Association of human height-related genetic variants with familial short stature in Han Chinese in Taiwan

Ying-Ju Lin,Ting-Hsu Lin,Chiu-Chu Liao,Wen-Kuei Chien,Chien-Hsiun Chen,Jer-Yuarn Wu,Jin-Hua Chen,Chi-Fung Cheng,Li-Ping Tsai,Fuu-Jen Tsai,Chih-Hsin Tang,Chung-Hsing Wang,Ai-Ru Hsieh,Wen-Ling Liao,Shao-Mei Huang,Chia-Ming Wu,Wen-Miin Liang

doi:10.1038/s41598-017-06766-z

Abstract

Human height can be described as a classical and inherited trait model. Genome-wide association studies (GWAS) have revealed susceptible loci and provided insights into the polygenic nature of human height. Familial short stature (FSS) represents a suitable trait for investigating short stature genetics because disease associations with short stature have been ruled out in this case. In addition, FSS is caused only by genetically inherited factors. In this study, we explored the correlations of FSS risk with the genetic loci associated with human height in previous GWAS, alone and cumulatively. We systematically evaluated 34 known human height single nucleotide polymorphisms (SNPs) in relation to FSS in the additive model (p < 0.00005). A cumulative effect was observed: the odds ratios gradually increased with increasing genetic risk score quartiles (p < 0.001; Cochran-Armitage trend test). Six affected genes—ZBTB38, ZNF638, LCORL, CABLES1, CDK10, and TSEN15—are located in the nucleus and have been implicated in embryonic, organismal, and tissue development. In conclusion, our study suggests that 13 human height GWAS-identified SNPs are associated with FSS risk both alone and cumulatively.

Highlights

Human height can be described as a classical, inherited, and polygenic trait model
familial short stature (FSS) risk, we chose genetic single nucleotide polymorphisms (SNPs) that have been related to human height according to published genome-wide association studies (GWAS), which were considered to be the closest genes potentially associated with FSS
34 SNPs were identified as candidate susceptibility SNPs for FSS according to the selection criteria [call rates of genotyping for both FSS and controls >95%, genotypes for genetic variants in controls conforming to Hardy-Weinberg equilibrium (p > 0.05), and p-value for the additive model

Summary

Introduction

Human height can be described as a classical, inherited, and polygenic trait model. The ultimate phenotype represents the outcome of genetics and developmental biology, including the enlargement of bone length and the sizes of tissues and organ sizes. The results of genome-wide association studies (GWAS) have contributed new information on the susceptibility loci related to human height and provide insights into the extreme polygenic nature of human height. Representing the majority of cases of short stature, FSS is characterized by a height below the 3rd percentile in the population, a normal annual growth rate, normal bone age, family history of short stature, normal onset of puberty, and normal results of biochemical analyses. FSS represents a very suitable study object for research on short stature genetics because disease association has been ruled out for the short stature in FSS. We explored the associations of FSS risk in Taiwan with genetic loci that have been related to human height according to previous GWAS, both alone and cumulatively

Methods

Results

Conclusion