Gene mapping for QT interval using linkage analysis and association studies in an isolated Mongolian population

다국어 초록 (Multilingual Abstract)

Introduction: QT interval of electrocardiogram (ECG), a representative of the cardiac repolarization is a complex trait and prognostic indicator of cardiac and non-cardiac sudden death in general population. Subjects with extremely prolonged QT interval are susceptible for ventricular arrhythmia or sudden death. Here, we conducted whole-genome linkage analysis and family-based association study for QT interval on an isolated Mongolian population.

Methods: The subjects of this study were recruited from Dashbalbar, Dornod Province, Mongolia as a part of the GENDISCAN (Gene Discovery for Complex traits in Asian population of Northeast area) project. A total of 1,039 short tandem repeat (STR) markers were typed for 1,000 individuals through 22 autosomes for the linkage analysis. In addition to STR genotyping, 756 individuals of them were genotyped with 610 k single nucleotide polymorphism (SNP) chip for family-based genome-wide association study (GWAS). Genome-wide linkage analysis was conducted separately for all age group (10-84 yrs.) and adults (18-84 yrs.), and only the adults were included in family-based GWAS. Replication study was conducted on 2,726 Koreans from 636 families.

Results: Heritability (r2) was estimated as 0.29 for both age groups. Two suggestive (8q22.3, logarithm of odds (LOD) = 2.1; 5p15.2, LOD = 1.9) and 1 potential (3p26.1, LOD = 1.8) linkage evidences for QTc interval was found in the whole-genome linkage analysis for adults. As the results of family-based GWAS, most significant 20 SNPs with overall family-based p-value below 5x10-5 were suggested. One of the association signals, rs16859461 (P = 2.26E-05, MAF = 0.057) was mapped to 49 kb downstream of potassium channel, subfamily K, member 1 (KCNK1) gene, a possible candidate for QT interval. Additional 19 signals were identified with association test with and without the assumption of linkage evidence on 1-LOD support area of a linkage peak on chromosome 3. The SNP rs9385707 from the GWAS was verified with the replication study on Koreans.

Conclusion: Taken together, our linkage and family-based association studies on QT interval will contribute to widen the understanding about the regulation of cardiac repolarization.

목차 (Table of Contents)

• Abstract ⅰ
• Contents ⅲ
• List of tables ⅴ
• List of figures ⅵ
• List of abbreviations ⅶ
• Introduction 1
• Ⅰ. Definition of QT interval and long QT syndrome (LQTS) 1
• Ⅱ. Genetic mapping for complex traits 2
• Ⅲ. QT interval in general population 4
• Ⅳ. Previous research on genetic mapping of QT interval 5
• Ⅴ. Strategies for this study 7
• Material and Methods 9
• Ⅰ. Study population 9
• Ⅱ. QT interval measurement 10
• Ⅲ. Heritability estimation and genome-wide linkage analysis 11
• Ⅳ. Family-based association study 12
• Ⅴ. Gene Ontology (GO) and KEGG pathway analysis 14
• Results 15
• Ⅰ. Characteristics of study population 15
• Ⅱ. Genome-wide linkage analysis 16
• Ⅲ. Family-based GWAS 17
• Ⅳ. GO and KEGG pathway analysis 18
• Ⅴ. Association at 1-LOD support area of the linkage peak on chromosome 3 19
• Ⅵ. Replication study in an family-based Korean population 21
• Discussion 22
• Ⅰ. Genome-wide linkage analysis 23
• Ⅱ. KCNK1 of family-based GWAS 24
• Ⅲ. Genes without previously identified relations with QT interval 26
• Ⅳ. Association at 1-LOD support area of the linkage peak on chromosome 3 29
• Ⅴ. Association of candidate genes 33
• Ⅵ. Limitations of this study 34
• Ⅶ. Summary of this study 35
• References 55
• Abstract in Korean 67