TY - JOUR
T1 - Polygenic risk score of sporadic late-onset Alzheimer's disease reveals a shared architecture with the familial and early-onset forms
AU - the
AU - Dominantly Inherited Alzheimer Network (DIAN)
AU - Disease Neuroimaging Initiative (ADNI)
AU - NIA-LOAD family study
AU - Cruchaga, Carlos
AU - Del-Aguila, Jorge L.
AU - Saef, Benjamin
AU - Black, Kathleen
AU - Fernandez, Maria Victoria
AU - Budde, John
AU - Ibanez, Laura
AU - Deming, Yuetiva
AU - Kapoor, Manav
AU - Tosto, Giuseppe
AU - Mayeux, Richard P.
AU - Holtzman, David M.
AU - Fagan, Anne M.
AU - Morris, John C.
AU - Bateman, Randall J.
AU - Goate, Alison M.
AU - Harari, Oscar
N1 - Funding Information:
Data collection and sharing for this project were supported by the Dominantly Inherited Alzheimer Network (DIAN; U19AG032438, P50 AG-16570, and P50 AG-005142) funded by the National Institute on Aging (NIA) and the German Center for Neurodegenerative Diseases (DZNE). This work was also supported by the NIHR Queen Square Dementia Biomedical Research Unit and the MRC Dementias Platform UK (MR/L023784/1 and MR/009076/1). Exome chip sequencing was supported by the DIAN-TU Pharma Consortium, (the DIAN-TU Pharma Consortium, http://dian-tu.wustl.edu/en/pharma-consortium-members ).
Funding Information:
This work was supported by grants from the National Institutes of Health ( R01-AG044546 , P01-AG003991 , RF1AG053303 , R01-AG035083 , and R01-NS085419 ) and the Alzheimer's Association ( NIRG-11-200110 ). This research was conducted while C.C. was a recipient of a New Investigator Award in Alzheimer's disease from the American Federation for Aging Research. C.C. is a recipient of a BrightFocus Foundation Alzheimer's Disease Research grant (A2013359S). The recruitment and clinical characterization of research participants at Washington University were supported by NIH P50 AG05681, P01 AG03991, and P01 AG026276.
Funding Information:
We thank the Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine for helping with genomic analysis. The Center is partially supported by NCI Cancer Center Support grant number P30 CA91842 to the Siteman Cancer Center and by ICTS/CTSA grant number UL1TR000448 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. This work was supported by access to equipment made possible by the Hope Center for Neurological Disorders and the Departments of Neurology and Psychiatry at Washington University School of Medicine.
Funding Information:
Data collection and sharing for this project were funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense, award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd. and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health ( www.fnih.org ). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.
Publisher Copyright:
© 2017 the Alzheimer's Association
PY - 2018/2
Y1 - 2018/2
N2 - Objective To determine whether the extent of overlap of the genetic architecture among the sporadic late-onset Alzheimer's Disease (sLOAD), familial late-onset AD (fLOAD), sporadic early-onset AD (sEOAD), and autosomal dominant early-onset AD (eADAD). Methods Polygenic risk scores (PRSs) were constructed using previously identified 21 genome-wide significant loci for LOAD risk. Results We found that there is an overlap in the genetic architecture among sEOAD, fLOAD, and sLOAD. The highest association of the PRS and risk (odds ratio [OR] = 2.27; P = 1.29 × 10−7) was observed in sEOAD, followed by fLOAD (OR = 1.75; P = 1.12 × 10−7) and sLOAD (OR = 1.40; P = 1.21 × 10−3). The PRS was associated with cerebrospinal fluid ptau181-Aβ42 on eADAD (P = 4.36 × 10−2). Conclusion Our analysis confirms that the genetic factors identified for LOAD modulate risk in sLOAD and fLOAD and also sEOAD cohorts. Specifically, our results suggest that the burden of these risk variants is associated with familial clustering and earlier onset of AD. Although these variants are not associated with risk in the eADAD, they may be modulating age at onset.
AB - Objective To determine whether the extent of overlap of the genetic architecture among the sporadic late-onset Alzheimer's Disease (sLOAD), familial late-onset AD (fLOAD), sporadic early-onset AD (sEOAD), and autosomal dominant early-onset AD (eADAD). Methods Polygenic risk scores (PRSs) were constructed using previously identified 21 genome-wide significant loci for LOAD risk. Results We found that there is an overlap in the genetic architecture among sEOAD, fLOAD, and sLOAD. The highest association of the PRS and risk (odds ratio [OR] = 2.27; P = 1.29 × 10−7) was observed in sEOAD, followed by fLOAD (OR = 1.75; P = 1.12 × 10−7) and sLOAD (OR = 1.40; P = 1.21 × 10−3). The PRS was associated with cerebrospinal fluid ptau181-Aβ42 on eADAD (P = 4.36 × 10−2). Conclusion Our analysis confirms that the genetic factors identified for LOAD modulate risk in sLOAD and fLOAD and also sEOAD cohorts. Specifically, our results suggest that the burden of these risk variants is associated with familial clustering and earlier onset of AD. Although these variants are not associated with risk in the eADAD, they may be modulating age at onset.
KW - APOE
KW - APP
KW - Age at onset
KW - Area under the curve
KW - Aβ
KW - Cerebrospinal fluid
KW - Disease modifier
KW - Dominantly inherited Alzheimer network
KW - Early-onset Alzheimer's disease
KW - Early-onset autosomal dominant
KW - Genetic architecture
KW - Genetic risk factor
KW - Late-onset Alzheimer's disease
KW - PSEN1
KW - PSEN2
KW - Polygenic risk score
KW - Sporadic late-onset Alzheimer's disease
KW - Tau
UR - http://www.scopus.com/inward/record.url?scp=85030027641&partnerID=8YFLogxK
U2 - 10.1016/j.jalz.2017.08.013
DO - 10.1016/j.jalz.2017.08.013
M3 - Article
C2 - 28943286
AN - SCOPUS:85030027641
SN - 1552-5260
VL - 14
SP - 205
EP - 214
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
IS - 2
ER -