Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease

H. Holstege; M. Hulsman; C. Charbonnier; B. Grenier-Boley; O. Quenez; D. Grozeva; J.G.J. van Rooij; R. Sims; S. Ahmad; N. Amin; P.J. Norsworthy; O. Dols-Icardo; H. Hummerich; A. Kawalia; P. Amouyel; G.W. Beecham; C. Berr; J.C. Bis; A. Boland; P. Bossù; F. Bouwman; J. Bras; D. Campion; J.N. Cochran; A. Daniele; J.-F. Dartigues; S. Debette; J.-F. Deleuze; N. Denning; A.L. DeStefano; L.A. Farrer; M.V. Fernández; N.C. Fox; D. Galimberti; E. Genin; J.J.P. Gille; Y. Le Guen; R. Guerreiro; J.L. Haines; C. Holmes; M.A. Ikram; M.K. Ikram; I.E. Jansen; R. Kraaij; M. Lathrop; A.W. Lemstra; A. Lleó; L. Luckcuck; M.M.A.M. Mannens; R. Marshall; E.R. Martin; C. Masullo; R. Mayeux; P. Mecocci; A. Meggy; M.O. Mol; K. Morgan; R.M. Myers; B. Nacmias; A.C. Naj; V. Napolioni; F. Pasquier; P. Pastor; M.A. Pericak-Vance; R. Raybould; R. Redon; M.J.T. Reinders; A.-C. Richard; S.G. Riedel-Heller; F. Rivadeneira; S. Rousseau; N.S. Ryan; S. Saad; P. Sanchez-Juan; G.D. Schellenberg; P. Scheltens; J.M. Schott; D. Seripa; S. Seshadri; D. Sie; E.A. Sistermans; S. Sorbi; R. van Spaendonk; G. Spalletta; N. Tesi; B. Tijms; A.G. Uitterlinden; S.J. van der Lee; P.J. Visser; M. Wagner; D. Wallon; L.-S. Wang; A. Zarea; J. Clarimon; J.C. van Swieten; M.D. Greicius; J.S. Yokoyama; C. Cruchaga; J. Hardy; A. Ramirez; S. Mead; W.M. van der Flier; C.M. van Duijn; J. Williams; G. Nicolas; C. Bellenguez; J.-C. Lambert

doi:https://doi.org/10.1038/s41588-022-01208-7

Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease

H. Holstege, M. Hulsman, C. Charbonnier, B. Grenier-Boley, O. Quenez, D. Grozeva, J.G.J. van Rooij, R. Sims, S. Ahmad, N. Amin, P.J. Norsworthy, O. Dols-Icardo, H. Hummerich, A. Kawalia, P. Amouyel, G.W. Beecham, C. Berr, J.C. Bis, A. Boland, P. BossùF. Bouwman, J. Bras, D. Campion, J.N. Cochran, A. Daniele, J.-F. Dartigues, S. Debette, J.-F. Deleuze, N. Denning, A.L. DeStefano, L.A. Farrer, M.V. Fernández, N.C. Fox, D. Galimberti, E. Genin, J.J.P. Gille, Y. Le Guen, R. Guerreiro, J.L. Haines, C. Holmes, M.A. Ikram, M.K. Ikram, I.E. Jansen, R. Kraaij, M. Lathrop, A.W. Lemstra, A. Lleó, L. Luckcuck, M.M.A.M. Mannens, R. Marshall, E.R. Martin, C. Masullo, R. Mayeux, P. Mecocci, A. Meggy, M.O. Mol, K. Morgan, R.M. Myers, B. Nacmias, A.C. Naj, V. Napolioni, F. Pasquier, P. Pastor, M.A. Pericak-Vance, R. Raybould, R. Redon, M.J.T. Reinders, A.-C. Richard, S.G. Riedel-Heller, F. Rivadeneira, S. Rousseau, N.S. Ryan, S. Saad, P. Sanchez-Juan, G.D. Schellenberg, P. Scheltens, J.M. Schott, D. Seripa, S. Seshadri, D. Sie, E.A. Sistermans, S. Sorbi, R. van Spaendonk, G. Spalletta, N. Tesi, B. Tijms, A.G. Uitterlinden, S.J. van der Lee, P.J. Visser, M. Wagner, D. Wallon, L.-S. Wang, A. Zarea, J. Clarimon, J.C. van Swieten, M.D. Greicius, J.S. Yokoyama, C. Cruchaga, J. Hardy, A. Ramirez, S. Mead, W.M. van der Flier, C.M. van Duijn, J. Williams, G. Nicolas, C. Bellenguez, J.-C. Lambert

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Abstract

© 2022, The Author(s).Alzheimer’s disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70%1. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants2. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals—16,036 AD cases and 16,522 controls. Next to variants in TREM2, SORL1 and ABCA7, we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10. Additionally, the rare-variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential drivers of respective AD-genome-wide association study loci. Variants associated with the strongest effect on AD risk, in particular loss-of-function variants, are enriched in early-onset AD cases. Our results provide additional evidence for a major role for amyloid-β precursor protein processing, amyloid-β aggregation, lipid metabolism and microglial function in AD.

Original language	English
Pages (from-to)	1786-1794
Number of pages	9
Journal	Nature Genetics
Volume	54
Issue number	12
Early online date	2022
DOIs	https://doi.org/10.1038/s41588-022-01208-7
Publication status	Published - 1 Dec 2022

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Holstege, H., Hulsman, M., Charbonnier, C., Grenier-Boley, B., Quenez, O., Grozeva, D., van Rooij, J. G. J., Sims, R., Ahmad, S., Amin, N., Norsworthy, P. J., Dols-Icardo, O., Hummerich, H., Kawalia, A., Amouyel, P., Beecham, G. W., Berr, C., Bis, J. C., Boland, A., ... Lambert, J.-C. (2022). Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease. Nature Genetics, 54(12), 1786-1794. https://doi.org/10.1038/s41588-022-01208-7

@article{748337d046ac4ca6a09b3695af1a12da,

title = "Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer{\textquoteright}s disease",

abstract = "{\textcopyright} 2022, The Author(s).Alzheimer{\textquoteright}s disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70%1. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants2. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals—16,036 AD cases and 16,522 controls. Next to variants in TREM2, SORL1 and ABCA7, we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10. Additionally, the rare-variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential drivers of respective AD-genome-wide association study loci. Variants associated with the strongest effect on AD risk, in particular loss-of-function variants, are enriched in early-onset AD cases. Our results provide additional evidence for a major role for amyloid-β precursor protein processing, amyloid-β aggregation, lipid metabolism and microglial function in AD.",

author = "H. Holstege and M. Hulsman and C. Charbonnier and B. Grenier-Boley and O. Quenez and D. Grozeva and {van Rooij}, J.G.J. and R. Sims and S. Ahmad and N. Amin and P.J. Norsworthy and O. Dols-Icardo and H. Hummerich and A. Kawalia and P. Amouyel and G.W. Beecham and C. Berr and J.C. Bis and A. Boland and P. Boss{\`u} and F. Bouwman and J. Bras and D. Campion and J.N. Cochran and A. Daniele and J.-F. Dartigues and S. Debette and J.-F. Deleuze and N. Denning and A.L. DeStefano and L.A. Farrer and M.V. Fern{\'a}ndez and N.C. Fox and D. Galimberti and E. Genin and J.J.P. Gille and {Le Guen}, Y. and R. Guerreiro and J.L. Haines and C. Holmes and M.A. Ikram and M.K. Ikram and I.E. Jansen and R. Kraaij and M. Lathrop and A.W. Lemstra and A. Lle{\'o} and L. Luckcuck and M.M.A.M. Mannens and R. Marshall and E.R. Martin and C. Masullo and R. Mayeux and P. Mecocci and A. Meggy and M.O. Mol and K. Morgan and R.M. Myers and B. Nacmias and A.C. Naj and V. Napolioni and F. Pasquier and P. Pastor and M.A. Pericak-Vance and R. Raybould and R. Redon and M.J.T. Reinders and A.-C. Richard and S.G. Riedel-Heller and F. Rivadeneira and S. Rousseau and N.S. Ryan and S. Saad and P. Sanchez-Juan and G.D. Schellenberg and P. Scheltens and J.M. Schott and D. Seripa and S. Seshadri and D. Sie and E.A. Sistermans and S. Sorbi and {van Spaendonk}, R. and G. Spalletta and N. Tesi and B. Tijms and A.G. Uitterlinden and {van der Lee}, S.J. and P.J. Visser and M. Wagner and D. Wallon and L.-S. Wang and A. Zarea and J. Clarimon and {van Swieten}, J.C. and M.D. Greicius and J.S. Yokoyama and C. Cruchaga and J. Hardy and A. Ramirez and S. Mead and {van der Flier}, W.M. and {van Duijn}, C.M. and J. Williams and G. Nicolas and C. Bellenguez and J.-C. Lambert",

note = "Funding Information: We thank all the study participants, their families, the participating medical staff, general practitioners, pharmacists and all laboratory personnel involved in patient diagnosis, blood collection, blood biobanking, DNA preparation and sequencing. The work in this manuscript was carried out on the Cartesius supercomputer, which is embedded in the Dutch national e-infrastructure with the support of the SURF Cooperative. Computing hours were granted in 2016, 2017, 2018 and 2019 to H. Holstege by the Dutch Research Council (project name: 100-plus; project nos. 15318 and 17232). This research was conducted using the funding obtained by the following study cohorts: ADES-FR, AgeCoDe-UKBonn; Barcelona SPIN; AC-EMC; ERF and Rotterdam; ADC-Amsterdam; 100-plus study; EMIF-90+; Control Brain Consortium; PERADES; StEP-AD; Knight-ADRC; UCSF/NYGC/UAB; UCL-DRC EOAD; ADSP. Data used in preparation of this article were obtained from the Alzheimer{\textquoteright}s Disease Neuroimaging Initiative (ADNI) database (https://adni.loni.usc.edu/). The investigators within ADNI are listed as supplementary authors and can be found in Section 5 of the Supplementary Note. Full consortium acknowledgements and funding sources are listed in Section 4 of the Supplementary Note. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

day = "1",

doi = "https://doi.org/10.1038/s41588-022-01208-7",

language = "English",

volume = "54",

pages = "1786--1794",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "12",

}

Holstege, H, Hulsman, M, Charbonnier, C, Grenier-Boley, B, Quenez, O, Grozeva, D, van Rooij, JGJ, Sims, R, Ahmad, S, Amin, N, Norsworthy, PJ, Dols-Icardo, O, Hummerich, H, Kawalia, A, Amouyel, P, Beecham, GW, Berr, C, Bis, JC, Boland, A, Bossù, P, Bouwman, F, Bras, J, Campion, D, Cochran, JN, Daniele, A, Dartigues, J-F, Debette, S, Deleuze, J-F, Denning, N, DeStefano, AL, Farrer, LA, Fernández, MV, Fox, NC, Galimberti, D, Genin, E, Gille, JJP, Le Guen, Y, Guerreiro, R, Haines, JL, Holmes, C, Ikram, MA, Ikram, MK, Jansen, IE, Kraaij, R, Lathrop, M, Lemstra, AW, Lleó, A, Luckcuck, L, Mannens, MMAM, Marshall, R, Martin, ER, Masullo, C, Mayeux, R, Mecocci, P, Meggy, A, Mol, MO, Morgan, K, Myers, RM, Nacmias, B, Naj, AC, Napolioni, V, Pasquier, F, Pastor, P, Pericak-Vance, MA, Raybould, R, Redon, R, Reinders, MJT, Richard, A-C, Riedel-Heller, SG, Rivadeneira, F, Rousseau, S, Ryan, NS, Saad, S, Sanchez-Juan, P, Schellenberg, GD, Scheltens, P, Schott, JM, Seripa, D, Seshadri, S, Sie, D , Sistermans, EA, Sorbi, S, van Spaendonk, R, Spalletta, G, Tesi, N , Tijms, B, Uitterlinden, AG, van der Lee, SJ , Visser, PJ, Wagner, M, Wallon, D, Wang, L-S, Zarea, A, Clarimon, J, van Swieten, JC, Greicius, MD, Yokoyama, JS, Cruchaga, C, Hardy, J, Ramirez, A, Mead, S, van der Flier, WM, van Duijn, CM, Williams, J, Nicolas, G, Bellenguez, C & Lambert, J-C 2022, 'Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease', Nature Genetics, vol. 54, no. 12, pp. 1786-1794. https://doi.org/10.1038/s41588-022-01208-7

TY - JOUR

T1 - Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease

AU - Holstege, H.

AU - Hulsman, M.

AU - Charbonnier, C.

AU - Grenier-Boley, B.

AU - Quenez, O.

AU - Grozeva, D.

AU - van Rooij, J.G.J.

AU - Sims, R.

AU - Ahmad, S.

AU - Amin, N.

AU - Norsworthy, P.J.

AU - Dols-Icardo, O.

AU - Hummerich, H.

AU - Kawalia, A.

AU - Amouyel, P.

AU - Beecham, G.W.

AU - Berr, C.

AU - Bis, J.C.

AU - Boland, A.

AU - Bossù, P.

AU - Bouwman, F.

AU - Bras, J.

AU - Campion, D.

AU - Cochran, J.N.

AU - Daniele, A.

AU - Dartigues, J.-F.

AU - Debette, S.

AU - Deleuze, J.-F.

AU - Denning, N.

AU - DeStefano, A.L.

AU - Farrer, L.A.

AU - Fernández, M.V.

AU - Fox, N.C.

AU - Galimberti, D.

AU - Genin, E.

AU - Gille, J.J.P.

AU - Le Guen, Y.

AU - Guerreiro, R.

AU - Haines, J.L.

AU - Holmes, C.

AU - Ikram, M.A.

AU - Ikram, M.K.

AU - Jansen, I.E.

AU - Kraaij, R.

AU - Lathrop, M.

AU - Lemstra, A.W.

AU - Lleó, A.

AU - Luckcuck, L.

AU - Mannens, M.M.A.M.

AU - Marshall, R.

AU - Martin, E.R.

AU - Masullo, C.

AU - Mayeux, R.

AU - Mecocci, P.

AU - Meggy, A.

AU - Mol, M.O.

AU - Morgan, K.

AU - Myers, R.M.

AU - Nacmias, B.

AU - Naj, A.C.

AU - Napolioni, V.

AU - Pasquier, F.

AU - Pastor, P.

AU - Pericak-Vance, M.A.

AU - Raybould, R.

AU - Redon, R.

AU - Reinders, M.J.T.

AU - Richard, A.-C.

AU - Riedel-Heller, S.G.

AU - Rivadeneira, F.

AU - Rousseau, S.

AU - Ryan, N.S.

AU - Saad, S.

AU - Sanchez-Juan, P.

AU - Schellenberg, G.D.

AU - Scheltens, P.

AU - Schott, J.M.

AU - Seripa, D.

AU - Seshadri, S.

AU - Sie, D.

AU - Sistermans, E.A.

AU - Sorbi, S.

AU - van Spaendonk, R.

AU - Spalletta, G.

AU - Tesi, N.

AU - Tijms, B.

AU - Uitterlinden, A.G.

AU - van der Lee, S.J.

AU - Visser, P.J.

AU - Wagner, M.

AU - Wallon, D.

AU - Wang, L.-S.

AU - Zarea, A.

AU - Clarimon, J.

AU - van Swieten, J.C.

AU - Greicius, M.D.

AU - Yokoyama, J.S.

AU - Cruchaga, C.

AU - Hardy, J.

AU - Ramirez, A.

AU - Mead, S.

AU - van der Flier, W.M.

AU - van Duijn, C.M.

AU - Williams, J.

AU - Nicolas, G.

AU - Bellenguez, C.

AU - Lambert, J.-C.

N1 - Funding Information: We thank all the study participants, their families, the participating medical staff, general practitioners, pharmacists and all laboratory personnel involved in patient diagnosis, blood collection, blood biobanking, DNA preparation and sequencing. The work in this manuscript was carried out on the Cartesius supercomputer, which is embedded in the Dutch national e-infrastructure with the support of the SURF Cooperative. Computing hours were granted in 2016, 2017, 2018 and 2019 to H. Holstege by the Dutch Research Council (project name: 100-plus; project nos. 15318 and 17232). This research was conducted using the funding obtained by the following study cohorts: ADES-FR, AgeCoDe-UKBonn; Barcelona SPIN; AC-EMC; ERF and Rotterdam; ADC-Amsterdam; 100-plus study; EMIF-90+; Control Brain Consortium; PERADES; StEP-AD; Knight-ADRC; UCSF/NYGC/UAB; UCL-DRC EOAD; ADSP. Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (https://adni.loni.usc.edu/). The investigators within ADNI are listed as supplementary authors and can be found in Section 5 of the Supplementary Note. Full consortium acknowledgements and funding sources are listed in Section 4 of the Supplementary Note. Publisher Copyright: © 2022, The Author(s).

PY - 2022/12/1

Y1 - 2022/12/1

N2 - © 2022, The Author(s).Alzheimer’s disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70%1. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants2. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals—16,036 AD cases and 16,522 controls. Next to variants in TREM2, SORL1 and ABCA7, we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10. Additionally, the rare-variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential drivers of respective AD-genome-wide association study loci. Variants associated with the strongest effect on AD risk, in particular loss-of-function variants, are enriched in early-onset AD cases. Our results provide additional evidence for a major role for amyloid-β precursor protein processing, amyloid-β aggregation, lipid metabolism and microglial function in AD.

AB - © 2022, The Author(s).Alzheimer’s disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70%1. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants2. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals—16,036 AD cases and 16,522 controls. Next to variants in TREM2, SORL1 and ABCA7, we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10. Additionally, the rare-variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential drivers of respective AD-genome-wide association study loci. Variants associated with the strongest effect on AD risk, in particular loss-of-function variants, are enriched in early-onset AD cases. Our results provide additional evidence for a major role for amyloid-β precursor protein processing, amyloid-β aggregation, lipid metabolism and microglial function in AD.

UR - http://www.scopus.com/inward/record.url?scp=85142346472&partnerID=8YFLogxK

U2 - https://doi.org/10.1038/s41588-022-01208-7

DO - https://doi.org/10.1038/s41588-022-01208-7

M3 - Article

C2 - 36411364

SN - 1061-4036

VL - 54

SP - 1786

EP - 1794

JO - Nature Genetics

JF - Nature Genetics

IS - 12

ER -

Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease

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