Pulmonary arterial hypertension (PAH) is a pathophysiological state of abnormally elevated pulmonary blood pressure and pulmonary vascular resistance caused by known or unknown causes (Humbert et al., 2007; Humbert et al., 2019), which can eventually lead to right heart hypertrophy, right heart failure and death. Although there have been advances in targeted therapy, surgery therapy and rehabilitation therapy, PAH remains a serious clinical condition with high mortality (Humbert et al., 2022). Also, patients with PAH may develop cognitive (Yuan et al., 2022) and psychiatric disorders (Zhang et al., 2021; Takita et al., 2021), impling a huge need for psychological and social support. In fact, PAH has placed a huge burden on global health (Delcroix and Howard, 2015). Based on those mentioned above, the presence of a lung-brain axis is suggested. The relationship between PAH and structural changes in the brain needs to be determined. Although, patients with PAH have many internal disturbances such as chronic inflammation (Huertas et al., 2020; Wang et al., 2022), oxidative stress (Pokharel et al., 2023), and neurohumoral activation (Maron et al., 2020), which may indirectly cause structural changes in the cerebral cortex (Althammer et al., 2023; Lecca et al., 2022). The direct genetically causal relationship between PAH and cortical structure is unclear.

Roy et al. (2021) first reported changes in gray matter volume in multiple brain regions in patients with PAH using magnetic resonance imaging (MRI), particularly in brain regions that regulate cognitive function. On the other hand, lifestyle has also been shown to influence the occurrence of depression by changing brain structure, suggesting a possible relationship between brain structure and neuropsychological disorders (Zhao et al., 2023). However, previous studies have shown limitations, including insufficient statistical power due to small population size, confounding factors such as sociocultural-demographic characteristics and pre-existing cerebrovascular events.

Mendelian randomization (MR) is an alternative method that uses genetic tools for intercausal exposure of risk factors associated with the disease as a proxy for exposure which are randomly assigned at the time of pregnancy, overcoming the confounding bias inherent in observational studies (Davey Smith and Hemani, 2014). Through MR analysis, several risk factors associated with PAH have been reported (Toshner et al., 2022; Zhang et al., 2023; Ulrich et al., 2020). However, the causal relationship between PAH and cerebral cortical structure has not been proven.

In this study, we use human genetic data within the MR framework to reveal the effects of PAH on cognitive function, depression, anxiety, and cerebral cortical structure, defined as human cortical thickness (TH) or surface area (SA). Our findings provide new insights into the possible existence of the lung-brain axis.