Journal article
A systematic genetic analysis and visualization of phenotypic heterogeneity among orofacial cleft GWAS signals
Genetic epidemiology, Vol.43(6), pp.704-716
09/2019
DOI: 10.1002/gepi.22214
PMCID: PMC6687557
PMID: 31172578
Abstract
Phenotypic heterogeneity is a hallmark of complex traits, and genetic studies of such traits may focus on them as a single diagnostic entity or by analyzing specific components. For example, in orofacial clefting (OFC), three subtypes-cleft lip (CL), cleft lip and palate (CLP), and cleft palate (CP) have been studied separately and in combination. To further dissect the genetic architecture of OFCs and how a given associated locus may be contributing to distinct subtypes of a trait we developed a framework for quantifying and interpreting evidence of subtype-specific or shared genetic effects in complex traits. We applied this technique to create a "cleft map" of the association of 30 genetic loci with three OFC subtypes. In addition to new associations, we found loci with subtype-specific effects (e.g., GRHL3 [CP], WNT5A [CLP]), as well as loci associated with two or all three subtypes. We cross-referenced these results with mouse craniofacial gene expression datasets, which identified additional promising candidate genes. However, we found no strong correlation between OFC subtypes and expression patterns. In aggregate, the cleft map revealed that neither subtype-specific nor shared genetic effects operate in isolation in OFC architecture. Our approach can be easily applied to any complex trait with distinct phenotypic subgroups.
Details
- Title: Subtitle
- A systematic genetic analysis and visualization of phenotypic heterogeneity among orofacial cleft GWAS signals
- Creators
- Jenna C Carlson - University of PittsburghDeepti Anand - University of DelawareAzeez Butali - University of IowaCarmen J Buxo - University of Puerto Rico SystemKaare Christensen - University of Southern DenmarkFrederic Deleyiannis - University of Colorado Colorado SpringsJacqueline T Hecht - The University of Texas Health Science Center at HoustonLina M Moreno - University of IowaIeda M Orioli - Universidade Federal do Rio de JaneiroCarmencita Padilla - University of the Philippines ManilaJohn R Shaffer - University of PittsburghAlexandre R Vieira - University of PittsburghGeorge L Wehby - University of IowaSeth M Weinberg - University of PittsburghJeffrey C Murray - University of IowaTerri H Beaty - Johns Hopkins UniversityIrfan Saadi - University of Kansas Medical CenterSalil A Lachke - University of DelawareMary L Marazita - University of PittsburghEleanor Feingold - University of PittsburghElizabeth J Leslie - Emory University
- Resource Type
- Journal article
- Publication Details
- Genetic epidemiology, Vol.43(6), pp.704-716
- DOI
- 10.1002/gepi.22214
- PMID
- 31172578
- PMCID
- PMC6687557
- NLM abbreviation
- Genet Epidemiol
- ISSN
- 0741-0395
- eISSN
- 1098-2272
- Grant note
- S21 MD001830 / NIMHD NIH HHS R01 DE026172 / NIDCR NIH HHS R01-DE012472 [MLM] / NIH HHS R00 DE022378 / NIDCR NIH HHS R01 DE016148 / NIDCR NIH HHS R21 DE016930 / NIDCR NIH HHS R01 DD000295 / NCBDD CDC HHS U54 HD090216 / NICHD NIH HHS R01 DE011948 / NIDCR NIH HHS U01 DE018993 / NIDCR NIH HHS R03 DE024776 / NIDCR NIH HHS U54 MD007587 / NIMHD NIH HHS R01 DE014667 / NIDCR NIH HHS R00 DE024571 / NIDCR NIH HHS UL1 TR003167 / NCATS NIH HHS R01 DE014581 / NIDCR NIH HHS X01-HG007485 [MLM / NIH HHS HHSN268201200008I / NHLBI NIH HHS R37 DE008559 / NIDCR NIH HHS R00 DE025060 / NIDCR NIH HHS HHSN268201200008C / NHLBI NIH HHS R01 DE009886 / NIDCR NIH HHS R01 DE011931 / NIDCR NIH HHS
- Language
- English
- Date published
- 09/2019
- Academic Unit
- Preventive and Community Dentistry; Orthodontics; Oral Pathology, Radiology and Medicine; Anatomy and Cell Biology; Health Management and Policy; Stead Family Department of Pediatrics; Epidemiology; Economics; Pediatric Dentistry; Craniofacial Anomalies Research Center; Public Policy Center (Archive); Dental Research
- Record Identifier
- 9984353847802771
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