A high-resolution haplotype-resolved Reference panel constructed from the China Kadoorie Biobank Study

Area of Science:

• Population Genetics
• Genomic Medicine
• Bioinformatics

Background:

• Precision medicine requires high-accuracy individual genotype data, but whole-genome sequencing (WGS) is cost-prohibitive for large studies.
• Accurate haplotype reference panels are crucial for genotype imputation from lower-density data like microarrays.
• Existing reference panels may not optimally serve the genetic diversity of specific populations, such as the Chinese population.

Purpose of the Study:

• To construct a highly accurate haplotype reference panel using medium-depth WGS data from 10,000 Chinese individuals.
• To evaluate the performance of the novel CKB reference panel for genotype imputation compared to existing panels.
• To generate the largest whole-genome imputed dataset for the Chinese population and assess its utility in genome-wide association studies (GWAS).

Main Methods:

• Medium-depth whole-genome sequencing (WGS) was performed on 10,000 samples to create the CKB reference panel.
• The CKB panel was used to impute genotype data from microarray datasets.
• Imputation accuracy and the number of well-imputed variants were compared against other reference panels.
• A large-scale imputation of 100,706 microarrays was conducted using the CKB panel.
• Genome-wide association studies (GWAS) for height were performed on imputed data.

Main Results:

• The CKB reference panel demonstrated superior performance in genotype imputation compared to existing panels, showing higher accuracy and more well-imputed variants.
• Imputation of 100,706 microarrays using the CKB panel resulted in the largest whole-genome imputed dataset for the Chinese population to date.
• GWAS for height using the CKB-imputed data led to a threefold increase in tested single nucleotide polymorphisms (SNPs) and a twofold increase in significant SNPs.

Conclusions:

• The CKB reference panel provides a valuable resource for accurate genotype imputation of microarray or low-coverage WGS data, particularly for Chinese and potentially admixed populations.
• The generated large-scale imputed dataset is a significant resource for population genetic studies investigating complex traits and diseases.
• An online server offering free genotype imputation services based on the CKB panel has been developed, facilitating broader research applications.