Proteome-wide analysis of disease-associated SNPs that show allele-specific transcription factor binding.
A causative role for single nucleotide polymorphisms (SNPs) in many genetic disorders has become evident through numerous genome-wide association studies. However, identification of these common causal variants and the molecular mechanisms underlying these associations remains a major challenge. Dif...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2012-09-01
|
| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1002982&type=printable |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849724630783229952 |
|---|---|
| author | Falk Butter Lucy Davison Tar Viturawong Marion Scheibe Michiel Vermeulen John A Todd Matthias Mann |
| author_facet | Falk Butter Lucy Davison Tar Viturawong Marion Scheibe Michiel Vermeulen John A Todd Matthias Mann |
| author_sort | Falk Butter |
| collection | DOAJ |
| description | A causative role for single nucleotide polymorphisms (SNPs) in many genetic disorders has become evident through numerous genome-wide association studies. However, identification of these common causal variants and the molecular mechanisms underlying these associations remains a major challenge. Differential transcription factor binding at a SNP resulting in altered gene expression is one possible mechanism. Here we apply PWAS ("proteome-wide analysis of SNPs"), a methodology based on quantitative mass spectrometry that enables rapid screening of SNPs for differential transcription factor binding, to 12 SNPs that are highly associated with type 1 diabetes at the IL2RA locus, encoding the interleukin-2 receptor CD25. We report differential, allele-specific binding of the transcription factors RUNX1, LEF1, CREB, and TFAP4 to IL2RA SNPs rs12722508*A, rs12722522*C, rs41295061*A, and rs2104286*A and demonstrate the functional influence of RUNX1 at rs12722508 by reporter gene assay. Thus, PWAS may be able to contribute to our understanding of the molecular consequences of human genetic variability underpinning susceptibility to multi-factorial disease. |
| format | Article |
| id | doaj-art-38c4800fdf094c3bb5252e9d1865a72f |
| institution | DOAJ |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2012-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-38c4800fdf094c3bb5252e9d1865a72f2025-08-20T03:10:41ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042012-09-0189e100298210.1371/journal.pgen.1002982Proteome-wide analysis of disease-associated SNPs that show allele-specific transcription factor binding.Falk ButterLucy DavisonTar ViturawongMarion ScheibeMichiel VermeulenJohn A ToddMatthias MannA causative role for single nucleotide polymorphisms (SNPs) in many genetic disorders has become evident through numerous genome-wide association studies. However, identification of these common causal variants and the molecular mechanisms underlying these associations remains a major challenge. Differential transcription factor binding at a SNP resulting in altered gene expression is one possible mechanism. Here we apply PWAS ("proteome-wide analysis of SNPs"), a methodology based on quantitative mass spectrometry that enables rapid screening of SNPs for differential transcription factor binding, to 12 SNPs that are highly associated with type 1 diabetes at the IL2RA locus, encoding the interleukin-2 receptor CD25. We report differential, allele-specific binding of the transcription factors RUNX1, LEF1, CREB, and TFAP4 to IL2RA SNPs rs12722508*A, rs12722522*C, rs41295061*A, and rs2104286*A and demonstrate the functional influence of RUNX1 at rs12722508 by reporter gene assay. Thus, PWAS may be able to contribute to our understanding of the molecular consequences of human genetic variability underpinning susceptibility to multi-factorial disease.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1002982&type=printable |
| spellingShingle | Falk Butter Lucy Davison Tar Viturawong Marion Scheibe Michiel Vermeulen John A Todd Matthias Mann Proteome-wide analysis of disease-associated SNPs that show allele-specific transcription factor binding. PLoS Genetics |
| title | Proteome-wide analysis of disease-associated SNPs that show allele-specific transcription factor binding. |
| title_full | Proteome-wide analysis of disease-associated SNPs that show allele-specific transcription factor binding. |
| title_fullStr | Proteome-wide analysis of disease-associated SNPs that show allele-specific transcription factor binding. |
| title_full_unstemmed | Proteome-wide analysis of disease-associated SNPs that show allele-specific transcription factor binding. |
| title_short | Proteome-wide analysis of disease-associated SNPs that show allele-specific transcription factor binding. |
| title_sort | proteome wide analysis of disease associated snps that show allele specific transcription factor binding |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1002982&type=printable |
| work_keys_str_mv | AT falkbutter proteomewideanalysisofdiseaseassociatedsnpsthatshowallelespecifictranscriptionfactorbinding AT lucydavison proteomewideanalysisofdiseaseassociatedsnpsthatshowallelespecifictranscriptionfactorbinding AT tarviturawong proteomewideanalysisofdiseaseassociatedsnpsthatshowallelespecifictranscriptionfactorbinding AT marionscheibe proteomewideanalysisofdiseaseassociatedsnpsthatshowallelespecifictranscriptionfactorbinding AT michielvermeulen proteomewideanalysisofdiseaseassociatedsnpsthatshowallelespecifictranscriptionfactorbinding AT johnatodd proteomewideanalysisofdiseaseassociatedsnpsthatshowallelespecifictranscriptionfactorbinding AT matthiasmann proteomewideanalysisofdiseaseassociatedsnpsthatshowallelespecifictranscriptionfactorbinding |