SNP Chip genes (MSExcel file)

The new custom SNP Chip was initiated by two research laboratories under the direction of Dr. Brian Van Ness (University of Minnesota) and Dr. Gareth Morgan (Marsden Clinic, London, UK). The initial goal was to develop a comprehensive list of SNPs that represented a variety of cellular functions that would influence normal and abnormal cell growth, influence disease (especially cancer) progression, and drug response. This design was of significant interest to a number of laboratories, and in later stages of design, additional laboratory directors provided input and expansion of the SNP list (see below). An initial candidate list of target genes was developed, representing the following pathways and functions:

• Angiogenesis
• Transcription factors
• Bone metabolism
• Cell Cycle
• Apoptosis
• DNA repair
• Environmental response genes
• Genes derived from expression comparisons of normal versus cancer cells
• Folate metabolism/Venous thrombosis
• Annotated cancer genes lists
• Growth factors and receptors
• Obesity related
• Peripheral neuropathy
• Drug response
• ADME lists (genes involved in activation, distribution, metabolism, export)
• Inflammatory response and immunity
• Mevalonate pathways
• Signaling cascades, including all kinases, phosphatases, and transferases

SNP Selection From the Candidate Gene List

1. A literature and database search of candidate genes was used to identify polymorphisms. The SNP id (rs number) of polymorphisms was derived from databases: SNP500(5) , SNPper(6) and MutDB(7). This resulted in a large pool of SNPs for each gene on the candidate list.

2. A systematic search for all non-synonymous SNPs with a validated, minor allele frequency greater than 2% in all of the candidate SNPs was completed in SNP 500 and dbSNP databases. This resulted in an extensive reduction in SNP entries, including all non-coding variations.

3. Minor allele frequencies that were below 2% in the population screen were re-examined, and SNPs added back in if the minor allele frequency was greater than 5% in one of three ethnic groups (African Americans, Asian, Caucasian).

4. A systematic search was made of the promoter/regulatory regions of all the candidate genes for SNPs present in homologous regions between Human and Mouse with a Minor Allele frequency greater than 2%, using Promolign(9), FESD(10), and PupaSNP(11). Many of the SNPs selected in this method were seen to lay in or adjacent to transcription factor binding sites, or potential splice sites.

5. The list was further refined by first identifying the major pathways represented by the SNP list, using Ingenuity and Pathway Assist Programs; then adding SNPs using the above criteria for additional genes within the pathways.

6. SNPs that were not validated by criteria of the dbSNP database were removed. However, Affymetrix/ParAllele provided additional validation lists from their own resources that were checked, and SNPs re-introduced if on their latest validation list.

7. Further SNP entries were provided by research directors at the University of Minnesota, who were interested in expanding the chip utility to more directed pharmacologic applications, cardiovascular screening, and transplant. Indeed, most of the SNPs of interest to these groups were already represented as overlap with the above list; with expansion resulting in 226 new entries. 40 new candidates were either newly identified locally, or without rs numbers, and were included.

The SNP chip contains 3,400 SNPs. So far there has been a 98.6% call rate with 99.9% reproducibility. Approximately 2ug of DNA is used per chip with an estimated cost of about $200/sample.

Contact Dr. Brian Van Ness (vanne001@umn.edu) for more information.