Journal article
The PAX1 locus at 20p11 is a potential genetic modifier for bilateral cleft lip
HGG advances, Vol.2(2), pp.100025-100025
04/08/2021
DOI: 10.1016/j.xhgg.2021.100025
PMCID: PMC8018676
PMID: 33817668
Abstract
Nonsyndromic orofacial clefts (OFCs) are a common birth defect and are phenotypically heterogenous in the structure affected by the cleft—cleft lip (CL) and cleft lip and palate (CLP)—as well as other features, such as the severity of the cleft. Here, we focus on bilateral and unilateral clefts as one dimension of OFC severity, because the genetic architecture of these subtypes is not well understood. We tested for subtype-specific genetic associations in 44 bilateral CL (BCL) individuals, 434 unilateral CL (UCL) individuals, 530 bilateral CLP individuals (BCLP), 1,123 unilateral CLP (UCLP) individuals, and unrelated control individuals (N = 1,626), using a mixed-model approach. While no novel loci were found, the genetic architecture of UCL was distinct compared to BCL, with 44.03% of suggestive loci having different effects between the two subtypes. To further understand the subtype-specific genetic risk factors, we performed a genome-wide scan for modifiers and found a significant modifier locus on 20p11 (p = 7.53 × 10−9), 300 kb downstream of PAX1, that associated with higher odds of BCL versus UCL and replicated in an independent cohort (p = 0.0018) with no effect in BCLP (p > 0.05). We further found that this locus was associated with normal human nasal shape. Taken together, these results suggest bilateral and unilateral clefts may have different genetic architectures. Moreover, our results suggest BCL, the rarest form of OFC, may be genetically distinct from the other OFC subtypes. This expands our understanding of modifiers for OFC subtypes and further elucidates the genetic mechanisms behind the phenotypic heterogeneity in OFCs.
Orofacial clefts (OFCs) are a common birth defect and phenotypically heterogenous, although the causes of this heterogeneity are not understood. We performed a genome-wide scan and identified a modifier locus near PAX1 that increased risk for bilateral cleft lip only. This expands our understanding of genetic modifiers for OFC subtypes.
Details
- Title: Subtitle
- The PAX1 locus at 20p11 is a potential genetic modifier for bilateral cleft lip
- Creators
- Sarah W. Curtis - Emory UniversityDaniel Chang - Emory UniversityMyoung Keun Lee - University of PittsburghJohn R. Shaffer - University of PittsburghKarlijne Indencleef - KU LeuvenMichael P. Epstein - Emory UniversityDavid J. Cutler - Emory UniversityJeffrey C. Murray - University of IowaEleanor Feingold - University of PittsburghTerri H. Beaty - Johns Hopkins UniversityPeter Claes - KU LeuvenSeth M. Weinberg - University of PittsburghMary L. Marazita - University of PittsburghJenna C. Carlson - University of PittsburghElizabeth J. Leslie - Emory University
- Resource Type
- Journal article
- Publication Details
- HGG advances, Vol.2(2), pp.100025-100025
- DOI
- 10.1016/j.xhgg.2021.100025
- PMID
- 33817668
- PMCID
- PMC8018676
- NLM abbreviation
- HGG Adv
- ISSN
- 2666-2477
- eISSN
- 2666-2477
- Publisher
- Elsevier Inc
- Language
- English
- Date published
- 04/08/2021
- Academic Unit
- Anatomy and Cell Biology; Stead Family Department of Pediatrics; Epidemiology; Pediatric Dentistry; Craniofacial Anomalies Research Center; Dental Research
- Record Identifier
- 9985035881902771
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