A Multi-Marker Genetic Association Test Based on the Rasch Model Applied to Alzheimer's Disease.

Results from Genome-Wide Association Studies (GWAS) have shown that the genetic basis of complex traits often include many genetic variants with small to moderate effects whose identification remains a challenging problem. In this context multi-marker analysis at the gene and pathway level can complement traditional point-wise approaches that treat the genetic markers individually. In this paper we propose a novel statistical approach for multi-marker analysis based on the Rasch model. The method summarizes the categorical genotypes of SNPs by a generalized logistic function into a genetic score that can be used for association analysis. Through different sets of simulations, the false-positive rate and power of the proposed approach are compared to a set of existing methods, and shows good performances. The application of the Rasch model on Alzheimer's Disease (AD) ADNI GWAS dataset also allows a coherent interpretation of the results. Our analysis supports the idea that APOE is a major susceptibility gene for AD. In the top genes selected by proposed method, several could be functionally linked to AD. In particular, a pathway analysis of these genes also highlights the metabolism of cholesterol, that is known to play a key role in AD pathogenesis. Interestingly, many of these top genes can be integrated in a hypothetic signalling network

Hypothetic signalling network integrating top genes identified through the Rasch analysis.

<p>Gene abbreviations: <i>PLXNC1</i>—plexin C1 receptor for semaphorins; <i>PTK2</i>—<i>FAK</i> kinase implicated in integrin signalling; <i>FYN</i>—src family tyrosine kinase, downstream target of <i>GRM5</i> receptor; <i>EEF2K</i>—eukaryotic elongation factor-2 kinase, activated by <i>GRM5</i> receptor, regulates global protein synthesis; <i>MDM2</i>—negative modulator of <i>TP53</i> tumour suppression gene; <i>RPTOR</i>—regulatory protein associated with <i>MTORC1</i> complex; <i>HDAC3</i>—histone deacetylase; <i>ARC</i>—activity-regulated cytoskeleton-associated protein.</p

Annotation of the 20 top genes resulting from the application of the Rasch-based multi-marker association test to the genes of the Alzheimer ADNI GWAS dataset.

<p>Annotation of the 20 top genes resulting from the application of the Rasch-based multi-marker association test to the genes of the Alzheimer ADNI GWAS dataset.</p