psychiatry · doi:10.1038/mp.2010.65 · Cited by 175
Polygenic risk of P arkinson disease is correlated with disease age at onset
Escott‐Price, V., Nalls, M. A., Morris, H. R., Lubbe, S. J., Brice, A., Gasser, T., Heutink, P., Wood, N. W., Hardy, J., Singleton, A., et al. (2015) · Annals of Neurology · doi:10.1002/ana.24335 · Cited by 142
Self-citationPolygenic Risk for Schizophrenia Is Associated with Cognitive Change Between Childhood and Old Age
McIntosh, A. M., Gow, A. J., Luciano, M., Davies, G., Liewald, D. C. M., Harris, S. E., Corley, J., Hall, J., Starr, J. M., Porteous, D. J., et al. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.01.011 · Cited by 123
Modeling the prevalence and incidence of Alzheimer’s disease and mild cognitive impairment
Yesavage, J. A., O'Hara, R. M., KRAEMER, H. C., Noda, A. M., Taylor, J. L., Ferris, S. H., Gély-Nargeot, M.-C., Rosen, A. C., Friedman, L., Sheikh, J. I., et al. (2002) · Journal of Psychiatric Research · doi:10.1016/s0022-3956(02)00020-1 · Cited by 109
Moskvina, V. (2013) · JAMA Neurology · doi:10.1001/jamaneurol.2013.448 · Cited by 61
Evidence for a polygenic contribution to androgenetic alopecia
Heilmann‐Heimbach, S., Brockschmidt, F. F., Hillmer, A. M., Hanneken, S., Eigelshoven, S., Ludwig, K. U., Herold, C., Mangold, E., Becker, T., Kruse, R., et al. (2013) · British Journal of Dermatology · doi:10.1111/bjd.12443 · Cited by 44
Chapman, J., Rees, E., Harold, D. H., Ivanov, D. K., Gerrish, A., Sims, R., Hollingworth, P., Stretton, A., Holmans, P., Owen, M. J., et al. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds476 · Cited by 34
Self-citationNo evidence that extended tracts of homozygosity are associated with Alzheimer's disease
Sims, R., Dwyer, S., Harold, D. H., Gerrish, A., Hollingworth, P., Chapman, J., Jones, N., Abraham, R., Ivanov, D. K., Pahwa, J. S., et al. (2011) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.31216 · Cited by 19
Self-citation
Flagged first, then by citations
1 of the 29 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Scheltens, P., De Strooper, B., Kivipelto, M., Holstege, H., Chételat, G., Teunissen, C. E., Cummings, J., & van der Flier, W. M. (2021) · The Lancet · doi:10.1016/s0140-6736(20)32205-4 · Cited by 5,465
Lane, C. A., Hardy, J., & Schott, J. M. (2018) · European Journal of Neurology · doi:10.1111/ene.13439 · Cited by 2,616
Self-citationARUK Consortium, Sims, R., GERAD/PERADES, C., van der Lee, S. J., Naj, A. C., Bellenguez, C., Badarinarayan, N., Jakobsdottir, J., Kunkle, B. W., Boland, A., et al. (2017) · Nature Genetics · doi:10.1038/ng.3916 · Cited by 1,012
Self-citationThe genetic architecture of Parkinson's disease
Blauwendraat, C., Nalls, M. A., & Singleton, A. B. (2020) · The Lancet Neurology · doi:10.1016/s1474-4422(19)30287-x · Cited by 1,114
Association of Lifestyle and Genetic Risk With Incidence of Dementia
Lourida, I., Hannon, E., Littlejohns, T. J., Langa, K. M., Hyppönen, E., Kuzma, E., & Llewellyn, D. J. (2019) · JAMA · doi:10.1001/jama.2019.9879 · Cited by 881
Metadata
- Authors
- Escott-Price, V., Sims, R., Bannister, C., Harold, D., Vronskaya, M., Majounie, E., Badarinarayan, N., GERAD/PERADES, consortia, I., Morgan, K., Passmore, P., Holmes, C., Powell, J., Brayne, C., Gill, M., Mead, S., Goate, A., Cruchaga, C., Lambert, J.-C., van Duijn, C., Maier, W., Ramirez, A., Holmans, P., Jones, L., Hardy, J., Seshadri, S., Schellenberg, G. D., Amouyel, P., & Williams, J.
- Affiliations
- Cardiff University (GB)
- Trinity College Dublin (IE)
- University of Nottingham (GB)
- Queen's University Belfast (GB)
- University of Cambridge (GB)
- King's College London (GB)
- Washington University in St. Louis (US)
- Inserm (FR)
- University of Bonn (DE)
- UCL Queen Square Institute of Neurology (GB)
- Boston University (US)
- ORCID
- Sims, Rebecca
- Bannister, Christian
- Harold, Denise
- Badarinarayan, Nandini
- Morgan, Kevin
- Passmore, Peter
- Holmes, Clive
- Powell, John
- Brayne, Carol
- Gill, Michael
- Mead, Simon
- Goate, Alison
- Cruchaga, Carlos
- Lambert, Jean-Charles
- van Duijn, Cornelia
- Holmans, Peter
- Jones, Lesley
- Hardy, John
- Seshadri, Sudha
- Schellenberg, Gerard D.
- Amouyel, Philippe
- Williams, Julie
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-10-21
- Volume
- 138
- Issue
- 12
- Pages
- 3673-3684
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC5006219
- OpenAlex
- W2193207784
- Cited by
- 414
- References
- 29
- Citations by year
- 2026: 20 · 2025: 34 · 2024: 29 · 2023: 52 · 2022: 45 · 2021: 51 · 2020: 51 · 2019: 52 · 2018: 31 · 2017: 31 · 2016: 16 · 2015: 2
- FWCI
- 19.64
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Brain (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- Nottingham ePrints (University of Nottingham) (submittedVersion, cc-by)
- Repository@Nottingham (University of Nottingham) (submittedVersion, cc-by)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Research Portal (King's College London) (submittedVersion, other-oa)
- Repository@Nottingham (University of Nottingham) (submittedVersion, other-oa)
- HighWire Press Open Archive (submittedVersion)
- DZNE Pub (submittedVersion)
- Research Portal (Queen's University Belfast) (submittedVersion)
- Funders
- National Institute for Social Care and Health Research
- Health and Care Research Wales
- EU Joint Programme – Neurodegenerative Disease Research
- Alzheimer's Society
- National Institute for Health and Care Research (NF-SI-0611-10084)
- Cardiff University
- Dementias Platform UK
- Medical Research Council (MR/L023784/2, MR/L023784/1, MR/L501517/1, MR/K013041/1, MR/L501529/1, MR/L010305/1, MR/M009076/1)
- National Institute on Aging (U01AG049505, P30AG010124, U01AG032984, R01AG033193, R01AG008122, U24AG021886)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, polygenic risk score, polygenic architecture, risk prediction, apolipoprotein E, genome-wide association study, prediction accuracy
- MeSH terms
- Alleles, Alzheimer Disease, Apolipoproteins E, Genetic Testing, Genotype, Humans, Risk, ROC Curve, Genetic Variation, Logistic Models, Case-Control Studies, Genetic Predisposition to Disease, Multifactorial Inheritance, Genome-Wide Association Study
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
