2 research outputs found
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Όλ¬Έ(λ°μ¬)--μμΈλνκ΅ λνμ :μκ³Όλν μνκ³Ό,2020. 2. λ°μμ£Ό.Thyroid cancer is the most common endocrine cancer and thyroid nodule is most common endocrine problem in Korea. Both phenotypes show a high degree of heritability. Several genome-wide association studies (GWAS) for thyroid cancer were conducted in European descendants and identified susceptibility loci of differentiated thyroid cancer (DTC). However, there is no GWAS for thyroid cancer in Asian population, and inherited genetic risk factors for thyroid nodules and their associations with thyroid cancer remain unknown.
Here, GWAS and replication study was performed using a total of 1,085 DTC cases and 8,884 controls of Koreans and these results were validated with an expression quantitative trait loci (eQTL) analysis and clinical phenotypes. The most robust associations were observed in the NRG1 gene (rs6996585, P=1.08Γ10-10), and this SNP was also associated with NRG1 expression in thyroid tissues. In addition, three previously reported loci (FOXE1, NKX2-1, and DIRC3) were confirmed and seven susceptibility loci (VAV3, PCNXL2,INSR, MRSB3, FHIT, SEPT11, and SLC24A6) associated with DTC were newly identified. Furthermore, I identified specific variants of DTC that have different effects according to the cancer type or ethnicity.
Furthermore, a three-stage GWAS for thyroid nodules was performed. The discovery stage involved a genome-wide scan of 811 subjects with thyroid nodules and 691 subjects with a normal thyroid from a population-based cohort. Replication studies were conducted in an additional 1981 cases and 3100 controls from the participants of a health check-up. Expression quantitative trait loci (eQTL) analysis was also performed using public data. The most robust association was observed in TRPM3 (rs4745021) in the joint analysis (OR=1.26,
P = 6.12 Γ 10-8) and meta-analysis (OR = 1.28, P = 2.11Γ10-8). Signals at MBIP/NKX2-1 were replicated but did not reach genome-wide significance in the joint analysis (rs2415317; P = 4.62 Γ 10-5, rs944289; P = 8.68 Γ 10-5). The eQTL analysis showed that TRPM3 expression was associated with the rs4745021 genotype in thyroid tissues. The results of GWAS for DTC provide deeper insight into the genetic contribution to thyroid cancer in different populations. And GWAS for thyroid nodule suggest that thyroid nodules have a genetic predisposition distinct from that of thyroid cancer.κ°μμ μμ νκ΅μμ κ°μ₯ νν λ΄λΆλΉμμ΄λ©° κ°μμ κ²°μ μ κ°μ₯ νν λ΄λΆλΉ μ§νμ΄λ€. λκ°μ§ μ§ν λͺ¨λ λμ μ μ μ±μ 보μΈλ€. λͺλͺμ κ°μμ μμ λν μ μ₯ μ μ 체 μ°κ΄ μ°κ΅¬κ° μμμΈλ€μκ²μ μ΄λ£¨μ΄μ‘κ³ , λΆνκ°μμ μμ λν κ°μμ± μ μ μμ’λ₯Ό λ°κ΅΄νμλ€. κ·Έλ¬λ μμμμΈμ λν μ μ₯ μ μ 체 μ°κ΄ μ°κ΅¬λ μνλ λ° μμΌλ©°, κ°μμ κ²°μ μ λν μ μ μ μ°κ΅¬λ μμμΌλ©° μ΄μ κ΄λ ¨λ μ μ μμ κ°μμ μκ³Όμ κ΄λ ¨μ±λ μ¬μ ν μ μ μλ μνμ΄λ€.
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μ λμ‘°κ΅°μΌλ‘ μ μ₯ μ μ 체 μ°κ΄ λΆμ λ° μ¬ν μ°κ΅¬λ₯Ό μννμκ³ , κ·Έ κ²°κ³Όλ₯Ό λ°ν μμ νμ§ μ μ μμ’ μ°κ΅¬ λ° μμ λ°ννμ§μ ν΅ν΄μ κ²μ¦νμλ€. κ°μ₯ λλ ·ν κ΄λ ¨μ±μ 보μ΄λ μ μ μμ’λ NRG1 μ μ μμμΌλ©° (rs6996585, P=1.08Γ10-10), μ΄ SNP μ NRG1 μ λ°νκ³Όλ κ΄λ ¨μ±μ΄ μμλ€. λΆκ°μ μΌλ‘ μ΄μ μ λ³΄κ³ λμλ μ μ μμ’ (FOXE1, NKX2-1, DIRC3)λ₯Ό νμΈνμμΌλ©° 7 κ°μ μ μ μμ’ (VAV3, PCNXL2, INSR, MRSB3, FHIT, SEPT11, SLC24A6)λ₯Ό μλ‘κ² λ°κ²¬νμλ€. λν,
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λν κ°μμ κ²°μ μ λν 3 λ¨κ³μ μ μ₯ μ μ 체 μ°κ΄ λΆμμ μννμλ€. λ°κ²¬ λ¨κ³μ μ μ₯ μ μ 체 μ€μΊμ μΈκ΅¬ κΈ°λ° μ½νΈνΈμ 811 λͺ
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μ μ μκ΅°μμ μνλμμΌλ©° λ°ν μμ νμ§ μ μ μμ’ λΆμλ 곡곡λ°μ΄ν°λ₯Ό ν΅ν΄μ μνλμλ€. κ°μ₯ μ μν κ΄λ ¨μ±μ κ²°ν©λΆμ (OR=1.26, P = 6.12 Γ 10-8) λ° λ©νλΆμ (OR = 1.28, P = 2.11Γ10-8) κ²°κ³Ό TRPM3 (rs4745021) μ μ μμμ κ΄μ°°λμλ€. MBIP/NKX2-1 λ³μ΄λ μ¬νμ΄ λμμΌλ μ μ₯ μ μ 체 μ μμ±μ 보μ΄μ§ λͺ»νλ€. λ°ν μμ νμ§ μ μ μμ’ λΆμμμ TRPM3 μ λ°νμ κ°μμ μ‘°μ§μμ rs4745021 μ μ μνκ³Ό κ΄λ ¨μ±μ΄ μμλ€.
λΆνκ°μμ μμ λν μ μ₯ μ μ 체 μ°κ΄ λΆμ κ²°κ³Όλ κ°μμ μμ λ°μμμ μ μ μ κΈ°μ¬μ λν μ΄ν΄ν μ μκ² ν΄μ£ΌμμΌλ©°, κ°μμ
κ²°μ μ λν μ μ₯ μ μ 체 μ°κ΅¬λ₯Ό ν΅ν΄ κ°μμ κ²°μ μ κ°μμ μκ³Ό μ°¨λ³λλ μ μ μ νΉμ§μ κ°μ§κ³ μμμ νμΈνμλ€.Introduction 1
1. Epidemiology of thyroid cancer 1
2. Risk factors of differentiated thyroid cancer 1
3. Heritability of differentiated thyroid cancer 3
4. Familial syndromes associated with thyroid cancer and germline mutation of differentiated thyroid cancer 4
5. Epidemiology of thyroid nodule 4
6. Clinical significance and heritability of thyroid nodule 4
7. Genome-wide association study for differentiated thyroid cancer 5
8. Genetic studies for thyroid nodule 6
9. Hypothesis 9
10. Aims of study 9
Chapter I. Genome-wide association and expression quantitative trait loci studies for thyroid cancer 10
Materials and methods 11
Study participants for the Stage 1 genome scan 11
Study participants for the Stage 2 follow-up 11
Discovery SNP genotyping and imputation 15
Replication SNP selection and genotyping 16
RNA sequencing and eQTL analysis 18
Statistical analysis 18
Ethics statement 20
Results 21
Stage 1 genome scan 21
Stage 2 follow-up and joint Stages 1 and 2 analyses 24
Validation of the candidate SNPs with cis-eQTL and GSEA analyses 29
Association between candidate SNPs and clinical phenotypes 35
The most significantly associated variant in the NRG1 locus 38
Other known associated variants in the NKX2-1, DIRC3, or FOXE1 loci 44
Novel candidate variants in the VAV3, PCNXL2, INSR, MRSB3, FHIT or SEPT11 loci 48
A comparison with the European GWAS results 51
Chapter II. Genome-wide association and expression quantitative trait loci studies for thyroid nodule 55
Materials and methods 56
Discovery series and thyroid ultrasonography 56
First replication series and ultrasonography 59
Second replication 59
Discovery GWAS and Imputation 60
Candidate SNP and genotyping of first replication 61
Genotyping of second replication 64
Comparison of allele frequencies between DTC, thyroid
nodules, and normal thyroid 64
Expression quantitative trait loci analysis 64
Statistical analysis 65
Ethics statement 66
Results 67
Discovery GWAS 67
Replication studies, joint analysis and meta-analysis 71
Comparison of allele frequencies between DTC, thyroid nodules, and normal thyroid 76
Expression quantitative trait loci analysis 80
Discussion 82
GWAS for DTC 82
GWAS for Thyroid nodule 92
Summary and conclusions 100
References 101
Abstract in Korean 116Docto
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Όλ¬Έ (μμ¬)-- μμΈλνκ΅ λνμ : μνκ³Ό(μ€κ°μν), 2015. 8. λ°λμ€.Background
Genome-wide association studies (GWASs) are widely used in human genetics to identify genes associated with various cancers. Several susceptibility loci of differentiated thyroid cancer (DTC) have been identified by GWASs (FOXE1, NKX2-1, DIRC3, NRG1, IMMP2L, RARRES1, and SNAPC4/CARD9). However, the relationship of these genetic markers with thyroid nodules has not been evaluated. Additionally, susceptibility loci of thyroid nodules have not been identified.
Objective
Our objective was to identify candidate loci that play a role in thyroid nodules by discovery GWAS.
Methods
We conducted a one-stage case-control GWAS for thyroid nodules in a population-based cohort. Individuals from the Ansung cohort underwent an initial thyroid ultrasonography and a follow-up 2 years later. Additionally, these individuals were evaluated using 1.43 million genotyped or imputed markers. In the two ultrasonographies, 809 individuals showed solid thyroid nodules in both ultrasonographies, while 689 subjects showed normal thyroids in both. We performed logistic regression adjusting for age and sex.
Results
Case-control comparisons identified two independent association signals (P < 1.0 Γ 10-5): a SNP at 18p11.31 in EPB41L3 (OR = 1.647, P = 2.09 Γ 10-7) and at 10p11.22 in ITGB1 (OR = 1.645, P = 5.85 Γ 10-6). In 13 additional suggestive signals (loci with single-point P values between 1.0 Γ 10-5 and 5.0 Γ 10-5), SNPs were located near NKX2-1 and RARRES1, which are known thyroid cancer susceptibility loci.
Conclusion
We found candidate susceptibility loci for thyroid nodules in a one-stage GWAS. Our findings suggest that thyroid nodules and thyroid cancer share a common genetic etiology.I. INTRODUCTION
II. METHODS
1. Study population and thyroid ultrasonography
2. Genotyping and imputation
3. Statistical analysis
III. RESULTS
IV. DISCUSSION
V. REFERENCESMaste