A two-sample Mendelian randomization analysis of the impact of GABA receptor subtypes on human height

Gamma-aminobutyric acid (GABA) supplements are increasingly marketed for promoting growth, yet the genetic influence of GABA receptor subtypes on human height remains unexplored. This Mendelian randomization (MR) study aimed to investigate the causal relationships between genetically predicted plasma levels of 2 GABA receptor subtypes (GABRA4 and GABRB2), and height-related outcomes, including body height (BH), idiopathic short stature (ISS), and constitutional tall stature (CTS). This study employed a two-sample MR approach to assess the causal effect of GABA receptor subtypes, specifically GABRA4 and GABRB2, on height-related traits. Genetic instruments for GABRA4 and GABRB2 were obtained from the UK Biobank Pharma Proteomics Project and INTERVAL study. Outcome data, including BH, ISS, and CTS, were sourced from large-scale genome-wide association studies, including datasets from the FINNGEN study, European Bioinformatics Institute (EBI), and the GIANT Consortium. The inverse variance-weighted method was employed as the primary analytical approach to estimate the causal effects. Sensitivity analyses included MR-Egger regression and the weighted median method to assess for pleiotropy and ensure robustness. Additionally, the MR-PRESSO method was applied to identify and exclude outlier SNPs with potential horizontal pleiotropy, further enhancing the reliability of the causal estimates. Our MR analysis revealed no significant associations between genetically predicted GABRA4 and height-related outcomes after Benjamini–Hochberg correction. In contrast, GABRB2 was positively associated with BH in the EBI dataset (β = 0.0203; P  = 1.737e ⁻⁰⁵ ), but this association was not replicated in the other datasets. No significant associations were observed for GABRB2 with ISS (OR = 0.82, P  = .165) or CTS (OR = 1.47, P  = .259). Sensitivity analyses did not suggest any pleiotropic effects. Our MR analysis did not reveal significant causal relationships between GABRA4 or GABRB2 and height-related outcomes, such as BH, ISS, and CTS. To the best of our knowledge, this is the first study to explore the GABA receptor subtypes on human height. This novel approach provides important evidence refuting any direct association between these receptors and human height, filling a critical gap in the existing literature.