ABCA7 p.G215S as potential protective factor for Alzheimer's disease.
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.
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.
Celeste
C
Sassi
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
Michael A
MA
Nalls
Department of Biology, Brigham Young University, Provo, UT, USA.
Perry G
PG
Ridge
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
Jesse R
JR
Gibbs
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
Jinhui
J
Ding
King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK; QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Michelle K
MK
Lupton
King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
Claire
C
Troakes
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.
Katie
K
Lunnon
King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
Safa
S
Al-Sarraj
Translation Cell Sciences-Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK.
Kristelle S
KS
Brown
Translation Cell Sciences-Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK.
Christopher
C
Medway
Translation Cell Sciences-Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK.
Naomi
N
Clement
Translation Cell Sciences-Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK.
Jenny
J
Lord
Translation Cell Sciences-Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK.
James
J
Turton
Reta Lila, Weston Research Laboratories, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
Jose
J
Bras
Neurogenetics Laboratory, Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
Maria R
MR
Almeida
Department of Neurology, Alzheimer Center, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands.
Henne
H
Holstege
Department of Neurology, Alzheimer Center, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands.
Eva
E
Louwersheimer
Department of Neurology, Alzheimer Center, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands.
Wiesje M
WM
van der Flier
Department of Neurology, Alzheimer Center, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands.
Philip
P
Scheltens
Department of Neurology, Alzheimer Center, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands; Department of Neurology, Erasmus Medical Centre, Rotterdam, the Netherlands.
John C
JC
Van Swieten
Neurology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal; Faculty of Medicine, Coimbra University, Coimbra, Portugal.
Isabel
I
Santana
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Laboratory of Biochemistry, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
Catarina
C
Oliveira
Translation Cell Sciences-Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK.
Kevin
K
Morgan
King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
John F
JF
Powell
Department of Biology, Brigham Young University, Provo, UT, USA; Department of Neuroscience, Brigham Young University, Provo, UT, USA.
John S
JS
Kauwe
Division of Biology and Biomedical Sciences, Washington University, St. Louis, MO, USA.
Carlos
C
Cruchaga
Icahn School of Medicine at Mount Sinai, Icahn Medical Institute, New York, NY, USA.
Alison M
AM
Goate
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
Andrew B
AB
Singleton
Reta Lila, Weston Research Laboratories, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
Rita
R
Guerreiro
Reta Lila, Weston Research Laboratories, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK. Electronic address: j.hardy@ucl.ac.uk.
John
J
Hardy
D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000502:physiology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D012306:Risk
C411895:ABCA7 protein, human; D018528:ATP-Binding Cassette Transporters
ABCA7; Alzheimer's disease (AD); Genome-wide association studies (GWASs); Protective variant; Whole exome sequencing (WES); Whole genome sequencing (WGS)