An optimized instrument variable selection approach to improve causality estimation in association studies

Autor: Jyoti Sharma, Vaishnavi Jangale, Asish Kumar Swain, Pankaj Yadav
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: Scientific Reports, Vol 14, Iss 1, Pp 1-12 (2024)
Druh dokumentu: article
ISSN: 2045-2322
DOI: 10.1038/s41598-024-73970-z
Popis: Abstract Mendelian randomization (MR) is an emerging tool for inferring causality in genetic epidemiology. MR studies suffer bias from weak genetic instrument variables (IVs) and horizontal pleiotropy. We introduce a robust integrative framework strictly adhering with STROBE-MR guidelines to improve causality inference through MR studies. We implemented novel t-statistics-based criteria to improve the reliability of selected IVs followed by various MR methods. Further, we include sensitivity analyses to remove horizontal-pleiotropy bias. For functional validation, we perform enrichment analysis of identified causal SNPs. We demonstrate effectiveness of our proposed approach on 5 different MR datasets selected from diverse populations. Our pipeline outperforms its counterpart MR analyses using default parameters on these datasets. Notably, we found a significant association between total cholesterol and coronary artery disease (P = 1.16 × 10−71) in a single-sample dataset using our pipeline. Contrarily, this same association was deemed ambiguous while using default parameters. Moreover, in a two-sample dataset, we uncover 13 new causal SNPs with enhanced statistical significance (P = 1.06 × 10−11) for liver-iron-content and liver-cell-carcinoma. Likewise, these SNPs remained undetected using the default parameters (P = 7.58 × 10−4). Furthermore, our analysis confirmed previously known pathways, such as hyperlipidemia in heart diseases and gene ME1 in liver cancer. In conclusion, we propose a robust and powerful framework to infer causality across diverse populations and easily adaptable to different diseases.
Databáze: Directory of Open Access Journals
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