Identification of common non-coding variants at 1p22 that are functional for non-syndromic orofacial clefting

Huan Liu; Elizabeth J Leslie; Jenna C Carlson; Terri H Beaty; Mary L Marazita; Andrew C Lidral; Robert A Cornell

doi:10.1038/ncomms14759

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Identification of common non-coding variants at 1p22 that are functional for non-syndromic orofacial clefting

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Identification of common non-coding variants at 1p22 that are functional for non-syndromic orofacial clefting

Huan Liu, Elizabeth J Leslie, Jenna C Carlson, Terri H Beaty, Mary L Marazita, Andrew C Lidral and Robert A Cornell

Nature communications, Vol.8(1), pp.14759-14759

03/13/2017

DOI: 10.1038/ncomms14759

PMCID: PMC5355807

PMID: 28287101

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Abstract

Genome-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.

Details

Title: Subtitle: Identification of common non-coding variants at 1p22 that are functional for non-syndromic orofacial clefting
Creators: Huan Liu - State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory for Oral Biomedicine of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, Hubei 430079, China
Elizabeth J Leslie - Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA
Jenna C Carlson - Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA
Terri H Beaty - Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205, USA
Mary L Marazita - Department of Human Genetics, Graduate School of Public Health and Clinical and Translational Science Institute, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA
Andrew C Lidral - Department of Orthodontics, College of Dentistry, University of Iowa, Iowa City, Iowa 52246, USA
Robert A Cornell - Department of Anatomy and Cell Biology, College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA
Resource Type: Journal article
Publication Details: Nature communications, Vol.8(1), pp.14759-14759
DOI: 10.1038/ncomms14759
PMID: 28287101
PMCID: PMC5355807
NLM abbreviation: Nat Commun
ISSN: 2041-1723
eISSN: 2041-1723
Publisher: England
Grant note: R01 DE023575 / NIDCR NIH HHS R01 DE014581 / NIDCR NIH HHS R01 DE016148 / NIDCR NIH HHS R01 DE008559 / NIDCR NIH HHS R37 DE008559 / NIDCR NIH HHS R00 DE025060 / NIDCR NIH HHS U01 DE018993 / NIDCR NIH HHS K99 DE025060 / NIDCR NIH HHS U01 HG005925 / NHGRI NIH HHS
Language: English
Date published: 03/13/2017
Academic Unit: Anatomy and Cell Biology; Dental Research
Record Identifier: 9984025341102771

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