Fetal genetic risk of isolated cleft lip only versus isolated cleft lip and palate: A subphenotype analysis using two population-based studies of orofacial clefts in scandinavia

Authors

  • Astanand Jugessur,

    Corresponding author
    1. Division of Epidemiology, Norwegian Institute of Public Health, N-0403 Oslo, Norway
    2. Craniofacial Research, Murdoch Childrens Research Institute, Royal Children's Hospital, 3052 Parkville, Victoria, Australia
    • Division of Epidemiology, Norwegian Institute of Public Health, P.O. Box 4404 Nydalen, N-0403 Oslo, Norway
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  • Min Shi,

    1. Biostatistics Branch, National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, Durham, North Carolina
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  • Håkon Kristian Gjessing,

    1. Division of Epidemiology, Norwegian Institute of Public Health, N-0403 Oslo, Norway
    2. Department of Public Health and Primary Health Care, Faculty of Medicine and Dentistry, University of Bergen, N-5018 Bergen, Norway
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  • Rolv Terje Lie,

    1. Department of Public Health and Primary Health Care, Faculty of Medicine and Dentistry, University of Bergen, N-5018 Bergen, Norway
    2. Medical Birth Registry of Norway, Norwegian Institute of Public Health, N-5018 Bergen, Norway
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  • Allen James Wilcox,

    1. Epidemiology Branch, National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, North Carolina
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  • Clarice Ring Weinberg,

    1. Biostatistics Branch, National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, Durham, North Carolina
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  • Kaare Christensen,

    1. Department of Epidemiology, University of Southern Denmark, DK-5000 Odense, Denmark
    2. Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, DK-5000 Odense, Denmark
    3. Department of Clinical Genetics, Odense University Hospital, DK-5000 Odense, Denmark
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  • Abee Lowman Boyles,

    1. Epidemiology Branch, National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, North Carolina
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  • Sandra Daack-Hirsch,

    1. College of Nursing, University of Iowa, Iowa City, Iowa
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  • Truc Trung Nguyen,

    1. Medical Birth Registry of Norway, Norwegian Institute of Public Health, N-5018 Bergen, Norway
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  • Lene Christiansen,

    1. Department of Epidemiology, University of Southern Denmark, DK-5000 Odense, Denmark
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  • Andrew Carl Lidral,

    1. Departments of Pediatrics, Epidemiology, and Biological Sciences, University of Iowa, Iowa City, Iowa
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  • Jeffrey Clark Murray

    1. Department of Epidemiology, University of Southern Denmark, DK-5000 Odense, Denmark
    2. Departments of Pediatrics, Epidemiology, and Biological Sciences, University of Iowa, Iowa City, Iowa
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  • Competing Interest: None.

Abstract

BACKGROUND: Cleft lip only (CLO) and cleft lip and palate (CLP) are commonly regarded as variants of the same defect and are traditionally combined to form the single group of cleft lip with or without cleft palate (CL/P) prior to analysis. However, recent data have suggested that at least a subgroup of isolated CLO may be etiologically distinct from isolated CLP. METHODS: To explore fetal genetic risk of isolated CLO separately from isolated CLP, we performed a subphenotype analysis using two population-based studies of clefts in Scandinavia. One hundred twenty-one isolated CLO, 190 isolated CLP, and 592 control triads were available from Norway (1996–2001), and a further 76 isolated CLO and 107 isolated CLP triads were available from Denmark (1991–2001). Genotypes for 1315 SNPs in 334 autosomal cleft candidate genes were analyzed using two complementary statistical methods, Triad Multi-Marker (TRIMM; Shi et al., 2007)) and HAPLIN (Gjessing and Lie, 2006), to look for genetic associations across the two national samples. RESULTS: Both TRIMM and HAPLIN identified strong associations between FGF12 and isolated CLO in both populations. In addition, only TRIMM identified associations with IRF6 and VCL, and only HAPLIN found an association with CX43. When analyses were repeated on the larger sample of isolated CLP, no significant associations were found with FGF12, IRF6, VCL, or CX43. CONCLUSIONS: Despite some inconsistency in the pattern of associations across the two populations, the associations themselves were phenotype-specific. While both IRF6 and FGF12 have previously shown strong associations with isolated CL/P, the associations with VCL and CX43 are novel and warrant further investigation in other isolated CLO samples. Birth Defects Research (Part A), 2010. © 2010 Wiley-Liss, Inc.

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