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Multi-Tissue Neocortical Transcriptome-Wide Associations Study Implicates 8 Genes Across 6 Genomic Loci in Alzheimer's Disease

By Jake Gockley, Kelsey S. Montgomery, William L. Poehlman, Jesse C Wiley, Yue Liu, Ekaterina Gerasimov, Anna K Greenwood, Solveig K. Sieberts, Aliza P. Wingo, Thomas S. Wingo, Lara M. Mangravite, Benjamin A Logsdon

Posted 30 Jun 2020
bioRxiv DOI: 10.1101/2020.06.29.178590

Background: Alzheimer's disease (AD), an incurable neurodegenerative disease, currently affecting 1.75% of the United States population, with projected growth to 3.46% by 2050. Identifying common genetic variants driving differences in transcript expression that confer AD-risk is necessary to elucidate AD mechanism and develop therapeutic interventions. We modify the FUSION Transcriptome Wide Association Study (TWAS) pipeline to ingest expression from multiple neocortical regions, provide a set of 6780 gene weights which are abstracatable across the neocortex, and leverage these to find 8 genes from six loci with associated AD risk validated through summary mendelian randomization (SMR) utilizing IGAP summary statistics. Method: A combined dataset of 2003 genotypes clustered to Central European (CEU) ancestry was used to construct a training set of 790 genotypes paired to 888 RNASeq profiles across 6 Neo-cortical tissues (TCX=248, FP=50, IFG=41, STG=34, PHG=34, DLPFC=461). Following within-tissue normalization and covariate adjustment, predictive weights to impute expression components based on a gene's surrounding cis-variants were trained. The FUSION pipeline was modified to support input of pre-scaled expression values and provide support for cross validation with a repeated measure design arising from the presence of multiple transcriptome samples from the same individual across different tissues. Results: Cis-variant architecture alone was informative to train weights and impute expression for 6780 (49.67%) autosomal genes, the majority of which significantly correlated with gene expression; FDR < 5%: N=6775 (99.92%), Bonferroni: N=6716 (99.06%). Validation of weights in 515 matched genotype to RNASeq profiles from the CommonMind Consortium (CMC) was (72.14%) in DLPFC profiles. Association of imputed expression components from all 2003 genotype profiles yielded 8 genes significantly associated with AD (FDR < 0.05); APOC1, EED, CD2AP, CEACAM19, CLPTM1, MTCH2, TREM2, KNOP1. Conclusion: We provide evidence of cis-genetic variation conferring AD risk through 8 genes across six distinct genomic loci. Moreover, we provide expression weights for 6780 genes as a valuable resource to the community, which can be abstracted across the neocortex and a wide range of neuronal phenotypes. ### Competing Interest Statement The authors have declared no competing interest.

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