Late-Onset Alzheimer’s disease (LOAD) is a common, complex genetic disorder well-known for its heterogeneous pathology. The genetic heterogeneity underlying common, complex diseases poses a major challenge for targeted therapies and the identification of novel disease-associated variants. Case-control approaches are often limited to examining a specific outcome in a group of heterogenous patients with different clinical characteristics. Here, we developed a novel approach to define relevant transcriptomic endophenotypes and stratify decedents based on molecular profiles in three independent human LOAD cohorts. By integrating post-mortem brain gene co-expression data from 2114 human samples with LOAD, we developed a novel quantitative, composite phenotype that can better account for the heterogeneity in genetic architecture underlying the disease. We used iterative weighted gene co-expression network analysis (WGCNA) to reduce data dimensionality and to isolate gene sets that are highly co-expressed within disease subtypes and represent specific molecular pathways. We then performed single variant association testing using whole genome-sequencing data for the novel composite phenotype in order to identify genetic loci that contribute to disease heterogeneity. Distinct LOAD subtypes were identified for all three study cohorts (two in ROSMAP, three in Mayo Clinic, and two in Mount Sinai Brain Bank). Single variant association analysis identified a genome-wide significant variant in TMEM106B (p-value < 5´10^-8, rs1990620^G) in the ROSMAP cohort that confers protection from the inflammatory LOAD subtype. Taken together, our novel approach can be used to stratify LOAD into distinct molecular subtypes based on affected disease pathways.

Whole-genome sequencing data and transcriptomic data (RNA-Seq) were collected from three independent human cohorts - ROSMAP, Mayo, and MSBB - made available by the AMP-AD consortium (https://adknowledgeportal.synapse.org/). Gene co-expression modules were derived that stratified Alzheimer's disease cases into transcriptomic subtypes. Summary phenotypes from each module and subtype scores were scanned for genome-wide associations using EMMAX software. Details on data processing and analysis are in the linked publication.

This data package includes the complete results of the genome-wide association analyses published in the associated manuscript, as generated by EMMAX. See the README file and the linked publication for further details.