ABCA7 p.G215S as potential protective factor for Alzheimer's disease

Celeste Sassi, Michael A. Nalls, Perry G. Ridge, Jesse R. Gibbs, Jinhui Ding, Michelle K. Lupton, Claire Troakes, Katie Lunnon, Safa Al-Sarraj, Kristelle S. Brown, Christopher Medway, Naomi Clement, Jenny Lord, James Turton, Jose Bras, Maria R. Almeida, Peter Passmore, David Craig, Janet Johnston, Bernadette McGuinnessStephen Todd, Reinhard Heun, Heike Kölsch, Patrick G. Kehoe, Emma R.L.C. Vardy, Nigel M. Hooper, David M. Mann, Stuart Pickering-Brown, Kristelle Brown, James Lowe, Kevin Morgan, A. David Smith, Gordon Wilcock, Donald Warden, Clive Holmes, Henne Holstege, Eva Louwersheimer, Wiesje M. van der Flier, Philip Scheltens, John C. Van Swieten, Isabel Santana, Catarina Oliveira, John F. Powell, John S. Kauwe, Carlos Cruchaga, Alison M. Goate, Andrew B. Singleton, Rita Guerreiro, John Hardy

Research output: Contribution to journalArticlepeer-review

38 Scopus citations


Genome-wide association studies (GWASs) have been effective approaches to dissect common genetic variability underlying complex diseases in a systematic and unbiased way. Recently, GWASs have led to the discovery of over 20 susceptibility loci for Alzheimer's disease (AD). Despite the evidence showing the contribution of these loci to AD pathogenesis, their genetic architecture has not been extensively investigated, leaving the possibility that low frequency and rare coding variants may also occur and contribute to the risk of disease. We have used exome and genome sequencing data to analyze the single independent and joint effect of rare and low-frequency protein coding variants in 9 AD GWAS loci with the strongest effect sizes after APOE (BIN1, CLU, CR1, PICALM, MS4A6A, ABCA7, EPHA1, CD33, and CD2AP) in a cohort of 332 sporadic AD cases and 676 elderly controls of British and North-American ancestry. We identified coding variability in ABCA7 as contributing to AD risk. This locus harbors a low-frequency coding variant (p.G215S, rs72973581, minor allele frequency = 4.3%) conferring a modest but statistically significant protection against AD (p-value = 0.024, odds ratio = 0.57, 95% confidence interval = 0.41–0.80). Notably, our results are not driven by an enrichment of loss of function variants in ABCA7, recently reported as main pathogenic factor underlying AD risk at this locus. In summary, our study confirms the role of ABCA7 in AD and provides new insights that should address functional studies.

Original languageEnglish
Pages (from-to)235.e1-235.e9
JournalNeurobiology of Aging
StatePublished - 1 Oct 2016


  • ABCA7
  • Alzheimer's disease (AD)
  • Genome-wide association studies (GWASs)
  • Protective variant
  • Whole exome sequencing (WES)
  • Whole genome sequencing (WGS)


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