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

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  • Huan Liu

    (College of Medicine, University of Iowa
    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)

  • Elizabeth J. Leslie

    (Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh)

  • Jenna C. Carlson

    (Graduate School of Public Health, University of Pittsburgh)

  • Terri H. Beaty

    (Bloomberg School of Public Health, Johns Hopkins University)

  • Mary L. Marazita

    (Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh
    Graduate School of Public Health and Clinical and Translational Science Institute, School of Medicine, University of Pittsburgh)

  • Andrew C. Lidral

    (College of Dentistry, University of Iowa)

  • Robert A. Cornell

    (College of Medicine, University of Iowa)

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.

Suggested Citation

  • Huan Liu & Elizabeth J. Leslie & Jenna C. Carlson & Terri H. Beaty & Mary L. Marazita & Andrew C. Lidral & Robert A. Cornell, 2017. "Identification of common non-coding variants at 1p22 that are functional for non-syndromic orofacial clefting," Nature Communications, Nature, vol. 8(1), pages 1-13, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14759
    DOI: 10.1038/ncomms14759
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    Cited by:

    1. Olga A Vsevolozhskaya & Min Shi & Fengjiao Hu & Dmitri V Zaykin, 2020. "DOT: Gene-set analysis by combining decorrelated association statistics," PLOS Computational Biology, Public Library of Science, vol. 16(4), pages 1-25, April.
    2. Debashree Ray & Sowmya Venkataraghavan & Wanying Zhang & Elizabeth J Leslie & Jacqueline B Hetmanski & Seth M Weinberg & Jeffrey C Murray & Mary L Marazita & Ingo Ruczinski & Margaret A Taub & Terri H, 2021. "Pleiotropy method reveals genetic overlap between orofacial clefts at multiple novel loci from GWAS of multi-ethnic trios," PLOS Genetics, Public Library of Science, vol. 17(7), pages 1-28, July.

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