|ZFIN ID: ZDB-PUB-181118-22|
Identification of common non-coding variants at 1p22 that are functional for non-syndromic orofacial clefting
Liu, H., Leslie, E.J., Carlson, J.C., Beaty, T.H., Marazita, M.L., Lidral, A.C., Cornell, R.A.
|Source:||Nature communications 8: 14759 (Journal)|
|Registered Authors:||Cornell, Robert|
|PubMed:||28287101 Full text @ Nat. Commun.|
Liu, H., Leslie, E.J., Carlson, J.C., Beaty, T.H., Marazita, M.L., Lidral, A.C., Cornell, R.A. (2017) Identification of common non-coding variants at 1p22 that are functional for non-syndromic orofacial clefting. Nature communications. 8:14759.
ABSTRACTGenome-wide association studies (GWAS) do not distinguish between single nucleotide polymorphisms (SNPs) that are causal and those that are merely in linkage-disequilibrium with causal mutations. Here we describe a versatile, functional pipeline and apply it to SNPs at 1p22, a locus identified in several GWAS for non-syndromic cleft lip with or without cleft palate (NS CL/P). First we amplified DNA elements containing the ten most-highly risk-associated SNPs and tested their enhancer activity in vitro, identifying three SNPs with allele-dependent effects on such activity. We then used in vivo reporter assays to test the tissue-specificity of these enhancers, chromatin configuration capture to test enhancer-promoter interactions, and genome editing in vitro to show allele-specific effects on ARHGAP29 expression and cell migration. Our results further indicate that two SNPs affect binding of CL/P-associated transcription factors, and one affects chromatin configuration. These results translate risk into potential mechanisms of pathogenesis.