Genome-wide association study identifies four novel loci associated with Alzheimer's endophenotypes and disease modifiers.

TitleGenome-wide association study identifies four novel loci associated with Alzheimer's endophenotypes and disease modifiers.
Publication TypeJournal Article
Year of Publication2017
AuthorsDeming Y, Li Z, Kapoor M, Harari O, Del-Aguila JL, Black K, Carrell D, Cai Y, Fernández MVictoria, Budde J, Ma S, Saef B, Howells B, Huang K-L, Bertelsen S, Fagan AM, Holtzman DM, Morris JC, Kim S, Saykin AJ, De Jager PL, Albert M, Moghekar A, O'Brien R, Riemenschneider M, Petersen RC, Blennow K, Zetterberg H, Minthon L, Van Deerlin VM, Lee VMan-Yee, Shaw LM, Trojanowski JQ, Schellenberg G, Haines JL, Mayeux R, Pericak-Vance MA, Farrer LA, Peskind ER, Li G, Di Narzo AF, Kauwe JSK, Goate AM, Cruchaga C
Corporate AuthorsAlzheimer’s Disease Neuroimaging Initiative(ADNI), Alzheimer Disease Genetic Consortium(ADGC)
JournalActa Neuropathol
Volume133
Issue5
Pagination839-856
Date Published2017 05
ISSN1432-0533
KeywordsAdult, Aged, Aged, 80 and over, Alzheimer Disease, Amyloid beta-Peptides, Apolipoproteins E, Biomarkers, Disease Progression, Endophenotypes, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Middle Aged, Risk Factors, tau Proteins
Abstract

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 (Aβ), tau, and phosphorylated tau (ptau) 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 ptau, including loci that have also been associated with AD risk or brain-related phenotypes. Two novel loci associated with Aβ near GLIS1 on 1p32.3 (β = -0.059, P = 2.08 × 10) and within SERPINB1 on 6p25 (β = -0.025, P = 1.72 × 10) were also associated with AD risk (GLIS1: OR = 1.105, P = 3.43 × 10), disease progression (GLIS1: β = 0.277, P = 1.92 × 10), and age at onset (SERPINB1: β = 0.043, P = 4.62 × 10). 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 Aβ (P = 0.001 and P = 0.009, respectively) and the INPP5D locus may affect ptau 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.

DOI10.1007/s00401-017-1685-y
Alternate JournalActa Neuropathol.
PubMed ID28247064
PubMed Central IDPMC5613285
Grant ListR01 AG054060 / AG / NIA NIH HHS / United States
P30 AG010124 / AG / NIA NIH HHS / United States
R01 AG019771 / AG / NIA NIH HHS / United States
R01 AG044546 / AG / NIA NIH HHS / United States
P30 AG010133 / AG / NIA NIH HHS / United States
U24 AG021886 / AG / NIA NIH HHS / United States
U01 AG032984 / AG / NIA NIH HHS / United States
RF1 AG053303 / AG / NIA NIH HHS / United States
U01 AG024904 / AG / NIA NIH HHS / United States
R01 NS085419 / NS / NINDS NIH HHS / United States
U01 AG016976 / AG / NIA NIH HHS / United States
P01 AG003991 / AG / NIA NIH HHS / United States
P50 AG005681 / AG / NIA NIH HHS / United States
P30 AG013846 / AG / NIA NIH HHS / United States
P01 AG026276 / AG / NIA NIH HHS / United States
P50 AG005136 / AG / NIA NIH HHS / United States
S10 OD018522 / OD / NIH HHS / United States
U24 AG041689 / AG / NIA NIH HHS / United States
R03 AG050856 / AG / NIA NIH HHS / United States
R01 LM012535 / LM / NLM NIH HHS / United States
/ / Wellcome Trust / United Kingdom
R01 AG048015 / AG / NIA NIH HHS / United States
R25 DA027995 / DA / NIDA NIH HHS / United States
R01 AG035083 / AG / NIA NIH HHS / United States