Chitinase-3-like 1 protein (CHI3L1) locus influences cerebrospinal fluid levels of YKL-40.
BACKGROUND
Alzheimer's disease (AD) pathology appears several years before clinical symptoms, so identifying ways to detect individuals in the preclinical stage is imperative. The cerebrospinal fluid (CSF) Tau/Aβ42ratio is currently the best known predictor of AD status and cognitive decline, and the ratio of CSF levels of chitinase-3-like 1 protein (CHI3L1, YKL-40) and amyloid beta (Aβ42) were reported as predictive, but individual variability and group overlap inhibits their utility for individual diagnosis making it necessary to find ways to improve sensitivity of these biomarkers.


METHODS
We used linear regression to identify genetic loci associated with CSF YKL-40 levels in 379 individuals (80 cognitively impaired and 299 cognitively normal) from the Charles F and Joanne Knight Alzheimer's Disease Research Center. We tested correlations between YKL-40 and CSF Tau/Aβ42ratio, Aβ42, tau, and phosphorylated tau (ptau181). We used studentized residuals from a linear regression model of the log-transformed, standardized protein levels and the additive reference allele counts from the most significant locus to adjust YKL-40 values and tested the differences in correlations with CSF Tau/Aβ42ratio, Aβ42, tau, and ptau181.


RESULTS
We found that genetic variants on the CH13L1 locus were significantly associated with CSF YKL-40 levels, but not AD risk, age at onset, or disease progression. The most significant variant is a reported expression quantitative trait locus for CHI3L1, the gene which encodes YKL-40, and explained 12.74 % of the variance in CSF YKL-40 in our study. YKL-40 was positively correlated with ptau181(r = 0.521) and the strength of the correlation significantly increased with the addition of genetic information (r = 0.573, p = 0.006).


CONCLUSIONS
CSF YKL-40 levels are likely a biomarker for AD, but we found no evidence that they are an AD endophenotype. YKL-40 levels are highly regulated by genetic variation, and by including genetic information the strength of the correlation between YKL-40 and ptau181levels is significantly improved. Our results suggest that studies of potential biomarkers may benefit from including genetic information.
Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA.
Yuetiva
http://orcid.org/0000-0001-7512-5703
Y
Deming
Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA.
Kathleen
K
Black
Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA.
David
D
Carrell
Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA.
Yefei
Y
Cai
Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA.
Jorge L
JL
Del-Aguila
Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA.
Maria Victoria
MV
Fernandez
Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA.
John
J
Budde
Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA.
ShengMei
S
Ma
Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA.
Benjamin
B
Saef
Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA.
Bill
B
Howells
Ronald M. Loeb Center for Alzheimer's disease, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Sarah
S
Bertelsen
Department of Genetics, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO, 63110, USA.
Kuan-Lin
KL
Huang
Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO, 63110, USA.
Courtney L
CL
Sutphen
Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO, 63110, USA.|Knight Alzheimer's Disease Research Center, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO, 63110, USA.|Hope Center for Neurological Disorders, Washington University School of Medicine, 660 S. Euclid Ave. B8111, St. Louis, MO, 63110, USA.
Rawan
R
Tarawneh
Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO, 63110, USA.|Knight Alzheimer's Disease Research Center, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO, 63110, USA.|Hope Center for Neurological Disorders, Washington University School of Medicine, 660 S. Euclid Ave. B8111, St. Louis, MO, 63110, USA.
Anne M
AM
Fagan
Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO, 63110, USA.|Knight Alzheimer's Disease Research Center, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO, 63110, USA.|Hope Center for Neurological Disorders, Washington University School of Medicine, 660 S. Euclid Ave. B8111, St. Louis, MO, 63110, USA.|Department of Developmental Biology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO, 63110, USA.
David M
DM
Holtzman
Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO, 63110, USA.|Knight Alzheimer's Disease Research Center, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO, 63110, USA.|Hope Center for Neurological Disorders, Washington University School of Medicine, 660 S. Euclid Ave. B8111, St. Louis, MO, 63110, USA.|Department of Developmental Biology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO, 63110, USA.
John C
JC
Morris
Ronald M. Loeb Center for Alzheimer's disease, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Alison M
AM
Goate
Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA.|Department of Genetics, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO, 63110, USA.
Joseph D
JD
Dougherty
Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA. ccruchaga@wustl.edu.|Hope Center for Neurological Disorders, Washington University School of Medicine, 660 S. Euclid Ave. B8111, St. Louis, MO, 63110, USA. ccruchaga@wustl.edu.
Carlos
C
Cruchaga
D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000175:diagnosis; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D015415:Biomarkers / Q000134:cerebrospinal fluid*; D000071451:Chitinase-3-Like Protein 1 / Q000134:cerebrospinal fluid* / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D056426:Genetic Loci; D006801:Humans; D016014:Linear Models; D008297:Male; D016875:tau Proteins / Q000134:cerebrospinal fluid
D016229:Amyloid beta-Peptides; D015415:Biomarkers; C084533:CHI3L1 protein, human; D000071451:Chitinase-3-Like Protein 1; D016875:tau Proteins
Alzheimer disease; CHI3L1; Cerebrospinal fluid; YKL-40