Alzheimer's & dementia : the journal of the Alzheimer's Association · 2017
Polygenic risk score of sporadic late-onset Alzheimer's disease reveals a shared architecture with the familial and early-onset forms.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Cruchaga Carlos, Del-Aguila 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, Dominantly Inherited Alzheimer Network (DIAN), Disease Neuroimaging Initiative (ADNI), NIA-LOAD family study, Harari Oscar
Аннотация
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.
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.