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

Sultan Chaudhury, Tulsi Patel, Imelda S. Barber, Tamar Guetta-Baranes, Keeley J. Brookes, Sally Chappell, James Turton, Rita Guerreiro, Jose Bras, Dena Hernandez, Andrew Singleton, John Hardy, David Mann, Peter Passmore, David Craig, Janet Johnston, Bernadette McGuinness, Stephen Todd, Reinhard Heun, Heike KölschPatrick G. Kehoe, Emma R.L.C. Vardy, Nigel M. Hooper, Stuart Pickering-Brown, Julie Snowden, Anna Richardson, Matthew Jones, David Neary, Jennifer Harris, James Lowe, A. David Smith, Gordon Wilcock, Donald Warden, Clive Holmes, Kevin Morgan

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)

Abstract

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 APOEε4 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 ε2 or ε4 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.
Original languageEnglish
Pages (from-to)244.e1-244.e8
JournalNeurobiology of Aging
Volume62
DOIs
Publication statusPublished - 01 Feb 2018

Keywords

  • Genotyping
  • NeuroChip
  • NeuroX
  • Polygenic risk score (PRS)
  • Sporadic early-onset Alzheimer's disease (sEOAD)

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