# Unraveling the genetic links between stature and disease in East Asians: A multi-biobank genetic correlation and risk prediction study

## TL;DR

This study explores how genes related to height and short stature in East Asians are linked to health risks like heart and reproductive issues, offering insights for precision health strategies.

## Contribution

The study identifies novel genetic links between stature and health outcomes in East Asians using large-scale GWAS and PRS analyses.

## Key findings

- 293 loci for height and 5 for FSS were identified in Han Taiwanese individuals.
- Tall stature is genetically linked to increased risks of atrial fibrillation and endometriosis.
- Short stature shows a weak protective effect against endometriosis.

## Abstract

Both genetic and environmental factors affect human stature, including overall height and familial short stature (FSS), and it is associated with various health outcomes. However, the study of genetic connections between stature and health conditions remains lacking in East Asian populations. Hence, we conducted parallel genome-wide association studies (GWAS) of body height and FSS in the Han Taiwanese population, aiming to elucidate the genetic influences of stature on health and facilitate the formulation of precision-health strategies. We analyzed large-scale GWAS data on adult height (120,301 Han Taiwanese) and FSS (FSS; 2,050 cases, 27,966 controls) to examine cross-trait genetic correlations across five East Asian biobanks, and applied phenome-wide association studies (PheWAS) and polygenic risk score (PRS) analyses to assess clinical outcomes using Cox proportional hazard models and Kaplan–Meier analyses. We identified 293 loci for height and five for FSS, with cross-biobank genetic correlations linking stature to body size, lung function, and cardiovascular/reproductive traits (atrial flutter/fibrillation [AF], menarche, and endometriosis). PheWAS showed that height PRS increased risks of AF and endometriosis, while FSS PRS had a protective effect against endometriosis. MR analyses showed that taller stature increased AF risk independently and endometriosis risk through menarche/weight, while shorter stature had a weak protective effect against endometriosis. Survival analyses showed the association of higher height PRS with greater AF risk and an earlier divergence of cumulative incidence curves. These time-to-event patterns were consistently replicated using meta-analysis–derived PRSs. The findings highlight stature-related genetic determinants, associated health outcomes, and polygenic risk scores as effective tools for early risk prediction and precision health strategies in East Asian populations.

Adult stature, including height and familial short stature (FSS), is influenced by genetic and environmental factors. Although stature has been associated with various health conditions, the genetic basis of stature-related health risks remains underexplored, especially in East Asian populations. Herein, genome-wide association studies (GWAS) of >120,000 Han Taiwanese individuals were analyzed, and 293 loci for height and 5 for FSS were identified. Cross-trait genetic correlations were assessed across five East Asian biobanks and analyzed via phenome-wide association studies and polygenic risk score (PRS) to evaluate clinical implications. Stature traits showed strong genetic correlations with body size, lung function, and cardiovascular and reproductive conditions, particularly AF, menarche timing, and endometriosis. Tall stature was associated with increased risks of AF and endometriosis, whereas short stature conferred a weak protective effect against endometriosis. These associations, confirmed through PRS-based risk estimates and divergence in survival curves, support the use of stature-related genetics for improved disease risk stratification. Our findings indicate that stature is a genetically informed, non-modifiable risk factor with potential utility in early risk prediction and precision health for East Asian populations.