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

<p><span><strong>Objectives</strong>: </span><span>With the accumulation of genetic basis for </span><span>familial (genetic) short stature (FSS)</span><span>, 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. </span></p> <p><span><strong>Methods</strong>:</span><span> We </span><span>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 (</span><span>TWB)_height (N = 67,452) and the China Medical University Hospital (CMUH)_height GWAS summary statistics (N = 88,854). </span><span>We calculated three polygenic risk scores (PRSs) of SNPs (<em>P</em> &lt; 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 </span><span>Mendelian randomization (MR) analysis</span><span> for the causal effect of FSS and Taiwanese meta-height with/without FSS, on anthropometric, bone mineral density (BMD), and female reproductive traits</span><span>. </span></p> <p><span><strong>Results</strong>: </span><span>FSS GWAS identified 172 SNPs in 4 genomic regions, reported in height </span><span>(<em>P</em> &lt; 5 x 10^-8)</span><span>. Higher FSS genetic scores correlate with an increased risk of short stature and height reduction tendency </span><span>(</span><em><span>p</span></em> <span>&lt;</span><span> 0.001).</span><span> The causal effect showed that a higher risk of FSS was associated with decreased body height, but increased body mass index, and body fat</span> <span>(</span><em><span>p</span></em> <span>&lt;</span><span> 0.001)</span><span>. 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 </span><span>(</span><em><span>p</span></em> <span>&lt;</span><span> 0.001)</span><span>. </span></p> <p><span><strong>Conclusion</strong>: </span><span>This study </span><span>contributes to the FSS and height genetic features and their causal effects on three quantitative traits </span><span>in individuals of Han Chinese ancestry in Taiwan. </span></p>