We request funding for a dual-purpose microarray platform, an iScan(R) system with Autoloader 2 by Illumina, Inc. This instrument will perform high-density genome wide association and methylation studies, custom single nucleotide polymorphism (SNP) detection and genome-scale expression profiling. The requested instrument will replace an outdated and leased BeadStation"""""""", also from Illlumina, Inc., which is now overwhelmed with queued projects and which will revert to the equipment owner on July 1, 2010. The requested instrument system is >10 times faster than the leased instrument. The new instrument will with higher throughput capacity will serve our NIH-funded projects more efficiently. The proposed Major Users are unified by their NIH funded work directed toward understanding systemic lupus erythematosus, its sub-phenotypes, and related autoimmune rheumatic disorders. Over 30,000 subjects have been collected to explain the genetics of lupus by genotyping and gene expression analysis. Experiments are underway that will require >20,000 array readings in the next few months. In the subsequent four years >100,000 array readings are anticipated generating billions of genotypes and gene expression measurements. This work often requires large sample sizes (>10,000) in order to have adequate statistical power. In addition to the genetic localization available from extensive fine mapping, the approach of trans-ancestry mapping of genetic association effects virtually always contributes toward the identification of the causative polymorphisms. In addition to lupus, other phenotypes are of interest to our NIH funded community of investigators including Sjvgren's syndrome, Behcet's disease, sarcoidosis, rheumatoid arthritis, diabetes, and malignancies. The Illumina iScan(R) system is currently the best system with respect to these parameters. Users may perform not only SNP detection and copy number variation but also genomic scale gene expression studies. The genotyping capabilities are especially important as both genome wide association studies (GWAS) with over 1 million polymorphisms are planned, as well as custom arrays from 1536 to over 200,000 single nucleotide polymorphisms (SNPs). By supporting multiple investigators in both small and large projects consisting of more than 14,000 samples in some single experiments our primary bottleneck is array scanning time. The iScan system equipped with a sample autoloader will increase our capacity nearly 40 fold. This capacity will allow the simultaneous completion of multiple projects from a large number of investigators to identify novel disease genes and examine disease related pathways in NIH funded projects. Our investigators have the funding, expertise and institutional support to fully exploit the requested instrument and the information this technology will provide. This technology will be used to its maximum potential value in advancing this NIH supported research.
| Lu, Xiaoming; Zoller, Erin E; Weirauch, Matthew T et al. (2015) Lupus Risk Variant Increases pSTAT1 Binding and Decreases ETS1 Expression. Am J Hum Genet 96:731-9 |
| Kottyan, Leah C; Zoller, Erin E; Bene, Jessica et al. (2015) The IRF5-TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share. Hum Mol Genet 24:582-96 |
| Lessard, Christopher J; Li, He; Adrianto, Indra et al. (2013) Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjögren's syndrome. Nat Genet 45:1284-92 |
| Vaughn, Samuel E; Kottyan, Leah C; Munroe, Melissa E et al. (2012) Genetic susceptibility to lupus: the biological basis of genetic risk found in B cell signaling pathways. J Leukoc Biol 92:577-91 |
