Causal effect of familial short stature on three quantitative traits in Taiwan

Objectives: With the accumulation of genetic basis for familial (genetic)
short stature (FSS), the genetic association of FSS with health-related
outcomes remains to be elucidated. In this study, we aimed to investigate
the FSS genetic architecture and its causal effect on three quantitative
traits in Taiwan. Methods: We conducted an FSS genome-wide association
study (GWAS) analysis (1,640 FSS cases and 22,372 controls). We performed
a GWAS meta-analysis for the Taiwanese meta-height from the Taiwan Biobank
(TWB)_height (N = 67,452) and the China Medical University Hospital
(CMUH)_height GWAS summary statistics (N = 88,854). We calculated three
polygenic risk scores (PRSs) of SNPs (P < 5 x 10-8) for FSS and
Taiwanese meta-height with/without FSS, respectively. We explored the
associations between three PRSs and the measured height, respectively. We
also performed Mendelian randomization (MR) analysis for the causal effect
of FSS and Taiwanese meta-height with/without FSS, on anthropometric, bone
mineral density (BMD), and female reproductive traits. Results: FSS GWAS
identified 172 SNPs in 4 genomic regions, reported in height (P < 5
x 10-8). Higher FSS genetic scores correlate with an increased risk of
short stature and height reduction tendency (p < 0.001). The causal
effect showed that a higher risk of FSS was associated with decreased body
height, but increased body mass index, and body fat (p < 0.001).
However, higher genetic scores of Taiwanese meta-height with/without FSS
correspond with increased body height, body weight, hip circumference, and
age at menarche, but decreased BMD_T-score, BMD_Z-score, and stiffness
index (p < 0.001). Conclusion: This study contributes to the FSS
and height genetic features and their causal effects on three quantitative
traits in individuals of Han Chinese ancestry in Taiwan.