Journal
NEUROBIOLOGY OF AGING
Volume 46, Issue -, Pages -Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2016.04.004
Keywords
Alzheimer's disease (AD); Genome-wide association studies (GWASs); ABCA7; Whole exome sequencing (WES); Whole genome sequencing (WGS); Protective variant
Categories
Funding
- Alzheimer's Research UK
- Medical Research Council (MRC)
- Wellcome Trust/MRC Joint Call in Neurodegeneration award [WT089698]
- National Institute for Health Research Biomedical Research Unit in Dementia at University College London Hospitals, University College London
- Intramural Research Programs of the National Institute on Aging
- National Institute of Neurological Disease and Stroke
- National Institutes of Health (Department of Health and Human Services) [ZO1 AG000950-10]
- ARUK
- AS
- Intramural Research Program of the National Institute on Aging
- National Institutes of Health
- Department of Health and Human Services [ZO1 AG000950-10]
- National Institute on Aging (NIA) [U24 AG21886]
- NIH [R01 AG042611]
- [P50 AG016574]
- [U01 AG006786]
- [R01 AG18023]
- Alzheimers Research UK [ARUK-TRFUS2012-3] Funding Source: researchfish
- Medical Research Council [MR/L016397/1, G1100695] Funding Source: researchfish
- MRC [G1100695, MR/L016397/1] Funding Source: UKRI
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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. (C) 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license.
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