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Neurobiol Aging. 2016 Oct;46:235.e1-9. doi: 10.1016/j.neurobiolaging.2016.04.004. Epub 2016 Apr 20.

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

Author information

1
Reta Lila, Weston Research Laboratories, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; Department of Experimental Neurology, Center for Stroke Research Berlin (CSB), Charite' Universitätmedizin, Berlin, Germany; German Center for Neurodegenerative Diseases (DZNE), Berlin site, Germany.
2
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
3
Department of Biology, Brigham Young University, Provo, UT, USA.
4
King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK; QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
5
King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
6
King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK; Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, Devon, UK.
7
Translation Cell Sciences-Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK.
8
Reta Lila, Weston Research Laboratories, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
9
Neurogenetics Laboratory, Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
10
Department of Neurology, Alzheimer Center, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands.
11
Department of Neurology, Alzheimer Center, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands; Department of Neurology, Erasmus Medical Centre, Rotterdam, the Netherlands.
12
Neurology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal; Faculty of Medicine, Coimbra University, Coimbra, Portugal.
13
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Laboratory of Biochemistry, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
14
Department of Biology, Brigham Young University, Provo, UT, USA; Department of Neuroscience, Brigham Young University, Provo, UT, USA.
15
Division of Biology and Biomedical Sciences, Washington University, St. Louis, MO, USA.
16
Icahn School of Medicine at Mount Sinai, Icahn Medical Institute, New York, NY, USA.
17
Reta Lila, Weston Research Laboratories, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK. Electronic address: j.hardy@ucl.ac.uk.

Abstract

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.

KEYWORDS:

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

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