PT - JOURNAL ARTICLE AU - Benjamin A. Logsdon AU - Thanneer M. Perumal AU - Vivek Swarup AU - Minghui Wang AU - Cory Funk AU - Chris Gaiteri AU - Mariet Allen AU - Xue Wang AU - Eric Dammer AU - Gyan Srivastava AU - Sumit Mukherjee AU - Solveig K. Sieberts AU - Larsson Omberg AU - Kristen D. Dang AU - James A. Eddy AU - Phil Snyder AU - Yooree Chae AU - Sandeep Amberkar AU - Wenbin Wei AU - Winston Hide AU - Christoph Preuss AU - Ayla Ergun AU - Phillip J Ebert AU - David C. Airey AU - Gregory W. Carter AU - Sara Mostafavi AU - Lei Yu AU - Hans-Ulrich Klein AU - the AMP-AD Consortium AU - David A. Collier AU - Todd Golde AU - Allan Levey AU - David A. Bennett AU - Karol Estrada AU - Michael Decker AU - Zhandong Liu AU - Joshua M. Shulman AU - Bin Zhang AU - Eric Schadt AU - Phillip L. De Jager AU - Nathan D. Price AU - Nilüfer Ertekin-Taner AU - Lara M. Mangravite TI - Meta-analysis of the human brain transcriptome identifies heterogeneity across human AD coexpression modules robust to sample collection and methodological approach AID - 10.1101/510420 DP - 2019 Jan 01 TA - bioRxiv PG - 510420 4099 - http://biorxiv.org/content/early/2019/01/03/510420.short 4100 - http://biorxiv.org/content/early/2019/01/03/510420.full AB - Alzheimer’s disease (AD) is a complex and heterogenous brain disease that affects multiple inter-related biological processes. This complexity contributes, in part, to existing difficulties in the identification of successful disease-modifying therapeutic strategies. To address this, systems approaches are being used to characterize AD-related disruption in molecular state. To evaluate the consistency across these molecular models, a consensus atlas of the human brain transcriptome was developed through coexpression meta-analysis across the AMP-AD consortium. Consensus analysis was performed across five coexpression methods used to analyze RNA-seq data collected from 2114 samples across 7 brain regions and 3 research studies. From this analysis, five consensus clusters were identified that described the major sources of AD-related alterations in transcriptional state that were consistent across studies, methods, and samples. AD genetic associations, previously studied AD-related biological processes, and AD targets under active investigation were enriched in only three of these five clusters. The remaining two clusters demonstrated strong heterogeneity between males and females in AD-related expression that was consistently observed across studies. AD transcriptional modules identified by systems analysis of individual AMP-AD teams were all represented in one of these five consensus clusters except ROS/MAP-identified Module 109, which was specific for genes that showed the strongest association with changes in AD-related gene expression across consensus clusters. The other two AMP-AD transcriptional analyses reported modules that were enriched in one of the two sex-specific Consensus Clusters. The fifth cluster has not been previously identified and was enriched for genes related to proteostasis. This study provides an atlas to map across biological inquiries of AD with the goal of supporting an expansion in AD target discovery efforts.