Functional annotation of genetic associations by transcriptome-wide association analysis provides insights into neutrophil development regulation

Yao Yao; Jia Yang; Qian Qin; Chao Tang; Zhidan Li; Li Chen; Kailong Li; Chunyan Ren; Lu Chen; Shuquan Rao

doi:10.1038/s42003-020-01527-7

Functional annotation of genetic associations by transcriptome-wide association analysis provides insights into neutrophil development regulation

Commun Biol. 2020 Dec 18;3(1):790. doi: 10.1038/s42003-020-01527-7.

Authors

Yao Yao^{1

2}, Jia Yang³, Qian Qin⁴, Chao Tang¹, Zhidan Li¹, Li Chen¹, Kailong Li⁵, Chunyan Ren⁶, Lu Chen⁷, Shuquan Rao⁸

Affiliations

¹ Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Medicine, West China Second Hospital, State Key Laboratory of Biotherapy and Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China.
² School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
³ Department of Dermatology, University of Californian San Francisco, San Francisco, CA, 94110, USA.
⁴ Molecular Pathology Unit, Center for Cancer Research, Center for Computational and Integrative Biology, Massachusetts General Hospital, Department of Pathology, Harvard Medical School, Boston, MA, 02115, USA.
⁵ Children's Medical Center Research Institute, Department of Pediatrics, Harold C. Simmons Comprehensive Cancer Center, Hamon Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
⁶ Division of Hematology/Oncology, Boston Children's Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA.
⁷ Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Medicine, West China Second Hospital, State Key Laboratory of Biotherapy and Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China. luchen@scu.edu.cn.
⁸ Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing, 100005, China. shuquan.rao@gmail.com.

Abstract

Genome-wide association studies (GWAS) have identified multiple genomic loci linked to blood cell traits, however understanding the biological relevance of these genetic loci has proven to be challenging. Here, we performed a transcriptome-wide association study (TWAS) integrating gene expression and splice junction usage in neutrophils (N = 196) with a neutrophil count GWAS (N = 173,480 individuals). We identified a total of 174 TWAS-significant genes enriched in target genes of master transcription factors governing neutrophil specification. Knockout of a TWAS candidate at chromosome 5q13.2, TAF9, in CD34⁺ hematopoietic and progenitor cells (HSPCs) using CRISPR/Cas9 technology showed a significant effect on neutrophil production in vitro. In addition, we identified 89 unique genes significant only for splice junction usage, thus emphasizing the importance of alternative splicing beyond gene expression underlying granulopoiesis. Our results highlight the advantages of TWAS, followed by gene editing, to determine the functions of GWAS loci implicated in hematopoiesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alleles
Cell Differentiation / genetics
Cell Lineage / genetics
Chromosome Mapping
Computational Biology* / methods
Gene Expression Profiling*
Genome-Wide Association Study*
Hematopoiesis / genetics
Humans
Leukocyte Count
Molecular Sequence Annotation*
Neutrophils / cytology
Neutrophils / immunology
Neutrophils / metabolism*
Polymorphism, Single Nucleotide
Quantitative Trait Loci
Reproducibility of Results
Sequence Analysis, DNA
Transcriptome*