# Rethinking GWAS: how lessons from genetic screens and artificial intelligence could reveal biological mechanisms

**Authors:** Dennis J Hazelett

PMC · DOI: 10.1093/bioinformatics/btaf153 · 2025-04-08

## TL;DR

This essay explores how insights from genetic screens and AI can help uncover biological mechanisms behind complex diseases identified by GWAS.

## Contribution

The paper proposes a new computational framework for interpreting GWAS results using lessons from genetic screens and AI.

## Key findings

- Genetic screens in model organisms offer parallels to GWAS that can guide biological interpretation.
- A computational framework is proposed to exhaustively interrogate GWAS results for biological mechanisms.
- Existing and future data, mechanisms, and technologies are discussed for advancing GWAS interpretation.

## Abstract

Modern single-cell omics data are key to unraveling the complex mechanisms underlying risk for complex diseases revealed by genome-wide association studies (GWAS). Phenotypic screens in model organisms have several important parallels to GWAS which the author explores in this essay.

The author provides the historical context of such screens, comparing and contrasting similarities to association studies, and how these screens in model organisms can teach us what to look for. Then the author considers how the results of GWAS might be exhaustively interrogated to interpret the biological mechanisms underpinning disease processes. Finally, the author proposes a general framework for tackling this problem computationally, and explore the data, mechanisms, and technology (both existing and yet to be invented) that are necessary to complete the task.

There are no data or code associated with this article.

## Full-text entities

- **Genes:** YAP1 (Yes1 associated transcriptional regulator) [NCBI Gene 10413] {aka COB1, YAP, YAP-1, YAP2, YAP65, YKI}, AR (androgen receptor) [NCBI Gene 367] {aka AIS, AR8, DHTR, HPCX3, HUMARA, HYSP1}, NCOA4 (nuclear receptor coactivator 4) [NCBI Gene 8031] {aka ARA70, ELE1, PTC3, RFG}, CTCF (CCCTC-binding factor) [NCBI Gene 10664] {aka CFAP108, FAP108, MRD21}, Ankle1 (ankyrin repeat and LEM domain containing 1) [NCBI Gene 361122] {aka Ankrd41, RGD1308184}, IGF2R (insulin like growth factor 2 receptor) [NCBI Gene 3482] {aka CD222, CI-M6PR, CIMPR, M6P-R, M6P/IGF2R, MPR 300}, F3 (coagulation factor III, tissue factor) [NCBI Gene 2152] {aka CD142, TF, TFA}, Tmprss2 (transmembrane serine protease 2) [NCBI Gene 156435], MDM4 (MDM4 regulator of p53) [NCBI Gene 4194] {aka BMFS6, HDMX, MDMX, MRP1}, FGF10 (fibroblast growth factor 10) [NCBI Gene 2255] {aka LADD3}, CCDC6 (coiled-coil domain containing 6) [NCBI Gene 8030] {aka D10S170, H4, PTC, PTC1, TPC, TST1}, PAX6 (paired box 6) [NCBI Gene 5080] {aka AN, AN1, AN2, ASGD5, D11S812E, FVH1}, SHH (sonic hedgehog signaling molecule) [NCBI Gene 6469] {aka HHG1, HLP3, HPE3, MCOPCB5, SMMCI, ShhNC}, FGFR2 (fibroblast growth factor receptor 2) [NCBI Gene 2263] {aka BBDS, BEK, BFR-1, CD332, CEK3, CFD1}, MLH1 (mutL homolog 1) [NCBI Gene 4292] {aka COCA2, FCC2, HNPCC, HNPCC2, LYNCH2, MLH-1}, IGF2 (insulin like growth factor 2) [NCBI Gene 3481] {aka C11orf43, GRDF, IGF-II, PP9974, SRS3}, Erg (ETS transcription factor ERG) [NCBI Gene 170909]
- **Diseases:** oncogenesis (MESH:D063646), Parkinson's disease (MESH:D010300), ovarian cancer (MESH:D010051), prostate cancer (MESH:D011471), breast cancer (MESH:D001943), inherited cancers (MESH:D009386), AD (MESH:D000544), hypertension (MESH:D006973), brain-related diseases (MESH:D001927), colorectal cancers (MESH:D015179), autoimmune diseases (MESH:D001327), cancer (MESH:D009369)
- **Chemicals:** cholesterol (MESH:D002784)
- **Species:** Diptera (flies, order) [taxon 7147], Danio rerio (leopard danio, species) [taxon 7955], Saccharomyces cerevisiae (baker's yeast, species) [taxon 4932], Drosophila melanogaster (fruit fly, species) [taxon 7227], Homo sapiens (human, species) [taxon 9606], Rattus norvegicus (brown rat, species) [taxon 10116], Mus musculus (house mouse, species) [taxon 10090], Nematoda (nematode, phylum) [taxon 6231]
- **Mutations:** rs356182

## Figures

2 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12014097/full.md

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Source: https://tomesphere.com/paper/PMC12014097