Orofacial clefts (OFCs) are the most common craniofacial birth defect in humans and are caused by multiple genetic and environmental risk factors. Elucidating the etiologies of clefting is critical not only for our knowledge of developmental biology and for how clefts arise, but ultimately for improved prevention, treatment, and prognosis for individuals affected by orofacial clefting. Our innovative approach for identifying genetic risk factors for orofacial clefts is to improve the power to detect associations by expanding the phenotypic spectrum to include subclinical phenotypes. These subclinical phenotypes, such as discontinuities of the orbicularis oris muscle of the upper lip, ar generally increased in unaffected family members compared to controls, providing evidence that they are part of the range of phenotypes associated with OFCs. The goal of this K99/R00 application is to use subclinical phenotypes to identify genetic risk factors for OFCs and improve our understanding of their role in causing clefts. The overall hypothesis for this project is that subclinical phenotypes are the mildest expression of OFC risk factors and genetic risk factors will be shared between individuals with subclinical phenotypes and individuals with OFCs. These hypotheses will be tested in three specific aims:
In Aim 1, I will examine subclinical phenotypes and genetic variants in a cohort of twin pairs who are discordant for orofacial clefts.
In Aim 2 I will conduct candidate gene association studies in OFCs and related subclinical phenotypes.
In Aim 3, I will perform exome sequencing in families with OFCs and subclinical phenotypes. The K99 phase of this project will be completed at the University of Pittsburgh under the guidance of Dr. Mary Marazita (mentor) and Dr. Eleanor Feingold (co-mentor). The Candidate has also assembled an accomplished group of consultants and external advisors who will provide the necessary training and support to accomplish the proposed research, facilitate the growth of the Candidate, and provide guidance during the transition to independence. The proposed training and research aims are tailored to provide additional training in subclinical phentoyping and statistical genetics to facilitate the Candidate's development as an independent craniofacial geneticist who integrates deep genetic resources with detailed phenotyping to study complex craniofacial disorders.
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| Claes, Peter; Roosenboom, Jasmien; White, Julie D et al. (2018) Genome-wide mapping of global-to-local genetic effects on human facial shape. Nat Genet 50:414-423 |
| Shaffer, John R; LeClair, Jessica; Carlson, Jenna C et al. (2018) Association of low-frequency genetic variants in regulatory regions with nonsyndromic orofacial clefts. Am J Med Genet A : |
| Carlson, Jenna C; Nidey, Nichole L; Butali, Azeez et al. (2018) Genome-wide interaction studies identify sex-specific risk alleles for nonsyndromic orofacial clefts. Genet Epidemiol 42:664-672 |
| Chernus, Jonathan; Roosenboom, Jasmien; Ford, Matthew et al. (2018) GWAS reveals loci associated with velopharyngeal dysfunction. Sci Rep 8:8470 |
| Carlson, Jenna C; Standley, Jennifer; Petrin, Aline et al. (2017) Identification of 16q21 as a modifier of nonsyndromic orofacial cleft phenotypes. Genet Epidemiol 41:887-897 |
| Carlson, Jenna C; Taub, Margaret A; Feingold, Eleanor et al. (2017) Identifying Genetic Sources of Phenotypic Heterogeneity in Orofacial Clefts by Targeted Sequencing. Birth Defects Res 109:1030-1038 |
| Shaffer, John R; Li, Jinxi; Lee, Myoung Keun et al. (2017) Multiethnic GWAS Reveals Polygenic Architecture of Earlobe Attachment. Am J Hum Genet 101:913-924 |
| Lee, Myoung Keun; Shaffer, John R; Leslie, Elizabeth J et al. (2017) Genome-wide association study of facial morphology reveals novel associations with FREM1 and PARK2. PLoS One 12:e0176566 |
| Everson, Joshua L; Fink, Dustin M; Yoon, Joon Won et al. (2017) Sonic hedgehog regulation of Foxf2 promotes cranial neural crest mesenchyme proliferation and is disrupted in cleft lip morphogenesis. Development 144:2082-2091 |
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