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Author Notes:

Corresponding Author: Elizabeth J. Leslie, Phone: (404) 727-3505, Address: 615 Michael St., Suite 301, Atlanta, GA 30322

The authors thank the dedicated field staff, collaborators, and participating families for their important contributions to this study.


Research Funding:

This work was supported by grants from the National Institutes of Health (NIH) including: R00-DE025060 [EJL], X01-HG007485 [MLM, EF], R01-DE016148 [MLM, SMW], U01-DE024425 [MLM], R37-DE008559 [JCM, MLM], R01-DE009886 [MLM], R21-DE016930 [MLM], R01-DE014667 [LMM], R01-DE012472 [MLM], R01-DE011931 [JTH], R01-DE011948 [KC], U01-DD000295 [GLW], R00-Grant DE022378 and Robert Wood Johnson Foundation Grant number 72429 [AB], K99-DE024571 [CJB], S21-MD001830 [CJB], R01-DE014581 [TB], U01-DE018993 [TB].

Other support for this work was provided by JSPS KAKENHI Grant-in-Aid for Scientific Research (C) Grant Number JP17K11863 [SS] and Grant-in-Aid for Scientific Research (A) Grant Number JP 24249092 [SS].

Genotyping and data cleaning were provided via an NIH contract to the Johns Hopkins Center for Inherited Disease Research: HHSN268201200008I.


  • Science & Technology
  • Life Sciences & Biomedicine
  • Genetics & Heredity
  • Mathematical & Computational Biology
  • complex trait
  • gene-gene interaction
  • genetic modifier
  • orofacial cleft
  • LIP
  • FOXE1
  • LOCI

Identification of 16q21 as a modifier of nonsyndromic orofacial cleft phenotypes

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Journal Title:

Genetic Epidemiology


Volume 41, Number 8


, Pages 887-897

Type of Work:

Article | Post-print: After Peer Review


Orofacial clefts (OFCs) are common, complex birth defects with extremely heterogeneous phenotypic presentations. Two common subtypes—cleft lip alone (CL) and CL plus cleft palate (CLP)—are typically grouped into a single phenotype for genetic analysis (i.e., CL with or without cleft palate, CL/P). However, mounting evidence suggests there may be unique underlying pathophysiology and/or genetic modifiers influencing expression of these two phenotypes. To this end, we performed a genome-wide scan for genetic modifiers by directly comparing 450 CL cases with 1,692 CLP cases from 18 recruitment sites across 13 countries from North America, Central or South America, Asia, Europe, and Africa. We identified a region on 16q21 that is strongly associated with different cleft type (P = 5.611 × 10−8). We also identified significant evidence of gene–gene interactions between this modifier locus and two recognized CL/P risk loci: 8q21 and 9q22 (FOXE1) (P = 0.012 and 0.023, respectively). Single nucleotide polymorphism (SNPs) in the 16q21 modifier locus demonstrated significant association with CL over CLP. The marker alleles on 16q21 that increased risk for CL were found at highest frequencies among individuals with a family history of CL (P = 0.003). Our results demonstrate the existence of modifiers for which type of OFC develops and suggest plausible elements responsible for phenotypic heterogeneity, further elucidating the complex genetic architecture of OFCs.

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