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DT‐02‐04: Tau kinetics in the human cns
Author(s) -
Sato Chihiro,
Mawuenyega Kwasi,
Barthelemy Nicolas,
Patterson Bruce W.,
Kasten Tom,
Jockel-Balsarotti Jennifer,
Chott Robert,
Yarasheski Kevin E.,
Miller Timothy M.,
Bateman Randall
Publication year - 2015
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2015.08.160
Subject(s) - kinetics , cerebrospinal fluid , human brain , chemistry , trypsin , amyloid beta , tau pathology , enzyme kinetics , amyloid (mycology) , alzheimer's disease , biochemistry , neuroscience , medicine , biology , pathology , disease , peptide , enzyme , physics , quantum mechanics , active site
new datasets), increasing our discovery sample to 21,433 cases and 44,340 controls. Methods: All datasets were imputed to a 1000 Genomes reference panel (Phase 1 v3, March 2012) of over 37 million variants, many of which are low-frequency single nucleotide variants (SNV) and indels. Single-variant-based association analysis was conducted adjusting for age, sex and population substructure. Individual datasets were analyzed with the score test for case-control datasets and general estimating equations (with generalized linear mixed model for rare variants) for family-based analyses. Within-study results were meta-analyzed in METAL. Gene-based testing was conducted on summary statistics using VEGAS. Results: Imputation produced approximately nine million high-quality low-frequency variants for analyses. Twenty-five loci were genomewide significant at P 5310-8, including five novel loci. Three of these novel loci are driven by significant low-frequency variants, while two are associations of common intergenic variants between the genes USP6NL and ECHDC3 at Chr10: 10:11720308 (P1⁄42.91x10) and the genes CYYR1 and ADAMTS1 at Chr21: 28,156,856 (P1⁄41.44x10). Previously reported rare and low-frequency variants in TREM2 and SORL1 were also significantly associated, while low-frequency SNVs in the common loci BIN1 (MAF1⁄40.026) and CLU (MAF1⁄40.029) show suggestive significance (P 5310-7). Twelve additional loci produced signals with suggestive significance, seven driven by low-frequency or rare variants and five driven by common variants. Genotyping to confirm imputation quality, and replication genotyping using the Sequenom MassArray are underway. Gene-based analyses identified 13 significantly associated genes (Bonferroni P 2.83x10-6), four of which are novel loci driven by nominally significant low-frequency variants. Conclusions: Using an imputation set with a large number of rare variants we identified several novel candidate loci for LOAD, giving support to the hypothesis that rare and low-frequency variant imputation can identify novel associations with disease.