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 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; 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

doi:10.1016/j.neurobiolaging.2016.04.004

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

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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 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 language	English
Pages (from-to)	235.e1-235.e9
Journal	Neurobiology of Aging
Volume	46
DOIs	https://doi.org/10.1016/j.neurobiolaging.2016.04.004
State	Published - 1 Oct 2016

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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Sassi, C., Nalls, M. A., Ridge, P. G., Gibbs, J. 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, 46, 235.e1-235.e9. https://doi.org/10.1016/j.neurobiolaging.2016.04.004

@article{2b026eb24cba4157bd30e300f1173421,

title = "ABCA7 p.G215S as potential protective factor for Alzheimer'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'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)",

author = "Celeste Sassi and Nalls, {Michael A.} and Ridge, {Perry G.} and Gibbs, {Jesse R.} and Jinhui Ding and Lupton, {Michelle K.} and Claire Troakes and Katie Lunnon and Safa Al-Sarraj and Brown, {Kristelle S.} and Christopher Medway and Naomi Clement and Jenny Lord and James Turton and Jose Bras and Almeida, {Maria R.} 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 Henne Holstege and Eva Louwersheimer and {van der Flier}, {Wiesje M.} and Philip Scheltens and {Van Swieten}, {John C.} and Isabel Santana and Catarina Oliveira and Powell, {John F.} and Kauwe, {John S.} and Carlos Cruchaga and Goate, {Alison M.} and Singleton, {Andrew B.} and Rita Guerreiro and John Hardy",

note = "Publisher Copyright: {\textcopyright} 2016 The Authors",

year = "2016",

month = oct,

day = "1",

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

language = "English",

volume = "46",

pages = "235.e1--235.e9",

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Sassi, C, Nalls, MA, Ridge, PG, Gibbs, JR, 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, WM, Scheltens, P, Van Swieten, JC, Santana, I, Oliveira, C, 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, vol. 46, pp. 235.e1-235.e9. 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, Celeste

AU - Nalls, Michael A.

AU - Ridge, Perry G.

AU - Gibbs, Jesse R.

AU - Ding, Jinhui

AU - Lupton, Michelle K.

AU - Troakes, Claire

AU - Lunnon, Katie

AU - Al-Sarraj, Safa

AU - Brown, Kristelle S.

AU - Medway, Christopher

AU - Clement, Naomi

AU - Lord, Jenny

AU - Turton, James

AU - Bras, Jose

AU - Almeida, Maria 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, Henne

AU - Louwersheimer, Eva

AU - van der Flier, Wiesje M.

AU - Scheltens, Philip

AU - Van Swieten, John C.

AU - Santana, Isabel

AU - Oliveira, Catarina

AU - Powell, John F.

AU - Kauwe, John S.

AU - Cruchaga, Carlos

AU - Goate, Alison M.

AU - Singleton, Andrew B.

AU - Guerreiro, Rita

AU - Hardy, John

PY - 2016/10/1

Y1 - 2016/10/1

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 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.

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 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.

KW - ABCA7

KW - Alzheimer's disease (AD)

KW - Genome-wide association studies (GWASs)

KW - Protective variant

KW - Whole exome sequencing (WES)

KW - Whole genome sequencing (WGS)

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U2 - 10.1016/j.neurobiolaging.2016.04.004

DO - 10.1016/j.neurobiolaging.2016.04.004

M3 - Article

C2 - 27289440

AN - SCOPUS:84989927778

SN - 0197-4580

VL - 46

SP - 235.e1-235.e9

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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