Editing GWAS: Experimental Approaches to Dissect and Exploit Disease-associated Genetic Variation

Overview

Journal Genome Med

Publisher Biomed Central

Specialty Genetics

Date 2021 Mar 11

PMID 33691767

Citations 23

Authors

Shuquan Rao

Yao Yao

Daniel E Bauer

Affiliations

Soon will be listed here.

Abstract

Genome-wide association studies (GWAS) have uncovered thousands of genetic variants that influence risk for human diseases and traits. Yet understanding the mechanisms by which these genetic variants, mainly noncoding, have an impact on associated diseases and traits remains a significant hurdle. In this review, we discuss emerging experimental approaches that are being applied for functional studies of causal variants and translational advances from GWAS findings to disease prevention and treatment. We highlight the use of genome editing technologies in GWAS functional studies to modify genomic sequences, with proof-of-principle examples. We discuss the challenges in interrogating causal variants, points for consideration in experimental design and interpretation of GWAS locus mechanisms, and the potential for novel therapeutic opportunities. With the accumulation of knowledge of functional genetics, therapeutic genome editing based on GWAS discoveries will become increasingly feasible.

Citing Articles

Patient-derived response estimates from zero-passage organoids of luminal breast cancer.

Przanowska R, Labban N, Przanowski P, Hawes R, Atkins K, Showalter S Breast Cancer Res. 2024; 26(1):192.

PMID: 39741344 PMC: 11687200. DOI: 10.1186/s13058-024-01931-5.

Integrative approaches to m6A and m5C RNA modifications in autism spectrum disorder revealing potential causal variants.

Jan S, Fahira A, Hassan E, Abdelhameed A, Wei D, Wadood A Mamm Genome. 2024; 36(1):280-292.

PMID: 39738578 DOI: 10.1007/s00335-024-10095-8.

Scarless genome editing technology and its application to crop improvement.

Ikeda K Breed Sci. 2024; 74(1):32-36.

PMID: 39246436 PMC: 11375429. DOI: 10.1270/jsbbs.23045.

A systematic strategy for identifying causal single nucleotide polymorphisms and their target genes on Juvenile arthritis risk haplotypes.

Jiang K, Liu T, Kales S, Tewhey R, Kim D, Park Y BMC Med Genomics. 2024; 17(1):185.

PMID: 38997781 PMC: 11241977. DOI: 10.1186/s12920-024-01954-z.

Functional dissection of complex and molecular trait variants at single nucleotide resolution.

Siraj L, Castro R, Dewey H, Kales S, Nguyen T, Kanai M bioRxiv. 2024; .

PMID: 38766054 PMC: 11100724. DOI: 10.1101/2024.05.05.592437.

References

Miller S, Wang T, Randolph P, Arbab M, Shen M, Huang T . Continuous evolution of SpCas9 variants compatible with non-G PAMs. Nat Biotechnol. 2020; 38(4):471-481. PMC: 7145744. DOI: 10.1038/s41587-020-0412-8. View

Trauernicht M, Martinez-Ara M, van Steensel B . Deciphering Gene Regulation Using Massively Parallel Reporter Assays. Trends Biochem Sci. 2019; 45(1):90-91. DOI: 10.1016/j.tibs.2019.10.006. View

Zhu Z, Zhang F, Hu H, Bakshi A, Robinson M, Powell J . Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets. Nat Genet. 2016; 48(5):481-7. DOI: 10.1038/ng.3538. View

Zeng J, Wu Y, Ren C, Bonanno J, Shen A, Shea D . Therapeutic base editing of human hematopoietic stem cells. Nat Med. 2020; 26(4):535-541. PMC: 7869435. DOI: 10.1038/s41591-020-0790-y. View

Cannon M, Mohlke K . Deciphering the Emerging Complexities of Molecular Mechanisms at GWAS Loci. Am J Hum Genet. 2018; 103(5):637-653. PMC: 6218604. DOI: 10.1016/j.ajhg.2018.10.001. View

Yeo N, Chavez A, Lance-Byrne A, Chan Y, Menn D, Milanova D . An enhanced CRISPR repressor for targeted mammalian gene regulation. Nat Methods. 2018; 15(8):611-616. PMC: 6129399. DOI: 10.1038/s41592-018-0048-5. View

Ulirsch J, Nandakumar S, Wang L, Giani F, Zhang X, Rogov P . Systematic Functional Dissection of Common Genetic Variation Affecting Red Blood Cell Traits. Cell. 2016; 165(6):1530-1545. PMC: 4893171. DOI: 10.1016/j.cell.2016.04.048. View

Gusev A, Ko A, Shi H, Bhatia G, Chung W, Penninx B . Integrative approaches for large-scale transcriptome-wide association studies. Nat Genet. 2016; 48(3):245-52. PMC: 4767558. DOI: 10.1038/ng.3506. View

Visscher P, Wray N, Zhang Q, Sklar P, McCarthy M, Brown M . 10 Years of GWAS Discovery: Biology, Function, and Translation. Am J Hum Genet. 2017; 101(1):5-22. PMC: 5501872. DOI: 10.1016/j.ajhg.2017.06.005. View

10.

Ranjha L, Howard S, Cejka P . Main steps in DNA double-strand break repair: an introduction to homologous recombination and related processes. Chromosoma. 2018; 127(2):187-214. DOI: 10.1007/s00412-017-0658-1. View

11.

Farnham P . Insights from genomic profiling of transcription factors. Nat Rev Genet. 2009; 10(9):605-16. PMC: 2846386. DOI: 10.1038/nrg2636. View

12.

Kim D, Luk K, Wolfe S, Kim J . Evaluating and Enhancing Target Specificity of Gene-Editing Nucleases and Deaminases. Annu Rev Biochem. 2019; 88:191-220. DOI: 10.1146/annurev-biochem-013118-111730. View

13.

Chavez A, Scheiman J, Vora S, Pruitt B, Tuttle M, Iyer E . Highly efficient Cas9-mediated transcriptional programming. Nat Methods. 2015; 12(4):326-8. PMC: 4393883. DOI: 10.1038/nmeth.3312. View

14.

Song F, Stieger K . Optimizing the DNA Donor Template for Homology-Directed Repair of Double-Strand Breaks. Mol Ther Nucleic Acids. 2017; 7:53-60. PMC: 5363683. DOI: 10.1016/j.omtn.2017.02.006. View

15.

Sharma K, Weber C, Bairlein M, Greff Z, Keri G, Cox J . Proteomics strategy for quantitative protein interaction profiling in cell extracts. Nat Methods. 2009; 6(10):741-4. DOI: 10.1038/nmeth.1373. View

16.

Li Y, van de Geijn B, Raj A, Knowles D, Petti A, Golan D . RNA splicing is a primary link between genetic variation and disease. Science. 2016; 352(6285):600-4. PMC: 5182069. DOI: 10.1126/science.aad9417. View

17.

Li B, Niu Y, Ji W, Dong Y . Strategies for the CRISPR-Based Therapeutics. Trends Pharmacol Sci. 2019; 41(1):55-65. PMC: 10082448. DOI: 10.1016/j.tips.2019.11.006. View

18.

Datlinger P, Rendeiro A, Schmidl C, Krausgruber T, Traxler P, Klughammer J . Pooled CRISPR screening with single-cell transcriptome readout. Nat Methods. 2017; 14(3):297-301. PMC: 5334791. DOI: 10.1038/nmeth.4177. View

19.

Cano-Gamez E, Trynka G . From GWAS to Function: Using Functional Genomics to Identify the Mechanisms Underlying Complex Diseases. Front Genet. 2020; 11:424. PMC: 7237642. DOI: 10.3389/fgene.2020.00424. View

20.

Ihry R, Worringer K, Salick M, Frias E, Ho D, Theriault K . p53 inhibits CRISPR-Cas9 engineering in human pluripotent stem cells. Nat Med. 2018; 24(7):939-946. DOI: 10.1038/s41591-018-0050-6. View