Polygenic risk score in postmortem diagnosed sporadic early-onset Alzheimer's disease

NEUROBIOLOGY OF AGING

卷:62

Article

Chaudhury, Sultan¹  Patel, Tulsi¹  Barber, Imelda S.¹  Guetta-Baranes, Tamar¹  Brookes, Keeley J.¹  Chappell, Sally¹  Turton, James¹  Guerreiro, Rita^2,3,4  Bras, Jose^2,3,4  Hernandez, Dena⁵  Singleton, Andrew⁵  Hardy, John^2,4  Mann, David⁶  Morgan, Kevin¹ 

[1] Univ Nottingham, Human Genet Grp, Nottingham, England

[2] UCL, Inst Neurol, Dept Mol Neurosci, London, England

[3] Univ Aveiro, Inst Biomed iBiMED, Dept Med Sci, Aveiro, Portugal

[4] UCL, UK DRI, London, England

[5] NIA, Lab Neurogenet, NIH, Bethesda, MD 20892 USA

[6] Univ Manchester, Inst Brain Behav & Mental Hlth, Fac Med & Human Sci, Manchester, Lancs, England

关键词: Polygenic risk score (PRS);    Sporadic early-onset Alzheimer's disease (sEOAD);    Genotyping;    NeuroX;    NeuroChip;   

DOI  :  10.1016/j.neurobiolaging.2017.09.035

来源: Elsevier

【 摘 要 】

Sporadic early-onset Alzheimer's disease (sEOAD) exhibits the symptoms of late-onset Alzheimer's disease but lacks the familial aspect of the early-onset familial form. The genetics of Alzheimer's disease (AD) identifies APOE epsilon 4 to be the greatest risk factor; however, it is a complex disease involving both environmental risk factors and multiple genetic loci. Polygenic risk scores (PRSs) accumulate the total risk of a phenotype in an individual based on variants present in their genome. We determined whether sEOAD cases had a higher PRS compared to controls. A cohort of sEOAD cases was genotyped on the NeuroX array, and PRSs were generated using PRSice. The target data set consisted of 408 sEOAD cases and 436 controls. The base data set was collated by the International Genomics of Alzheimer's Project consortium, with association data from 17,008 late-onset Alzheimer's disease cases and 37,154 controls, which can be used for identifying sEOAD cases due to having shared phenotype. PRSs were generated using all common single nucleotide polymorphisms between the base and target data set, PRS were also generated using only single nucleotide polymorphisms within a 500 kb region surrounding the APOE gene. Sex and number of APOE epsilon 2 or epsilon 4 alleles were used as variables for logistic regression and combined with PRS. The results show that PRS is higher on average in sEOAD cases than controls, although there is still overlap among the whole cohort. Predictive ability of identifying cases and controls using PRSice was calculated with 72.9% accuracy, greater than the APOE locus alone (65.2%). Predictive ability was further improved with logistic regression, identifying cases and controls with 75.5% accuracy. (C) 2017 Elsevier Inc. All rights reserved.

【 授权许可】

Free