Multivariate GWAS of Alzheimer’s disease CSF biomarker profiles implies GRIN2D in synaptic functioning

Alexander Neumann; Olena Ohlei; Fahri Küçükali; Isabelle J. Bos; Jigyasha Timsina; Stephanie Vos; Dmitry Prokopenko; Betty M. Tijms; Ulf Andreasson; Kaj Blennow; Rik Vandenberghe; Philip Scheltens; Charlotte E. Teunissen; Sebastiaan Engelborghs; Giovanni B. Frisoni; Oliver Blin; Jill C. Richardson; Régis Bordet; Alberto Lleó; Daniel Alcolea; Julius Popp; Thomas W. Marsh; Priyanka Gorijala; Christopher Clark; Gwendoline Peyratout; Pablo Martinez-Lage; Mikel Tainta; Richard J.B. Dobson; Cristina Legido-Quigley; Christine Van Broeckhoven; Rudolph E. Tanzi; Mara ten Kate; Christina M. Lill; Frederik Barkhof; Carlos Cruchaga; Simon Lovestone; Johannes Streffer; Henrik Zetterberg; Pieter Jelle Visser; Kristel Sleegers; Lars Bertram

doi:10.1186/s13073-023-01233-z

Multivariate GWAS of Alzheimer’s disease CSF biomarker profiles implies GRIN2D in synaptic functioning

Alexander Neumann, Olena Ohlei, Fahri Küçükali, Isabelle J. Bos, Jigyasha Timsina, Stephanie Vos, Dmitry Prokopenko, Betty M. Tijms, Ulf Andreasson, Kaj Blennow, Rik Vandenberghe, Philip Scheltens, Charlotte E. Teunissen, Sebastiaan Engelborghs, Giovanni B. Frisoni, Oliver Blin, Jill C. Richardson, Régis Bordet, Alberto Lleó, Daniel AlcoleaJulius Popp, Thomas W. Marsh, Priyanka Gorijala, Christopher Clark, Gwendoline Peyratout, Pablo Martinez-Lage, Mikel Tainta, Richard J.B. Dobson, Cristina Legido-Quigley, Christine Van Broeckhoven, Rudolph E. Tanzi, Mara ten Kate, Christina M. Lill, Frederik Barkhof, Carlos Cruchaga, Simon Lovestone, Johannes Streffer, Henrik Zetterberg, Pieter Jelle Visser, Kristel Sleegers, Lars Bertram

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

3 Scopus citations

Abstract

Background: Genome-wide association studies (GWAS) of Alzheimer’s disease (AD) have identified several risk loci, but many remain unknown. Cerebrospinal fluid (CSF) biomarkers may aid in gene discovery and we previously demonstrated that six CSF biomarkers (β-amyloid, total/phosphorylated tau, NfL, YKL-40, and neurogranin) cluster into five principal components (PC), each representing statistically independent biological processes. Here, we aimed to (1) identify common genetic variants associated with these CSF profiles, (2) assess the role of associated variants in AD pathophysiology, and (3) explore potential sex differences. Methods: We performed GWAS for each of the five biomarker PCs in two multi-center studies (EMIF-AD and ADNI). In total, 973 participants (n = 205 controls, n = 546 mild cognitive impairment, n = 222 AD) were analyzed for 7,433,949 common SNPs and 19,511 protein-coding genes. Structural equation models tested whether biomarker PCs mediate genetic risk effects on AD, and stratified and interaction models probed for sex-specific effects. Results: Five loci showed genome-wide significant association with CSF profiles, two were novel (rs145791381 [inflammation] and GRIN2D [synaptic functioning]) and three were previously described (APOE, TMEM106B, and CHI3L1). Follow-up analyses of the two novel signals in independent datasets only supported the GRIN2D locus, which contains several functionally interesting candidate genes. Mediation tests indicated that variants in APOE are associated with AD status via processes related to amyloid and tau pathology, while markers in TMEM106B and CHI3L1 are associated with AD only via neuronal injury/inflammation. Additionally, seven loci showed sex-specific associations with AD biomarkers. Conclusions: These results suggest that pathway and sex-specific analyses can improve our understanding of AD genetics and may contribute to precision medicine.

Original language	English
Article number	79
Journal	Genome medicine
Volume	15
Issue number	1
DOIs	https://doi.org/10.1186/s13073-023-01233-z
State	Published - Dec 2023

Keywords

Alzheimer’s disease
Biomarkers
Cerebrospinal fluid (CSF)
Dementia
Genome-wide association study (GWAS)
Mediation
Multivariate analysis
Principal component analysis
Structural equation modeling

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10.1186/s13073-023-01233-z

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Neumann, A., Ohlei, O., Küçükali, F., Bos, I. J., Timsina, J., Vos, S., Prokopenko, D., Tijms, B. M., Andreasson, U., Blennow, K., Vandenberghe, R., Scheltens, P., Teunissen, C. E., Engelborghs, S., Frisoni, G. B., Blin, O., Richardson, J. C., Bordet, R., Lleó, A., ... Bertram, L. (2023). Multivariate GWAS of Alzheimer’s disease CSF biomarker profiles implies GRIN2D in synaptic functioning. Genome medicine, 15(1), Article 79. https://doi.org/10.1186/s13073-023-01233-z

@article{9ab42c7abc4142a78898cabd7218de9e,

title = "Multivariate GWAS of Alzheimer{\textquoteright}s disease CSF biomarker profiles implies GRIN2D in synaptic functioning",

abstract = "Background: Genome-wide association studies (GWAS) of Alzheimer{\textquoteright}s disease (AD) have identified several risk loci, but many remain unknown. Cerebrospinal fluid (CSF) biomarkers may aid in gene discovery and we previously demonstrated that six CSF biomarkers (β-amyloid, total/phosphorylated tau, NfL, YKL-40, and neurogranin) cluster into five principal components (PC), each representing statistically independent biological processes. Here, we aimed to (1) identify common genetic variants associated with these CSF profiles, (2) assess the role of associated variants in AD pathophysiology, and (3) explore potential sex differences. Methods: We performed GWAS for each of the five biomarker PCs in two multi-center studies (EMIF-AD and ADNI). In total, 973 participants (n = 205 controls, n = 546 mild cognitive impairment, n = 222 AD) were analyzed for 7,433,949 common SNPs and 19,511 protein-coding genes. Structural equation models tested whether biomarker PCs mediate genetic risk effects on AD, and stratified and interaction models probed for sex-specific effects. Results: Five loci showed genome-wide significant association with CSF profiles, two were novel (rs145791381 [inflammation] and GRIN2D [synaptic functioning]) and three were previously described (APOE, TMEM106B, and CHI3L1). Follow-up analyses of the two novel signals in independent datasets only supported the GRIN2D locus, which contains several functionally interesting candidate genes. Mediation tests indicated that variants in APOE are associated with AD status via processes related to amyloid and tau pathology, while markers in TMEM106B and CHI3L1 are associated with AD only via neuronal injury/inflammation. Additionally, seven loci showed sex-specific associations with AD biomarkers. Conclusions: These results suggest that pathway and sex-specific analyses can improve our understanding of AD genetics and may contribute to precision medicine.",

keywords = "Alzheimer{\textquoteright}s disease, Biomarkers, Cerebrospinal fluid (CSF), Dementia, Genome-wide association study (GWAS), Mediation, Multivariate analysis, Principal component analysis, Structural equation modeling",

author = "Alexander Neumann and Olena Ohlei and Fahri K{\"u}{\c c}{\"u}kali and Bos, {Isabelle J.} and Jigyasha Timsina and Stephanie Vos and Dmitry Prokopenko and Tijms, {Betty M.} and Ulf Andreasson and Kaj Blennow and Rik Vandenberghe and Philip Scheltens and Teunissen, {Charlotte E.} and Sebastiaan Engelborghs and Frisoni, {Giovanni B.} and Oliver Blin and Richardson, {Jill C.} and R{\'e}gis Bordet and Alberto Lle{\'o} and Daniel Alcolea and Julius Popp and Marsh, {Thomas W.} and Priyanka Gorijala and Christopher Clark and Gwendoline Peyratout and Pablo Martinez-Lage and Mikel Tainta and Dobson, {Richard J.B.} and Cristina Legido-Quigley and {Van Broeckhoven}, Christine and Tanzi, {Rudolph E.} and {ten Kate}, Mara and Lill, {Christina M.} and Frederik Barkhof and Carlos Cruchaga and Simon Lovestone and Johannes Streffer and Henrik Zetterberg and Visser, {Pieter Jelle} and Kristel Sleegers and Lars Bertram",

note = "Publisher Copyright: {\textcopyright} 2023, BioMed Central Ltd., part of Springer Nature.",

year = "2023",

month = dec,

doi = "10.1186/s13073-023-01233-z",

language = "English",

volume = "15",

journal = "Genome medicine",

issn = "1756-994X",

number = "1",

}

Neumann, A, Ohlei, O, Küçükali, F, Bos, IJ, Timsina, J, Vos, S, Prokopenko, D, Tijms, BM, Andreasson, U, Blennow, K, Vandenberghe, R, Scheltens, P, Teunissen, CE, Engelborghs, S, Frisoni, GB, Blin, O, Richardson, JC, Bordet, R, Lleó, A, Alcolea, D, Popp, J, Marsh, TW, Gorijala, P, Clark, C, Peyratout, G, Martinez-Lage, P, Tainta, M, Dobson, RJB, Legido-Quigley, C, Van Broeckhoven, C, Tanzi, RE, ten Kate, M, Lill, CM, Barkhof, F, Cruchaga, C, Lovestone, S, Streffer, J, Zetterberg, H, Visser, PJ, Sleegers, K & Bertram, L 2023, 'Multivariate GWAS of Alzheimer’s disease CSF biomarker profiles implies GRIN2D in synaptic functioning', Genome medicine, vol. 15, no. 1, 79. https://doi.org/10.1186/s13073-023-01233-z

TY - JOUR

T1 - Multivariate GWAS of Alzheimer’s disease CSF biomarker profiles implies GRIN2D in synaptic functioning

AU - Neumann, Alexander

AU - Ohlei, Olena

AU - Küçükali, Fahri

AU - Bos, Isabelle J.

AU - Timsina, Jigyasha

AU - Vos, Stephanie

AU - Prokopenko, Dmitry

AU - Tijms, Betty M.

AU - Andreasson, Ulf

AU - Blennow, Kaj

AU - Vandenberghe, Rik

AU - Scheltens, Philip

AU - Teunissen, Charlotte E.

AU - Engelborghs, Sebastiaan

AU - Frisoni, Giovanni B.

AU - Blin, Oliver

AU - Richardson, Jill C.

AU - Bordet, Régis

AU - Lleó, Alberto

AU - Alcolea, Daniel

AU - Popp, Julius

AU - Marsh, Thomas W.

AU - Gorijala, Priyanka

AU - Clark, Christopher

AU - Peyratout, Gwendoline

AU - Martinez-Lage, Pablo

AU - Tainta, Mikel

AU - Dobson, Richard J.B.

AU - Legido-Quigley, Cristina

AU - Van Broeckhoven, Christine

AU - Tanzi, Rudolph E.

AU - ten Kate, Mara

AU - Lill, Christina M.

AU - Barkhof, Frederik

AU - Cruchaga, Carlos

AU - Lovestone, Simon

AU - Streffer, Johannes

AU - Zetterberg, Henrik

AU - Visser, Pieter Jelle

AU - Sleegers, Kristel

AU - Bertram, Lars

PY - 2023/12

Y1 - 2023/12

N2 - Background: Genome-wide association studies (GWAS) of Alzheimer’s disease (AD) have identified several risk loci, but many remain unknown. Cerebrospinal fluid (CSF) biomarkers may aid in gene discovery and we previously demonstrated that six CSF biomarkers (β-amyloid, total/phosphorylated tau, NfL, YKL-40, and neurogranin) cluster into five principal components (PC), each representing statistically independent biological processes. Here, we aimed to (1) identify common genetic variants associated with these CSF profiles, (2) assess the role of associated variants in AD pathophysiology, and (3) explore potential sex differences. Methods: We performed GWAS for each of the five biomarker PCs in two multi-center studies (EMIF-AD and ADNI). In total, 973 participants (n = 205 controls, n = 546 mild cognitive impairment, n = 222 AD) were analyzed for 7,433,949 common SNPs and 19,511 protein-coding genes. Structural equation models tested whether biomarker PCs mediate genetic risk effects on AD, and stratified and interaction models probed for sex-specific effects. Results: Five loci showed genome-wide significant association with CSF profiles, two were novel (rs145791381 [inflammation] and GRIN2D [synaptic functioning]) and three were previously described (APOE, TMEM106B, and CHI3L1). Follow-up analyses of the two novel signals in independent datasets only supported the GRIN2D locus, which contains several functionally interesting candidate genes. Mediation tests indicated that variants in APOE are associated with AD status via processes related to amyloid and tau pathology, while markers in TMEM106B and CHI3L1 are associated with AD only via neuronal injury/inflammation. Additionally, seven loci showed sex-specific associations with AD biomarkers. Conclusions: These results suggest that pathway and sex-specific analyses can improve our understanding of AD genetics and may contribute to precision medicine.

AB - Background: Genome-wide association studies (GWAS) of Alzheimer’s disease (AD) have identified several risk loci, but many remain unknown. Cerebrospinal fluid (CSF) biomarkers may aid in gene discovery and we previously demonstrated that six CSF biomarkers (β-amyloid, total/phosphorylated tau, NfL, YKL-40, and neurogranin) cluster into five principal components (PC), each representing statistically independent biological processes. Here, we aimed to (1) identify common genetic variants associated with these CSF profiles, (2) assess the role of associated variants in AD pathophysiology, and (3) explore potential sex differences. Methods: We performed GWAS for each of the five biomarker PCs in two multi-center studies (EMIF-AD and ADNI). In total, 973 participants (n = 205 controls, n = 546 mild cognitive impairment, n = 222 AD) were analyzed for 7,433,949 common SNPs and 19,511 protein-coding genes. Structural equation models tested whether biomarker PCs mediate genetic risk effects on AD, and stratified and interaction models probed for sex-specific effects. Results: Five loci showed genome-wide significant association with CSF profiles, two were novel (rs145791381 [inflammation] and GRIN2D [synaptic functioning]) and three were previously described (APOE, TMEM106B, and CHI3L1). Follow-up analyses of the two novel signals in independent datasets only supported the GRIN2D locus, which contains several functionally interesting candidate genes. Mediation tests indicated that variants in APOE are associated with AD status via processes related to amyloid and tau pathology, while markers in TMEM106B and CHI3L1 are associated with AD only via neuronal injury/inflammation. Additionally, seven loci showed sex-specific associations with AD biomarkers. Conclusions: These results suggest that pathway and sex-specific analyses can improve our understanding of AD genetics and may contribute to precision medicine.

KW - Alzheimer’s disease

KW - Biomarkers

KW - Cerebrospinal fluid (CSF)

KW - Dementia

KW - Genome-wide association study (GWAS)

KW - Mediation

KW - Multivariate analysis

KW - Principal component analysis

KW - Structural equation modeling

UR - http://www.scopus.com/inward/record.url?scp=85173180888&partnerID=8YFLogxK

U2 - 10.1186/s13073-023-01233-z

DO - 10.1186/s13073-023-01233-z

M3 - Article

C2 - 37794492

AN - SCOPUS:85173180888

SN - 1756-994X

VL - 15

JO - Genome medicine

JF - Genome medicine

IS - 1

M1 - 79

ER -

Multivariate GWAS of Alzheimer’s disease CSF biomarker profiles implies GRIN2D in synaptic functioning

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