Gastroesophageal reflux disease (GERD) is a highly prevalent condition with substantial clinical and public health impact. Although historically viewed as a disorder driven by esophageal motility dysfunction and mucosal injury, accumulating evidence points to a more complex etiology involving epithelial integrity, immune activation, sensory processing, and central neural regulation (Azer and Goosenberg, 2025). In parallel, GERD shows strong epidemiological comorbidity with several psychiatric disorders, including major depression, anxiety disorders, post-traumatic stress disorder, and attention-deficit/hyperactivity disorder (Ding et al., 2025). These co-occurrence patterns suggest that shared biological pathways may contribute to susceptibility across both gastrointestinal and mental health domains.

Genome-wide association studies (GWAS) have identified numerous loci associated with GERD and psychiatric traits; however, most existing studies have been conducted in European-ancestry populations (An et al., 2019; Anurag et al., 2024). The genetic architecture of complex diseases often differs across ancestral groups due to variation in allele frequencies, linkage disequilibrium (LD) structure, and environmental exposures. As a result, the transferability of European-derived findings to East Asian populations remains limited, and ancestry-specific genetic determinants of GERD and psychiatric disorders are still poorly understood. Given the unique LD patterns and allele distributions in East Asians, leveraging population-specific GWAS offers an opportunity to uncover novel shared mechanisms that may not be detectable in European datasets.

Traditional single-trait GWAS may lack the statistical power to fully resolve the polygenic overlap between GERD and psychiatric disorders. Recently developed conditional false discovery rate (condFDR) approaches provide a powerful framework for enhancing genetic discovery by exploiting cross-trait enrichment patterns (Smeland et al., 2019). By conditioning GERD association statistics on the strength of association with a genetically correlated trait, condFDR increases sensitivity to detect true GERD risk loci, including those with sub-genome-wide effects. This strategy is particularly advantageous in East Asian populations, where sample sizes for individual traits are still modest compared to large European consortia, yet shared polygenic structure can be leveraged to boost effective statistical power (Wang et al., 2025; Zhi et al., 2025; Song et al., 2025; Yang L. et al., 2025).

In this study, we performed a comprehensive condFDR analysis of GERD and multiple psychiatric disorders specifically within East Asian populations. Our primary aim was to identify novel GERD susceptibility loci through cross-trait genetic architecture. By integrating East Asian GWAS resources with cross-trait enrichment models, our work seeks to expand the catalog of GERD-associated loci, illuminate ancestry-specific biology, and clarify the genetic links between gastrointestinal and psychiatric phenotypes.

In this study, we investigated the shared genetic architecture between GERD and major psychiatric disorders specifically within East Asian populations, integrating ancestry-matched GWAS, cross-trait heritability analyses, and condFDR methods. Although single-trait GERD GWAS in East Asians lacked genome-wide significant findings—largely reflecting modest sample sizes relative to European consortia—our cross-phenotype analytic framework revealed previously unrecognized susceptibility loci by leveraging genetic enrichment with psychiatric traits. These results demonstrate that substantial biological insight can be gained even from underpowered datasets when multivariate genetic information is appropriately incorporated.

Our LDSC analyses highlight meaningful polygenic covariance between GERD and both MDD and SCZ in East Asians. This observation is consistent with extensive epidemiological evidence documenting elevated rates of depressive and psychotic symptoms among individuals with reflux-related disorders. Importantly, the presence of positive genetic correlations suggests that shared heritable liabilities—rather than environmental confounding alone—contribute to these comorbidity patterns. The absence of detectable genome-wide overlap with BIP underscores the specificity of these links and supports the notion that GERD shares genetic substrates selectively with certain psychiatric dimensions, particularly those related to mood regulation and cognitive–perceptual processing.

By applying condFDR, we identified two loci—near MEIS1 and ZBTB20—that would not have been captured by single-trait GERD analyses. Both genes have established roles in neurodevelopment and higher-order brain functions, pointing to central neural pathways as potential mediators of GERD liability. MEIS1 participates in autonomic network development and sensory integration, offering a plausible biological mechanism through which variation at this locus could influence esophageal sensation, pain perception, or reflexive motor control. Similarly, ZBTB20 regulates cortical and hippocampal maturation, with downstream effects on stress responsivity, visceral perception, and neuroimmune signaling. The observation that rs9844126 is an eQTL for ZBTB20 further supports the interpretation that regulatory variation affecting this transcription factor may shape both psychiatric vulnerability and GERD risk via shared neural or systemic pathways.

More broadly, these findings reinforce emerging evidence that gastrointestinal disorders with prominent sensory or pain components exhibit genetic and biological convergence with psychiatric traits. Such convergence likely reflects the intertwined nature of the neural circuits governing affect, interoception, autonomic function, and gastrointestinal physiology. By conducting these analyses in East Asian populations, our study also underscores the value of ancestry-specific genetic investigation. The loci identified here may represent risk variants that are more detectable—or perhaps even unique—in the East Asian genomic landscape due to population-specific allele frequencies and linkage disequilibrium patterns.

Several limitations warrant consideration. First, the available East Asian GERD GWAS datasets remain modest in sample size, which constrains statistical power for locus discovery and fine-mapping and likely contributes to the absence of genome-wide significant loci in the primary GERD GWAS meta-analysis. As a result, loci highlighted through downstream cross-trait analyses using condFDR should be interpreted as exploratory and hypothesis-generating, rather than definitive GERD risk loci, and will require confirmation in larger and independent GERD GWAS datasets. In addition, GERD is a clinically heterogeneous phenotype, and the contributing GWAS primarily relied on clinical diagnoses or standardized phenotype definitions within individual cohorts. Such heterogeneity may capture overlapping but not identical clinical presentations and is therefore expected to attenuate effect sizes and reduce sensitivity, rather than introduce spurious associations. Consequently, the shared genetic signals observed in this study are likely to reflect core biological components common across GERD definitions. Psychiatric traits, while substantially powered in some cases, also exhibit heterogeneity in ancestry composition and phenotypic ascertainment, which may influence the sensitivity of cross-trait analyses. Moreover, the cross-trait analyses in this study were limited to major depressive disorder, schizophrenia, and bipolar disorder, reflecting the availability of well-powered GWAS summary statistics in East Asian populations. Other relevant psychiatric and stress-related phenotypes, such as anxiety-related traits or ADHD, could not be examined and should be explored in future studies as suitable datasets become available. Finally, although genes such as MEIS1 and ZBTB20 were highlighted through integrative genetic analyses, the mechanistic links inferred here remain speculative and require experimental validation in relevant neural and peripheral tissues. Independent replication and functional validation using complementary datasets were not feasible given current data availability. Future studies incorporating larger multi-ancestry meta-analyses, refined phenotyping, and cell-type–specific functional genomics—particularly within brain–gut axis models—will be essential to further delineate causal pathways.

In summary, our study demonstrates that cross-trait genetic enrichment can substantially enhance locus discovery for GERD in East Asian populations and reveals shared neurobiological architecture with major depressive disorder and schizophrenia. These results provide a foundation for refining mechanistic models of GERD that incorporate central neural regulation and highlight the importance of considering psychiatric dimensions in understanding the genetic basis of gastrointestinal disorders.