Premium
Polygenic risk score of sporadic late‐onset Alzheimer's disease reveals a shared architecture with the familial and early‐onset forms
Author(s) -
Cruchaga Carlos,
DelAguila Jorge L.,
Saef Benjamin,
Black Kathleen,
Fernandez Maria Victoria,
Budde John,
Ibanez Laura,
Deming Yuetiva,
Kapoor Manav,
Tosto Giuseppe,
Mayeux Richard P.,
Holtzman David M.,
Fagan Anne M.,
Morris John C.,
Bateman Randall J.,
Goate Alison M.,
Harari Oscar
Publication year - 2018
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2017.08.013
Subject(s) - genetic architecture , disease , early onset alzheimer's disease , odds ratio , age of onset , genome wide association study , polygenic risk score , medicine , genetics , alzheimer's disease , biology , single nucleotide polymorphism , genotype , quantitative trait locus , gene
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 ptau 181 ‐Aβ 42 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.