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

C. Sassi; M.A. Nalls; P.G. Ridge; R. Gibbs; J. Ding; M.K. Lupton; C. Troakes; K. Lunnon; S. Al-Sarraj; K.S. Brown; C. Medway; N. Clement; J. Lord; J. Turton; J. Bras; M.R. Almeida; Peter Passmore; David Craig; Janet Johnston; Bernadette McGuinness; Stephen 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; H. Holstege; E. Louwersheimer; W. van der Flier; P. Scheltens; J.C. Van Swieten; I. Santana; C. Oliveira; K. Morgan; J.F. Powell; J.S. Kauwe; C. Cruchaga; A.M. Goate; A.B. Singleton; R. Guerreiro; J. Hardy

doi:10.1016/j.neurobiolaging.2016.04.004

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

C. Sassi, M.A. Nalls, P.G. Ridge, R. Gibbs, J. Ding, M.K. Lupton, C. Troakes, K. Lunnon, S. Al-Sarraj, K.S. Brown, C. Medway, N. Clement, J. Lord, J. Turton, J. Bras, M.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, H. Holstege, E. Louwersheimer, W. van der Flier, P. Scheltens, J.C. Van Swieten, I. Santana, C. Oliveira, K. Morgan, J.F. Powell, J.S. Kauwe, C. Cruchaga, A.M. Goate, A.B. Singleton, R. Guerreiro, J. Hardy

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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 analyse 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, 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, MAF=4.3%) conferring a modest but statistically significant protection against AD (p-value= 6x10-4, OR= 0.57, 95% CI 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 provide new insights that should address functional studies.

Original language	English
Journal	Neurobiology of Aging
Early online date	20 Apr 2016
DOIs	https://doi.org/10.1016/j.neurobiolaging.2016.04.004
Publication status	E-pub ahead of print - 20 Apr 2016

Keywords

Alzheimer´s disease (AD)
Genome-wide association studies (GWASs)
ABCA7
whole exome sequencing (WES)
whole genome sequencing (WGS)
protective variant

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10.1016/j.neurobiolaging.2016.04.004

1-s2.0-S0197458016300318-mainAccepted author manuscript, 622 KBLicence: CC BY-NC-ND

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Sassi, C., Nalls, M. A., Ridge, P. G., Gibbs, R., Ding, J., Lupton, M. K., Troakes, C., Lunnon, K., Al-Sarraj, S., Brown, K. S., Medway, C., Clement, N., Lord, J., Turton, J., Bras, J., Almeida, M. R., Passmore, P., Craig, D., Johnston, J., ... Hardy, J. (2016). ABCA7 p.G215S as potential protective factor for Alzheimer’s disease. Neurobiology of Aging. Advance online publication. https://doi.org/10.1016/j.neurobiolaging.2016.04.004

@article{6f698269c05c4eb9b78b8ef4e2c06634,

title = "ABCA7 p.G215S as potential protective factor for Alzheimer{\textquoteright}s disease",

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{\textquoteright}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 analyse 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, 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, MAF=4.3%) conferring a modest but statistically significant protection against AD (p-value= 6x10-4, OR= 0.57, 95% CI 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 provide new insights that should address functional studies.",

keywords = "Alzheimer´s disease (AD), Genome-wide association studies (GWASs), ABCA7, whole exome sequencing (WES), whole genome sequencing (WGS), protective variant",

author = "C. Sassi and M.A. Nalls and P.G. Ridge and R. Gibbs and J. Ding and M.K. Lupton and C. Troakes and K. Lunnon and S. Al-Sarraj and K.S. Brown and C. Medway and N. Clement and J. Lord and J. Turton and J. Bras and M.R. Almeida and Peter Passmore and David Craig and Janet Johnston and Bernadette McGuinness and Stephen Todd and Reinhard Heun and Heike K{\"o}lsch and Kehoe, {Patrick G.} and Vardy, {Emma R.L.C.} and Hooper, {Nigel M.} and Mann, {David M.} and Stuart Pickering-Brown and Kristelle Brown and James Lowe and Kevin Morgan and Smith, {A. David} and Gordon Wilcock and Donald Warden and Clive Holmes and H. Holstege and E. Louwersheimer and {van der Flier}, W. and P. Scheltens and {Van Swieten}, J.C. and I. Santana and C. Oliveira and K. Morgan and J.F. Powell and J.S. Kauwe and C. Cruchaga and A.M. Goate and A.B. Singleton and R. Guerreiro and J. Hardy",

year = "2016",

month = apr,

day = "20",

doi = "10.1016/j.neurobiolaging.2016.04.004",

language = "English",

journal = "Neurobiology of Aging",

issn = "0197-4580",

publisher = "Elsevier B.V.",

}

Sassi, C, Nalls, MA, Ridge, PG, Gibbs, R, Ding, J, Lupton, MK , Troakes, C , Lunnon, K , Al-Sarraj, S, Brown, KS, Medway, C, Clement, N, Lord, J, Turton, J, Bras, J, Almeida, MR, Passmore, P, Craig, D, Johnston, J, McGuinness, B, Todd, S, Heun, R, Kölsch, H, Kehoe, PG, Vardy, ERLC, Hooper, NM, Mann, DM, Pickering-Brown, S, Brown, K, Lowe, J, Morgan, K, Smith, AD, Wilcock, G, Warden, D, Holmes, C, Holstege, H, Louwersheimer, E, van der Flier, W, Scheltens, P, Van Swieten, JC, Santana, I, Oliveira, C, Morgan, K, Powell, JF, Kauwe, JS, Cruchaga, C, Goate, AM, Singleton, AB, Guerreiro, R & Hardy, J 2016, 'ABCA7 p.G215S as potential protective factor for Alzheimer’s disease', Neurobiology of Aging. https://doi.org/10.1016/j.neurobiolaging.2016.04.004

TY - JOUR

T1 - ABCA7 p.G215S as potential protective factor for Alzheimer’s disease

AU - Sassi, C.

AU - Nalls, M.A.

AU - Ridge, P.G.

AU - Gibbs, R.

AU - Ding, J.

AU - Lupton, M.K.

AU - Troakes, C.

AU - Lunnon, K.

AU - Al-Sarraj, S.

AU - Brown, K.S.

AU - Medway, C.

AU - Clement, N.

AU - Lord, J.

AU - Turton, J.

AU - Bras, J.

AU - Almeida, M.R.

AU - Passmore, Peter

AU - Craig, David

AU - Johnston, Janet

AU - McGuinness, Bernadette

AU - Todd, Stephen

AU - Heun, Reinhard

AU - Kölsch, Heike

AU - Kehoe, Patrick G.

AU - Vardy, Emma R.L.C.

AU - Hooper, Nigel M.

AU - Mann, David M.

AU - Pickering-Brown, Stuart

AU - Brown, Kristelle

AU - Lowe, James

AU - Morgan, Kevin

AU - Smith, A. David

AU - Wilcock, Gordon

AU - Warden, Donald

AU - Holmes, Clive

AU - Holstege, H.

AU - Louwersheimer, E.

AU - van der Flier, W.

AU - Scheltens, P.

AU - Van Swieten, J.C.

AU - Santana, I.

AU - Oliveira, C.

AU - Morgan, K.

AU - Powell, J.F.

AU - Kauwe, J.S.

AU - Cruchaga, C.

AU - Goate, A.M.

AU - Singleton, A.B.

AU - Guerreiro, R.

AU - Hardy, J.

PY - 2016/4/20

Y1 - 2016/4/20

N2 - 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 analyse 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, 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, MAF=4.3%) conferring a modest but statistically significant protection against AD (p-value= 6x10-4, OR= 0.57, 95% CI 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 provide new insights that should address functional studies.

AB - 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 analyse 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, 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, MAF=4.3%) conferring a modest but statistically significant protection against AD (p-value= 6x10-4, OR= 0.57, 95% CI 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 provide new insights that should address functional studies.

KW - Alzheimer´s disease (AD)

KW - Genome-wide association studies (GWASs)

KW - ABCA7

KW - whole exome sequencing (WES)

KW - whole genome sequencing (WGS)

KW - protective variant

U2 - 10.1016/j.neurobiolaging.2016.04.004

DO - 10.1016/j.neurobiolaging.2016.04.004

M3 - Article

SN - 0197-4580

JO - Neurobiology of Aging

JF - Neurobiology of Aging

ER -

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

Abstract

Keywords

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