Module Analysis Using Single-Patient Differential Expression Signatures Improves the Power of Association Studies for Alzheimer's Disease

The causal mechanism of Alzheimer's disease is extremely complex. Achieving great statistical power in association studies usually requires a large number of samples. In this work, we illustrated a different strategy to identify AD risk genes by clustering AD patients into modules based on their single-patient differential expression signatures. The evaluation suggested that our method could enrich AD patients with similar clinical manifestations. Applying this to a cohort of only 310 AD patients, we identified 174 AD risk loci at a strict threshold of empirical p < 0.05, while only two loci were identified using all the AD patients. As an evaluation, we collected 23 AD risk genes reported in a recent large-scale meta-analysis and found that 18 of them were rediscovered by association studies using clustered AD patients, while only three of them were rediscovered using all AD patients. Functional annotation suggested that AD-associated genetic variants mainly disturbed neuronal/synaptic function. Our results suggested module analysis helped to enrich AD patients affected by the common risk variants.