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• W2897846698 abstract "Despite the findings in genome-wide association studies (GWASs) for late-onset Alzheimer's disease (LOAD), our understanding of its genetic architecture is far from complete. Transcriptome-wide association analysis that integrates GWAS data with large-scale transcriptomic databases is a powerful method to study complex traits’ genetic architecture. It is challenging to effectively utilize transcriptomic information given limited and unbalanced sample sizes in different tissues. Here we introduce and apply a novel method to perform statistically powerful transcriptome-wide association testing for LOAD via multi-tissue integrative modeling. We developed Unified Test for MOlecular SignaTures (UTMOST), a principled framework to jointly impute gene expression levels across multiple tissues and perform cross-tissue gene-level association testing using GWAS summary statistics. A total of 51 tissue-specific molecular phenotypes including gene expression and splicing events were imputed using data from the GTEx, STARNET, and BLUEPRINT consortia. Single-tissue association results were combined using generalized Berk-Jones test to quantify overall gene-trait associations. We analyzed LOAD Stage-I GWAS summary statistics from the International Genomics of Alzheimer's Project (IGAP) and replicated our findings in two independent GWAS datasets (Ntotal=175,776). Compared with single-tissue methods, UTMOST achieved 39% improvement in expression imputation accuracy and generated effective imputation models for 120% more genes in each tissue. A total of 69 genes reached the Bonferroni-corrected significance level in the transcriptome-wide association meta-analysis (see Figure). Among these genes, we replicated associations at ten previously known LOAD risk loci. In addition, we identified five novel risk loci for LOAD: NICN1 (p=2.2E-07), RAB43 (p=2.0E-06), VKORC1 (p=3.5E-09), HPR (p=3.0E-07), and PARD6G (p=3.6E-07). Our analysis also highlighted LIMS2 (p=9.4E-12) near BIN1, IL10 (p=3.7E-07) which is 700kb upstream of CR1, and two novel genes ADRA1A (p=1.3E-09) and EXTL3 (p=5.1E-12) at the CLU-PTK2B locus." @default.
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• W2897846698 date "2018-07-01" @default.
• W2897846698 modified "2023-10-18" @default.
• W2897846698 title "O3‐03‐06: CROSS‐TISSUE TRANSCRIPTOME‐WIDE ASSOCIATION META‐ANALYSIS IDENTIFIES NOVEL RISK GENES FOR LATE‐ONSET ALZHEIMER'S DISEASE" @default.
• W2897846698 doi "https://doi.org/10.1016/j.jalz.2018.06.2787" @default.
• W2897846698 hasPublicationYear "2018" @default.
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