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
AU - EMIF-AD & ADNI study group
PY - 2023/10/4
Y1 - 2023/10/4
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 (ß-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 (ß-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
U2 - 10.1186/s13073-023-01233-z
DO - 10.1186/s13073-023-01233-z
M3 - Article
SN - 1756-994X
VL - 15
JO - Genome Medicine
JF - Genome Medicine
IS - 1
M1 - 79
ER -