Screening Of Children's Height-related Genes And Analysis Of Their Mode Of Action

Human height is a highly hereditary,typical polygenic trait,and 80%of the height differences between individuals come from genetic factors.The preschool period(3-6 years old)is a critical period of individual growth and development,and the developmental status of this period will affect the individual's adult height.The height of preschool children has just escaped from the maternal influence and the effect of natural environment is not significant,The height velocity of children within this specific status becomes relatively smoothly growing,and the influence of genetic factors is relatively prominent.Comparing with the genetics studies about adult's height,it seems more promising to uncover the genetic bases of children's height.First all,with the sample of preschool children,it can be rather easier to isolate genetic factors of human height from individual differences and quantify their influence.Compared with the current large number of adult sample studies,the research on the height genetic factors of preschool children is not only an exploration of human height theory,but also has a broader application prospect,which is helpful for height prediction and the diagnosis and correction of developmental abnormalities.As of October 2019,a total of 32 projects have studied the genetic basis of human height,collected more than 1.65 million adult height information,and reported thousands of single nucleotides polymorphism(SNP)genetic markers and genes related to height using a genome-wide association analysis strategy.Do all these SNPs and their marked affect the height of preschool children?The impact of these genes on the growth rate of children's height and whether their effects have temporal and spatial characteristics are still unclear.Additionally,too many SNPs and genes reported to confirm which one response for human height with such GWAS studies,and SNPs and genes that are truly related to height still need to be further screened and verified.Here,11 genes(ACAN Entrez ID:176;ADAMTSL3Entrez ID:57188;ANTXR1 Entrez ID:84168;DIRC3;DYM Entrez ID:54808;FBN2 Entrez ID:2201;HMGA2 Entrez ID:8091;SERPINH1 Entrez ID:871;ZBTB38 Entrez ID:253461;ZFAT Entrez ID:57623)were screened out through bioinformatics analysis and optimization selection such as race difference analysis,function prediction,enrichment analysis,gene interaction network prediction,etc.To study the effects of these genes on the height,percentile of height,height growth rate of preschool children,and the cumulative effect of these genes on height,explore the genetic basis of human height and its function characteristics.1 The relationship between DYM,HMGA2,ZFAT and other genetic polymorphisms and heightTotally,there were 12 SNPs of these candidate genes as their genetic markers to investigate the effect of them on children height.We have completed the detection,genotyping and mathematical statistical analysis of 12 SNP genetic markers in a sample of 1067 preschool children(aged from 3 to 6 years).Results showed that:(1)The rs343093 locus of HMGA2gene and the rs202219940 locus of FBN2 gene were significantly correlated with children's height(standardized height).The height(N=1033,M±Se:0.19±0.03)of individuals with the TT genotype at the rs343093 locus of the HMGA2 gene was significantly higher than that of carriers of the C allele(N=34,M±Se:-0.41±0.16),t ₁₀₆₅=-3.56,p<0.01.The height(N=308,M±Se:0.27±0.06)of carriers of the T allele at rs202219940 of the FBN2gene was significantly higher than that of individuals with the CC genotype(N=759,M±Se:0.13±0.03),t ₁₀₆₅=-2.06,p=0.04.After controlling for age and gender,these two genes still had a significant effect on height.(2)The genetic variants of the above two genes and the percentile of height also showed a significant correlation(for rs343093:t ₁₀₆₅=-3.10,p<0.01;and for rs202219940:t ₁₀₆₅=-2.46,p=0.01).However,other sites had no significant effect on children's height and the percentile of their height(p>0.05).(3)Combining genes that have no significant effect on height and height percentiles,the cumulative effect is significantly related to children's height(?=0.10,R²=0.02,t ₁₀₄₈=3.25,p<0.01),it has a significant impact on the percentile of height(?=0.11,R²=0.01,t ₁₀₄₈=3.42,p<0.01),although the effect of most of them on children's height is too small to be grasped in current study.2 The relationship between HMGA2,FBN2,LCORL and genes and height growth rate The results of follow-up study on the height of 123 children showed that:(1)LCORL(rs73242137)was significantly correlated with the growth rate of children's height,the height growth rate of A allele carriers(N=51,M±Se:0.44±0.13)was significantly higher than that of CC genotype individuals(N=72,M±Se:0.08±0.05),t ₁₂₁=-2.67,p=0.01.HMGA2(rs1042725),ZBTB38(rs6763931)were weakly correlated with the growth rate of children's height.The height growth rate of individuals with AA genotype at HMGA2rs1042725 locus(N=37,M±Se:0.47±0.16)was higher than that of T allele carriers(N=86,M±Se:0.13±0.05),t ₁₂₁=2.00,p=0.05.The height growth rate of individuals with TT genotype at ZBTB38 rs6763931 locus(N=117,M±Se:0.26±0.06)was higher than that of individuals with AT genotype(N=6,M±Se:-0.31±0.20),t ₁₂₁=-2.01,p=0.05),other sites have no significant effect on the growth rate of children's height(p>0.05).(2)A single gene that has no significant effect on the growth rate of children's height has a significant cumulative effect(?=0.34,R²=0.12,t₁₂₁=4.01,p<0.01).Conclusion:This study screened out 11 human height-related genes from the existing 32GWAS data.Through the study of candidate genes,it was found that HMGA2 and FBN2were significantly related to the height of children;LCORL was significantly related to the growth rate of children's height,and HMGA2 and ZBTB38 were weakly related to the growth rate of children's height.It was also found that although these genes have temporal and spatial differences in the height of preschool children,the cumulative effect of multiple genes on children's height is also more significant than the effect of a single gene on children's height.