Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers

Iris E Jansen; Sven J van der Lee; Duber Gomez-Fonseca; Itziar de Rojas; Maria Carolina Dalmasso; Benjamin Grenier-Boley; Anna Zettergren; Aniket Mishra; Muhammad Ali; Victor Andrade; Céline Bellenguez; Luca Kleineidam; Fahri Küçükali; Yun Ju Sung; Niccolo Tesí; Ellen M Vromen; Douglas P Wightman; Daniel Alcolea; Montserrat Alegret; Ignacio Alvarez; Philippe Amouyel; Lavinia Athanasiu; Shahram Bahrami; Henri Bailly; Olivia Belbin; Sverre Bergh; Lars Bertram; Geert Jan Biessels; Kaj Blennow; Rafael Blesa; Mercè Boada; Anne Boland; Katharina Buerger; Ángel Carracedo; Laura Cervera-Carles; Geneviève Chene; Jurgen A H R Claassen; Stephanie Debette; Jean-Francois Deleuze; Peter Paul de Deyn; Janine Diehl-Schmid; Srdjan Djurovic; Oriol Dols-Icardo; Carole Dufouil; Emmanuelle Duron; Emrah Düzel; Tormod Fladby; Inez Ramakers; Pieter J Visser; EADB consortium

doi:10.1007/s00401-022-02454-z

Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers

Iris E Jansen^*, Sven J van der Lee, Duber Gomez-Fonseca, Itziar de Rojas, Maria Carolina Dalmasso, Benjamin Grenier-Boley, Anna Zettergren, Aniket Mishra, Muhammad Ali, Victor Andrade, Céline Bellenguez, Luca Kleineidam, Fahri Küçükali, Yun Ju Sung, Niccolo Tesí, Ellen M Vromen, Douglas P Wightman, Daniel Alcolea, Montserrat Alegret, Ignacio AlvarezPhilippe Amouyel, Lavinia Athanasiu, Shahram Bahrami, Henri Bailly, Olivia Belbin, Sverre Bergh, Lars Bertram, Geert Jan Biessels, Kaj Blennow, Rafael Blesa, Mercè Boada, Anne Boland, Katharina Buerger, Ángel Carracedo, Laura Cervera-Carles, Geneviève Chene, Jurgen A H R Claassen, Stephanie Debette, Jean-Francois Deleuze, Peter Paul de Deyn, Janine Diehl-Schmid, Srdjan Djurovic, Oriol Dols-Icardo, Carole Dufouil, Emmanuelle Duron, Emrah Düzel, Tormod Fladby, Inez Ramakers, Pieter J Visser, EADB consortium

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.

Original language	English
Pages (from-to)	821-842
Number of pages	22
Journal	Acta Neuropathologica
Volume	144
Issue number	5
Early online date	6 Sept 2022
DOIs	https://doi.org/10.1007/s00401-022-02454-z
Publication status	Published - Nov 2022

Access to Document

10.1007/s00401-022-02454-zLicence: CC BY

Cite this

Jansen, I. E., van der Lee, S. J., Gomez-Fonseca, D., de Rojas, I., Dalmasso, M. C., Grenier-Boley, B., Zettergren, A., Mishra, A., Ali, M., Andrade, V., Bellenguez, C., Kleineidam, L., Küçükali, F., Sung, Y. J., Tesí, N., Vromen, E. M., Wightman, D. P., Alcolea, D., Alegret, M., ... EADB consortium (2022). Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers. Acta Neuropathologica, 144(5), 821-842. https://doi.org/10.1007/s00401-022-02454-z

@article{f385a690ddd848bea9717b5c7fdebd1e,

title = "Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers",

abstract = "Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.",

author = "Jansen, {Iris E} and {van der Lee}, {Sven J} and Duber Gomez-Fonseca and {de Rojas}, Itziar and Dalmasso, {Maria Carolina} and Benjamin Grenier-Boley and Anna Zettergren and Aniket Mishra and Muhammad Ali and Victor Andrade and C{\'e}line Bellenguez and Luca Kleineidam and Fahri K{\"u}{\c c}{\"u}kali and Sung, {Yun Ju} and Niccolo Tes{\'i} and Vromen, {Ellen M} and Wightman, {Douglas P} and Daniel Alcolea and Montserrat Alegret and Ignacio Alvarez and Philippe Amouyel and Lavinia Athanasiu and Shahram Bahrami and Henri Bailly and Olivia Belbin and Sverre Bergh and Lars Bertram and Biessels, {Geert Jan} and Kaj Blennow and Rafael Blesa and Merc{\`e} Boada and Anne Boland and Katharina Buerger and {\'A}ngel Carracedo and Laura Cervera-Carles and Genevi{\`e}ve Chene and Claassen, {Jurgen A H R} and Stephanie Debette and Jean-Francois Deleuze and {de Deyn}, {Peter Paul} and Janine Diehl-Schmid and Srdjan Djurovic and Oriol Dols-Icardo and Carole Dufouil and Emmanuelle Duron and Emrah D{\"u}zel and Tormod Fladby and Inez Ramakers and Visser, {Pieter J} and {EADB consortium}",

note = "{\textcopyright} 2022. The Author(s).",

year = "2022",

month = nov,

doi = "10.1007/s00401-022-02454-z",

language = "English",

volume = "144",

pages = "821--842",

journal = "Acta Neuropathologica",

issn = "0001-6322",

publisher = "Springer, Cham",

number = "5",

}

Jansen, IE, van der Lee, SJ, Gomez-Fonseca, D, de Rojas, I, Dalmasso, MC, Grenier-Boley, B, Zettergren, A, Mishra, A, Ali, M, Andrade, V, Bellenguez, C, Kleineidam, L, Küçükali, F, Sung, YJ, Tesí, N, Vromen, EM, Wightman, DP, Alcolea, D, Alegret, M, Alvarez, I, Amouyel, P, Athanasiu, L, Bahrami, S, Bailly, H, Belbin, O, Bergh, S, Bertram, L, Biessels, GJ, Blennow, K, Blesa, R, Boada, M, Boland, A, Buerger, K, Carracedo, Á, Cervera-Carles, L, Chene, G, Claassen, JAHR, Debette, S, Deleuze, J-F, de Deyn, PP, Diehl-Schmid, J, Djurovic, S, Dols-Icardo, O, Dufouil, C, Duron, E, Düzel, E, Fladby, T, Ramakers, I , Visser, PJ & EADB consortium 2022, 'Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers', Acta Neuropathologica, vol. 144, no. 5, pp. 821-842. https://doi.org/10.1007/s00401-022-02454-z

TY - JOUR

T1 - Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers

AU - Jansen, Iris E

AU - van der Lee, Sven J

AU - Gomez-Fonseca, Duber

AU - de Rojas, Itziar

AU - Dalmasso, Maria Carolina

AU - Grenier-Boley, Benjamin

AU - Zettergren, Anna

AU - Mishra, Aniket

AU - Ali, Muhammad

AU - Andrade, Victor

AU - Bellenguez, Céline

AU - Kleineidam, Luca

AU - Küçükali, Fahri

AU - Sung, Yun Ju

AU - Tesí, Niccolo

AU - Vromen, Ellen M

AU - Wightman, Douglas P

AU - Alcolea, Daniel

AU - Alegret, Montserrat

AU - Alvarez, Ignacio

AU - Amouyel, Philippe

AU - Athanasiu, Lavinia

AU - Bahrami, Shahram

AU - Bailly, Henri

AU - Belbin, Olivia

AU - Bergh, Sverre

AU - Bertram, Lars

AU - Biessels, Geert Jan

AU - Blennow, Kaj

AU - Blesa, Rafael

AU - Boada, Mercè

AU - Boland, Anne

AU - Buerger, Katharina

AU - Carracedo, Ángel

AU - Cervera-Carles, Laura

AU - Chene, Geneviève

AU - Claassen, Jurgen A H R

AU - Debette, Stephanie

AU - Deleuze, Jean-Francois

AU - de Deyn, Peter Paul

AU - Diehl-Schmid, Janine

AU - Djurovic, Srdjan

AU - Dols-Icardo, Oriol

AU - Dufouil, Carole

AU - Duron, Emmanuelle

AU - Düzel, Emrah

AU - Fladby, Tormod

AU - Ramakers, Inez

AU - Visser, Pieter J

AU - EADB consortium

PY - 2022/11

Y1 - 2022/11

N2 - Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.

AB - Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.

U2 - 10.1007/s00401-022-02454-z

DO - 10.1007/s00401-022-02454-z

M3 - Article

C2 - 36066633

SN - 0001-6322

VL - 144

SP - 821

EP - 842

JO - Acta Neuropathologica

JF - Acta Neuropathologica

IS - 5

ER -