Gene expression endophenotypes: a novel approach for gene discovery in Alzheimer's disease

Nilüfer Ertekin-Taner

doi:10.1186/1750-1326-6-31

Abstract

Uncovering the underlying genetic component of any disease is key to the understanding of its pathophysiology and may open new avenues for development of therapeutic strategies and biomarkers. In the past several years, there has been an explosion of genome-wide association studies (GWAS) resulting in the discovery of novel candidate genes conferring risk for complex diseases, including neurodegenerative diseases. Despite this success, there still remains a substantial genetic component for many complex traits and conditions that is unexplained by the GWAS findings. Additionally, in many cases, the mechanism of action of the newly discovered disease risk variants is not inherently obvious. Furthermore, a genetic region with multiple genes may be identified via GWAS, making it difficult to discern the true disease risk gene. Several alternative approaches are proposed to overcome these potential shortcomings of GWAS, including the use of quantitative, biologically relevant phenotypes. Gene expression levels represent an important class of endophenotypes. Genetic linkage and association studies that utilize gene expression levels as endophenotypes determined that the expression levels of many genes are under genetic influence. This led to the postulate that there may exist many genetic variants that confer disease risk via modifying gene expression levels. Results from the handful of genetic studies which assess gene expression level endophenotypes in conjunction with disease risk suggest that this combined phenotype approach may both increase the power for gene discovery and lead to an enhanced understanding of their mode of action. This review summarizes the evidence in support of gene expression levels as promising endophenotypes in the discovery and characterization of novel candidate genes for complex diseases, which may also represent a novel approach in the genetic studies of Alzheimer's and other neurodegenerative diseases.

Highlights

It is well established that the risk for many neurodegenerative diseases such as Alzheimer’s disease (AD) [1,2], Parkinson’s disease (PD) [2,3], frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) [4,5] is under substantial genetic control
This review focuses on gene expression levels as a potentially powerful group of endophenotypes and discusses the endophenotype concept, the evidence in support of a substantial genetic component for human gene expression, the genomewide association studies (GWAS) examples that combine disease phenotype and expression endophenotypes, the use of gene expression endophenotype in the Alzheimer’s and other neurodegenerative disease literature to-date and future directions
This study demonstrated that strong linkage predicts strong association for expression levels and expression GWAS may be a feasible and powerful approach to identify genetic determinants of expression phenotypes

Summary

Introduction

It is well established that the risk for many neurodegenerative diseases such as Alzheimer’s disease (AD) [1,2], Parkinson’s disease (PD) [2,3], frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) [4,5] is under substantial genetic control. To investigate the contribution of a different type of genetic variation, namely copy number variants (CNVs) to gene expression levels, Stranger et al [36], performed association of 14,925 transcripts (14,072 genes) with CNVs in the same four HapMap populations [35] and determined that there are significant CNV associations that replicate across ethnic groups as well as those that are unique to one ethnic group.

Results

Conclusion