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Genomic Insights into Early Childhood Caries: A Comprehensive Analysis using GWAS, TWAS, and Rare Variant Approaches

Orlova, Ekaterina (2024) Genomic Insights into Early Childhood Caries: A Comprehensive Analysis using GWAS, TWAS, and Rare Variant Approaches. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Early childhood caries (ECC) is a rapidly progressive form of early-onset tooth decay. Despite the established heritability of caries, comprehensive genetic association studies have not yet been performed for ECC. This dissertation leverages data from five cohorts of children in two countries (COHRA1, COHRA2, IFS, IHS, ALSPAC) to investigate the genetic basis for ECC. Recognizing the limitations of the case definition of ECC, this study incorporates a range of early caries phenotypes (ECPs) which capture additional dimensions, such as ECC severity and time-dependence. These include ECC case status, severe ECC (SECC), quantitative scores representing counts of the number of decayed and restored primary teeth (dft) and tooth surfaces (dfs), CIPD score (an age-informed caries staging system), and primary maxillary incisor caries (MIC).

The study took three approaches to investigate the role of common and rare variants in caries risk:

(1) Through genome-wide association studies (GWASs) of ECPs, we identified for the first time thirteen genome-wide significant loci, predominantly located in regions linked with tooth and salivary gland development, the innate immune system, periodontal disease, and craniofacial and bone development (e.g., near TMTC2, ALPL, DEFB1, STX6, KIAA1614, IFITM5, and MIR6874).

(2) The first transcriptome-wide association studies (TWASs) of ECPs nominated fourteen significantly associated gene transcripts. These transcripts are linked to taste and olfactory receptors, as well as bone and tooth biology, anxiety/neurological health and the innate immune system of the oral cavity (e.g., CDH17, TAS2R43, SMIM10L1, TAS2R14, GPR158, TTC19, NCOR1 and ADORA2A).

(3) Rare and low-frequency variant analyses for the first time confirmed a role for rare and low-frequency coding variants in ECPs. The gene-based analyses identified 34 genes, many of which are differentially expressed in the brain. Key genes include ATF7IP2, CCDC65, PCDH9, POU2F1, and PDK2.

The study validates the utility of the employed caries phenotypes for genetic investigations of ECC and underscores the potential of novel phenotypes like CIPD and more narrow ones like SECC and MIC, which isolate disease severity and specific teeth. This study has public health significance. It provides insights into ECC pathogenesis and lays foundations for screening, prevention and treatment strategies for this prevalent disease.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Orlova, Ekaterinaeko8@pitt.eduEKO80000-0002-7129-5796
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairShaffer, John R.john.r.shaffer@pitt.edujrs51
Committee MemberMarazita, Marymarazita@pitt.edumarazita
Committee MemberRoman, Bethromanb@pitt.eduromanb
Committee MemberUrban, Zsolturbanz@pitt.eduurbanz
Date: 16 May 2024
Date Type: Publication
Defense Date: 15 December 2023
Approval Date: 16 May 2024
Submission Date: 19 April 2024
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 423
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Human Genetics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Caries, ECC, GWAS, TWAS, rare variant, complex disease, genetic, meta-analysis
Related URLs:
Date Deposited: 16 May 2024 17:33
Last Modified: 16 May 2024 17:33


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