Ultra-low-coverage genome-wide association study—insights into gestational age using 17,844 embryo samples with preimplantation genetic testing

Genome Medicine

Research

Jianliang Lu¹  Bin Yan¹  Shumin Li¹  Tak-Wah Lam¹  Ruibang Luo¹  Yuexuan Wang²  Thomas K. T. Li³  Pingyuan Xie⁴  Yifan Gu⁵  Fei Gong⁵  Yueqiu Tan⁵  Ge Lin⁶ 

[1] Department of Computer Science, The University of Hong Kong, Hong Kong, China;Department of Computer Science, The University of Hong Kong, Hong Kong, China;College of Computer Science and Technology, Zhejiang University, Hangzhou, China;Department of Obstetrics & Gynecology, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China;Hunan Normal University School of Medicine, 410013, Changsha, Hunan, China;National Engineering and Research Center of Human Stem Cell, Changsha, Hunan, China;NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, School of Basic Medical Science, Institute of Reproductive and Stem Cell Engineering, Central South University, 410008, Changsha, Hunan, China;Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-Xiangya, 410013, Changsha, Hunan, China;NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, School of Basic Medical Science, Institute of Reproductive and Stem Cell Engineering, Central South University, 410008, Changsha, Hunan, China;Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-Xiangya, 410013, Changsha, Hunan, China;National Engineering and Research Center of Human Stem Cell, Changsha, Hunan, China;

关键词: Ultra-low-coverage whole genome sequencing;    Imputation;    Single-nucleotide polymorphisms;    Genome-wide association study;    Gestational age;    Preterm birth;   

DOI  :  10.1186/s13073-023-01158-7

 received in 2022-06-15, accepted in 2023-01-26,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundVery low-coverage (0.1 to 1×) whole genome sequencing (WGS) has become a promising and affordable approach to discover genomic variants of human populations for genome-wide association study (GWAS). To support genetic screening using preimplantation genetic testing (PGT) in a large population, the sequencing coverage goes below 0.1× to an ultra-low level. However, the feasibility and effectiveness of ultra-low-coverage WGS (ulcWGS) for GWAS remains undetermined.MethodsWe built a pipeline to carry out analysis of ulcWGS data for GWAS. To examine its effectiveness, we benchmarked the accuracy of genotype imputation at the combination of different coverages below 0.1× and sample sizes from 2000 to 16,000, using 17,844 embryo PGT samples with approximately 0.04× average coverage and the standard Chinese sample HG005 with known genotypes. We then applied the imputed genotypes of 1744 transferred embryos who have gestational ages and complete follow-up records to GWAS.ResultsThe accuracy of genotype imputation under ultra-low coverage can be improved by increasing the sample size and applying a set of filters. From 1744 born embryos, we identified 11 genomic risk loci associated with gestational ages and 166 genes mapped to these loci according to positional, expression quantitative trait locus, and chromatin interaction strategies. Among these mapped genes, CRHBP, ICAM1, and OXTR were more frequently reported as preterm birth related. By joint analysis of gene expression data from previous studies, we constructed interrelationships of mainly CRHBP, ICAM1, PLAGL1, DNMT1, CNTLN, DKK1, and EGR2 with preterm birth, infant disease, and breast cancer.ConclusionsThis study not only demonstrates that ulcWGS could achieve relatively high accuracy of adequate genotype imputation and is capable of GWAS, but also provides insights into the associations between gestational age and genetic variations of the fetal embryos from Chinese population.

【 授权许可】

CC BY   
© The Author(s) 2023

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