This is a proposal to perform a genome-wide gene expression profiling in peripheral blood in a sample of Amyotrophic Lateral Sclerosis (ALS) patients and matched controls, all from a relatively homogeneous population in The Netherlands. Once ALS-specific expression profiles have been identified, these will be used as phenotypes to identify underlying genetic variation. A replication sample is available from the same population as well as samples with ALS-related phenotypes. Identification of ALS-specific expression profiles equals the discovery of functional biomarkers for the disease. Since variation in gene expression is to a large degree associated with genetic variation, these functional biomarkers can be used to identify common genetic variants associated with the complex neurological disorder of ALS. The study population is ideal for genetic studies given the uniformity of its ascertainment, the population-based sample collection, and the homogeneous population structure. The patients remain under care of the same clinicians who enrolled them in the study, permitting unusual opportunities for longitudinal evaluations within the time span of the disease, as well as family-based follow-up studies. Genome-wide expression profiles will be established for the sample using the high- throughput BeadChip arrays containing >23,000 RefSeq transcripts. Systematic statistical analyses will be applied in order to identify gene-expression profiles associated with ALS phenotype. Network-based analysis will be performed to identify expression modules, and the most significant changes related to disease phenotype(s). Since for the vast majority of these samples high-density 300K SNP genotyping is available through an independent effort, the expression profiles can be used as quantitative traits for genome-wide association studies. Follow-up studies will be initiated to further delineate the underlying genetic variation associated with ALS expression profiles as well as study of specific ALS characteristics and expression profiles. Ultimately, the developments of functional biomarkers for ALS can be used for diagnostic purposes and identification of underlying genetic variation associated with ALS-specific expression profiles and disease susceptibility. This is a proposal to perform a genome-wide gene expression profiling in peripheral blood in a sample of Amyotrophic Lateral Sclerosis (ALS) patients and matched controls, all from a relatively homogeneous population in The Netherlands.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS058980-05
Application #
8288254
Study Section
Genomics, Computational Biology and Technology Study Section (GCAT)
Program Officer
Gubitz, Amelie
Project Start
2008-09-15
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$310,415
Indirect Cost
$92,610
Name
University of California Los Angeles
Department
None
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
van Eijk, Kristel R; de Jong, Simone; Strengman, Eric et al. (2015) Identification of schizophrenia-associated loci by combining DNA methylation and gene expression data from whole blood. Eur J Hum Genet 23:1106-10
De Jong, Simone; Neeleman, Marjolein; Luykx, Jurjen J et al. (2014) Seasonal changes in gene expression represent cell-type composition in whole blood. Hum Mol Genet 23:2721-8
Fu, Jingyuan; Wolfs, Marcel G M; Deelen, Patrick et al. (2012) Unraveling the regulatory mechanisms underlying tissue-dependent genetic variation of gene expression. PLoS Genet 8:e1002431
Diekstra, Frank P; Saris, Christiaan G J; van Rheenen, Wouter et al. (2012) Mapping of gene expression reveals CYP27A1 as a susceptibility gene for sporadic ALS. PLoS One 7:e35333
Fehrmann, Rudolf S N; Jansen, Ritsert C; Veldink, Jan H et al. (2011) Trans-eQTLs reveal that independent genetic variants associated with a complex phenotype converge on intermediate genes, with a major role for the HLA. PLoS Genet 7:e1002197
Sotoodehnia, Nona; Isaacs, Aaron; de Bakker, Paul I W et al. (2010) Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction. Nat Genet 42:1068-76
Dubois, Patrick C A; Trynka, Gosia; Franke, Lude et al. (2010) Multiple common variants for celiac disease influencing immune gene expression. Nat Genet 42:295-302
Saris, Christiaan G J; Horvath, Steve; van Vught, Paul W J et al. (2009) Weighted gene co-expression network analysis of the peripheral blood from Amyotrophic Lateral Sclerosis patients. BMC Genomics 10:405