Genome-wide association study of CSF biomarkers Abeta1-42, t-tau, and p-tau181p in the ADNI cohort.
OBJECTIVE
CSF levels of Aβ1-42, t-tau, and p-tau181p are potential early diagnostic markers for probable Alzheimer disease (AD). The influence of genetic variation on these markers has been investigated for candidate genes but not on a genome-wide basis. We report a genome-wide association study (GWAS) of CSF biomarkers (Aβ1-42, t-tau, p-tau181p, p-tau181p/Aβ1-42, and t-tau/Aβ1-42).


METHODS
A total of 374 non-Hispanic Caucasian participants in the Alzheimer's Disease Neuroimaging Initiative cohort with quality-controlled CSF and genotype data were included in this analysis. The main effect of single nucleotide polymorphisms (SNPs) under an additive genetic model was assessed on each of 5 CSF biomarkers. The p values of all SNPs for each CSF biomarker were adjusted for multiple comparisons by the Bonferroni method. We focused on SNPs with corrected p<0.01 (uncorrected p<3.10×10(-8)) and secondarily examined SNPs with uncorrected p values less than 10(-5) to identify potential candidates.


RESULTS
Four SNPs in the regions of the APOE, LOC100129500, TOMM40, and EPC2 genes reached genome-wide significance for associations with one or more CSF biomarkers. SNPs in CCDC134, ABCG2, SREBF2, and NFATC4, although not reaching genome-wide significance, were identified as potential candidates.


CONCLUSIONS
In addition to known candidate genes, APOE, TOMM40, and one hypothetical gene LOC100129500 partially overlapping APOE; one novel gene, EPC2, and several other interesting genes were associated with CSF biomarkers that are related to AD. These findings, especially the new EPC2 results, require replication in independent cohorts.
Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, 950 West Walnut Street, R2 E124, Indianapolis, IN 46202, USA.
S
S
Kim
S
S
Swaminathan
L
L
Shen
S L
SL
Risacher
K
K
Nho
T
T
Foroud
L M
LM
Shaw
J Q
JQ
Trojanowski
S G
SG
Potkin
M J
MJ
Huentelman
D W
DW
Craig
B M
BM
DeChairo
P S
PS
Aisen
R C
RC
Petersen
M W
MW
Weiner
A J
AJ
Saykin
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000235:genetics / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid* / Q000235:genetics*; D000951:Antigens, Neoplasm / Q000134:cerebrospinal fluid / Q000235:genetics; D001057:Apolipoproteins E / Q000235:genetics; D003072:Cognition Disorders / Q000134:cerebrospinal fluid / Q000235:genetics / Q000473:pathology; D015331:Cohort Studies; D003952:Diagnostic Imaging; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D026901:Membrane Transport Proteins / Q000134:cerebrospinal fluid / Q000235:genetics; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D010446:Peptide Fragments / Q000134:cerebrospinal fluid* / Q000235:genetics*; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D013912:Threonine / Q000378:metabolism*; D016875:tau Proteins / Q000134:cerebrospinal fluid* / Q000235:genetics*
D016229:Amyloid beta-Peptides; D000951:Antigens, Neoplasm; D001057:Apolipoproteins E; D026901:Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D010446:Peptide Fragments; C400783:TOMM40 protein, human; C075222:amyloid beta-protein (1-42); C542166:early prostate cancer antigen-2, human; D016875:tau Proteins; D013912:Threonine