Transcriptomic stratification of late-onset Alzheimer's cases reveals novel genetic modifiers of disease pathology

Autoři: Nikhil Milind aff001;  Christoph Preuss aff001;  Annat Haber aff001;  Guruprasad Ananda aff001;  Shubhabrata Mukherjee aff003;  Cai John aff001;  Sarah Shapley aff001;  Benjamin A. Logsdon aff005;  Paul K. Crane aff003;  Gregory W. Carter aff001
Působiště autorů: The Jackson Laboratory, Bar Harbor, Maine, United States of America aff001;  Program in Genetics, Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina, United States of America aff002;  Department of Medicine, School of Medicine, University of Washington, Seattle, Washington, United States of America aff003;  Program in Neuroscience, Department of Biology and Geology, Baldwin Wallace University, Berea, Ohio, United States of America aff004;  Sage Bionetworks, Seattle, Washington, United States of America aff005
Vyšlo v časopise: Transcriptomic stratification of late-onset Alzheimer's cases reveals novel genetic modifiers of disease pathology. PLoS Genet 16(6): e32767. doi:10.1371/journal.pgen.1008775
Kategorie: Research Article


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, rs1990620G) 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.

Klíčová slova:

Alzheimer's disease – Cognitive impairment – Gene expression – Gene mapping – Genetic loci – Genetics of disease – RNA sequencing – Transcriptome analysis


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