TY - JOUR
T1 - Genome-wide association study identifies four novel loci associated with Alzheimer’s endophenotypes and disease modifiers
AU - Alzheimer’s Disease Neuroimaging Initiative (ADNI)
AU - The Alzheimer Disease Genetic Consortium (ADGC)
AU - Deming, Yuetiva
AU - Li, Zeran
AU - Kapoor, Manav
AU - Harari, Oscar
AU - Del-Aguila, Jorge L.
AU - Black, Kathleen
AU - Carrell, David
AU - Cai, Yefei
AU - Fernandez, Maria Victoria
AU - Budde, John
AU - Ma, Shengmei
AU - Saef, Benjamin
AU - Howells, Bill
AU - Huang, Kuan lin
AU - Bertelsen, Sarah
AU - Fagan, Anne M.
AU - Holtzman, David M.
AU - Morris, John C.
AU - Kim, Sungeun
AU - Saykin, Andrew J.
AU - De Jager, Philip L.
AU - Albert, Marilyn
AU - Moghekar, Abhay
AU - O’Brien, Richard
AU - Riemenschneider, Matthias
AU - Petersen, Ronald C.
AU - Blennow, Kaj
AU - Zetterberg, Henrik
AU - Minthon, Lennart
AU - Van Deerlin, Vivianna M.
AU - Lee, Virginia Man Yee
AU - Shaw, Leslie M.
AU - Trojanowski, John Q.
AU - Schellenberg, Gerard
AU - Haines, Jonathan L.
AU - Mayeux, Richard
AU - Pericak-Vance, Margaret A.
AU - Farrer, Lindsay A.
AU - Peskind, Elaine R.
AU - Li, Ge
AU - Di Narzo, Antonio F.
AU - Kauwe, John S.K.
AU - Goate, Alison M.
AU - Cruchaga, Carlos
N1 - Publisher Copyright:
© 2017, Springer-Verlag Berlin Heidelberg.
PY - 2017/5/1
Y1 - 2017/5/1
N2 - More than 20 genetic loci have been associated with risk for Alzheimer’s disease (AD), but reported genome-wide significant loci do not account for all the estimated heritability and provide little information about underlying biological mechanisms. Genetic studies using intermediate quantitative traits such as biomarkers, or endophenotypes, benefit from increased statistical power to identify variants that may not pass the stringent multiple test correction in case–control studies. Endophenotypes also contain additional information helpful for identifying variants and genes associated with other aspects of disease, such as rate of progression or onset, and provide context to interpret the results from genome-wide association studies (GWAS). We conducted GWAS of amyloid beta (Aβ42), tau, and phosphorylated tau (ptau181) levels in cerebrospinal fluid (CSF) from 3146 participants across nine studies to identify novel variants associated with AD. Five genome-wide significant loci (two novel) were associated with ptau181, including loci that have also been associated with AD risk or brain-related phenotypes. Two novel loci associated with Aβ42 near GLIS1 on 1p32.3 (β = −0.059, P = 2.08 × 10−8) and within SERPINB1 on 6p25 (β = −0.025, P = 1.72 × 10−8) were also associated with AD risk (GLIS1: OR = 1.105, P = 3.43 × 10−2), disease progression (GLIS1: β = 0.277, P = 1.92 × 10−2), and age at onset (SERPINB1: β = 0.043, P = 4.62 × 10−3). Bioinformatics indicate that the intronic SERPINB1 variant (rs316341) affects expression of SERPINB1 in various tissues, including the hippocampus, suggesting that SERPINB1 influences AD through an Aβ-associated mechanism. Analyses of known AD risk loci suggest CLU and FERMT2 may influence CSF Aβ42 (P = 0.001 and P = 0.009, respectively) and the INPP5D locus may affect ptau181 levels (P = 0.009); larger studies are necessary to verify these results. Together the findings from this study can be used to inform future AD studies.
AB - More than 20 genetic loci have been associated with risk for Alzheimer’s disease (AD), but reported genome-wide significant loci do not account for all the estimated heritability and provide little information about underlying biological mechanisms. Genetic studies using intermediate quantitative traits such as biomarkers, or endophenotypes, benefit from increased statistical power to identify variants that may not pass the stringent multiple test correction in case–control studies. Endophenotypes also contain additional information helpful for identifying variants and genes associated with other aspects of disease, such as rate of progression or onset, and provide context to interpret the results from genome-wide association studies (GWAS). We conducted GWAS of amyloid beta (Aβ42), tau, and phosphorylated tau (ptau181) levels in cerebrospinal fluid (CSF) from 3146 participants across nine studies to identify novel variants associated with AD. Five genome-wide significant loci (two novel) were associated with ptau181, including loci that have also been associated with AD risk or brain-related phenotypes. Two novel loci associated with Aβ42 near GLIS1 on 1p32.3 (β = −0.059, P = 2.08 × 10−8) and within SERPINB1 on 6p25 (β = −0.025, P = 1.72 × 10−8) were also associated with AD risk (GLIS1: OR = 1.105, P = 3.43 × 10−2), disease progression (GLIS1: β = 0.277, P = 1.92 × 10−2), and age at onset (SERPINB1: β = 0.043, P = 4.62 × 10−3). Bioinformatics indicate that the intronic SERPINB1 variant (rs316341) affects expression of SERPINB1 in various tissues, including the hippocampus, suggesting that SERPINB1 influences AD through an Aβ-associated mechanism. Analyses of known AD risk loci suggest CLU and FERMT2 may influence CSF Aβ42 (P = 0.001 and P = 0.009, respectively) and the INPP5D locus may affect ptau181 levels (P = 0.009); larger studies are necessary to verify these results. Together the findings from this study can be used to inform future AD studies.
KW - Alzheimer’s disease
KW - Cerebrospinal fluid biomarkers
KW - Endophenotype
KW - Genome-wide association study
UR - http://www.scopus.com/inward/record.url?scp=85014028462&partnerID=8YFLogxK
U2 - 10.1007/s00401-017-1685-y
DO - 10.1007/s00401-017-1685-y
M3 - Article
C2 - 28247064
AN - SCOPUS:85014028462
SN - 0001-6322
VL - 133
SP - 839
EP - 856
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 5
ER -