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Background: Gene set tests can pinpoint genes and biological pathways that exert small to moderate effects on complex diseases like Type 2 Diabetes (T2D). By aggregating genetic markers based on biological information, these tests can enhance the statistical power needed to detect genetic associations., Results: Our goal was to develop a gene set test utilizing Bayesian Linear Regression (BLR) models, which account for both linkage disequilibrium (LD) and the complex genetic architectures intrinsic to diseases, thereby increasing the detection power of genetic associations. Through a series of simulation studies, we demonstrated how the efficacy of BLR derived gene set tests is influenced by several factors, including the proportion of causal markers, the size of gene sets, the percentage of genetic variance explained by the gene set, and the genetic architecture of the traits. By using KEGG pathways, eQTLs, and regulatory elements as different kinds of gene sets with T2D results, we also assessed the performance of gene set tests in explaining more about real phenotypes., Conclusions: Comparing our method with other approaches, such as the gold standard MAGMA (Multi-marker Analysis of Genomic Annotation) approach, our BLR gene set test showed superior performance. Combining performance of our method in simulated and real phenotypes, this suggests that our BLR-based approach could more accurately identify genes and biological pathways underlying complex diseases., Competing Interests: Declarations. Ethics approval and consent to participate: Human studies in the UK Biobank project have received approval from the Ethics and Governance Framework (EGF), which ensures data and sample usage adheres to scientific and ethical standards. The consent to participation will apply throughout the lifetime of the UK Biobank, unless participants withdraw, and involves the collection and storage of biological samples (blood, saliva, urine) and electronic health records (GP, hospitals, dental, prescriptions). Individual data is anonymized, with each research project receiving its own anonymized dataset. The ethics committee waived the need for written informed consent. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)