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


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 (A?42), 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 A?42 near GLIS1 on 1p32.3 (? = -0.059, P = 2.08 × 10-8) and within SERPINB1 on 6p25 (? = -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: ? = 0.277, P = 1.92 × 10-2), and age at onset (SERPINB1: ? = 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 A?-associated mechanism. Analyses of known AD risk loci suggest CLU and FERMT2 may influence CSF A?42 (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.

SUBMITTER: Deming Y 

PROVIDER: S-EPMC5613285 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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

Deming Yuetiva Y   Li Zeran Z   Kapoor Manav M   Harari Oscar O   Del-Aguila Jorge L JL   Black Kathleen K   Carrell David D   Cai Yefei Y   Fernandez Maria Victoria MV   Budde John J   Ma Shengmei S   Saef Benjamin B   Howells Bill B   Huang Kuan-Lin KL   Bertelsen Sarah S   Fagan Anne M AM   Holtzman David M DM   Morris John C JC   Kim Sungeun S   Saykin Andrew J AJ   De Jager Philip L PL   Albert Marilyn M   Moghekar Abhay A   O'Brien Richard R   Riemenschneider Matthias M   Petersen Ronald C RC   Blennow Kaj K   Zetterberg Henrik H   Minthon Lennart L   Van Deerlin Vivianna M VM   Lee Virginia Man-Yee VM   Shaw Leslie M LM   Trojanowski John Q JQ   Schellenberg Gerard G   Haines Jonathan L JL   Mayeux Richard R   Pericak-Vance Margaret A MA   Farrer Lindsay A LA   Peskind Elaine R ER   Li Ge G   Di Narzo Antonio F AF   Kauwe John S K JS   Goate Alison M AM   Cruchaga Carlos C  

Acta neuropathologica 20170228 5


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. Endophenotyp  ...[more]

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