Risk prediction of late-onset Alzheimer’s disease implies an oligogenic architecture
-
Published:2020-09-23
Issue:1
Volume:11
Page:
-
ISSN:2041-1723
-
Container-title:Nature Communications
-
language:en
-
Short-container-title:Nat Commun
Author:
Zhang Qian, Sidorenko JuliaORCID, Couvy-Duchesne Baptiste, Marioni Riccardo E., Wright Margaret J.ORCID, Goate Alison M.ORCID, Marcora EdoardoORCID, Huang Kuan-linORCID, Porter Tenielle, Laws Simon M.ORCID, Masters Colin L., Bush Ashley I., Fowler Christopher, Darby David, Pertile Kelly, Restrepo Carolina, Roberts Blaine, Robertson Jo, Rumble Rebecca, Ryan Tim, Collins Steven, Thai Christine, Trounson Brett, Lennon Kate, Li Qiao-Xin, Ugarte Fernanda Yevenes, Volitakis Irene, Vovos Michael, Williams Rob, Baker Jenalle, Russell Alyce, Peretti Madeline, Milicic Lidija, Lim Lucy, Rodrigues Mark, Taddei Kevin, Taddei Tania, Hone Eugene, Lim Florence, Fernandez Shane, Rainey-Smith Stephanie, Pedrini Steve, Martins Ralph, Doecke James, Bourgeat Pierrick, Fripp Jurgen, Gibson Simon, Leroux Hugo, Hanson David, Dore Vincent, Zhang Ping, Burnham Samantha, Rowe Christopher C., Villemagne Victor L., Yates Paul, Pejoska Sveltana Bozin, Jones Gareth, Ames David, Cyarto Elizabeth, Lautenschlager Nicola, Barnham Kevin, Cheng Lesley, Hill Andy, Killeen Neil, Maruff Paul, Silbert Brendan, Brown Belinda, Sohrabi Harmid, Savage Greg, Vacher Michael, Sachdev Perminder S.ORCID, Mather Karen A., Armstrong Nicola J., Thalamuthu Anbupalam, Brodaty HenryORCID, Yengo Loic, Yang JianORCID, Wray Naomi R.ORCID, McRae Allan F., Visscher Peter M.ORCID,
Abstract
AbstractGenetic association studies have identified 44 common genome-wide significant risk loci for late-onset Alzheimer’s disease (LOAD). However, LOAD genetic architecture and prediction are unclear. Here we estimate the optimal P-threshold (Poptimal) of a genetic risk score (GRS) for prediction of LOAD in three independent datasets comprising 676 cases and 35,675 family history proxy cases. We show that the discriminative ability of GRS in LOAD prediction is maximised when selecting a small number of SNPs. Both simulation results and direct estimation indicate that the number of causal common SNPs for LOAD may be less than 100, suggesting LOAD is more oligogenic than polygenic. The best GRS explains approximately 75% of SNP-heritability, and individuals in the top decile of GRS have ten-fold increased odds when compared to those in the bottom decile. In addition, 14 variants are identified that contribute to both LOAD risk and age at onset of LOAD.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
Reference60 articles.
1. Harman, D. Alzheimer’s disease pathogenesis: role of aging. Ann. N.Y. Acad. Sci. 1067, 454–460 (2006). 2. Gatz, M. et al. Role of genes and environments for explaining Alzheimer disease. Arch. Gen. Psychiatry 63, 168–174 (2006). 3. Lee, S. H. et al. Estimation and partitioning of polygenic variation captured by common SNPs for Alzheimer’s disease, multiple sclerosis and endometriosis. Hum. Mol. Genet. 22, 832–841 (2013). 4. Ridge, P. G., Mukherjee, S., Crane, P. K. & Kauwe, J. S. Alzheimer’s Disease Genetics Consortium.Alzheimer’s disease: analyzing the missing heritability. PLoS ONE 8, e79771 (2013). 5. Brainstorm Consortium et al. Analysis of shared heritability in common disorders of the brain. Science 360, eaap8757 (2018).
Cited by
109 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
|
|