Me: I found this rather short article very insightful on the deeper hormonal and genetic influences that results in the variation of height. It is a very important read.

Genetics of Stature

« Back to Volume 24, Issue 2, November 2008 – Table of Contents

Adult height is primarily (approximately 80% to 90%) determined by hereditary factors. Socioeconomic status, nutrition, and disease influence only a relatively small proportion of attained stature. It has long been suspected that there are a multitude of genes that impact upon this polygenic trait, with each gene exerting an additive but only very limited effect. From genome-wide association studies employing single nucleotide polymorphism (SNP) analyses in approximately 80,000 individuals of European ancestry (UK, Scandinavia, Holland, Iceland), these 3 investigative groups have identified more than 30 chromosomal sites and the potential genes that appear to be partially involved in the regulation of adult stature in humans (Table). Gudbjartsson et al divided the candidate genes into 3 functional groups—those associated with skeletal development (eg, BMP2, BMP6), those that encode zinc-dependent metalloproteinases (ADAMTS10) and glycoproteins (eg, FBN1) that affect cartilage composition, and those that are involved with the processes of chromosome segregation and mitosis (eg, CDK6, HMGA2). The gene most frequently associated with stature in all 3 studies was ZBTB38. This zinc-finger protein binds methylated DNA—specifically the methylated allele of the differentially methylated region of H19/IGF2.¹ This is the site at which epigenetic errors of imprinting result in either the Beckwith-Wiedemann syndrome (OMIM 130650) of somatic overgrowth or the growth retardation syndrome of Russell-Silver (OMIM 180860).² ZBTB38 represses transcription of methylated regions. Thus, it is interesting to speculate that ZBTB38 might affect adult stature through regulation of the production of insulin-like growth factor (IGF)-II, perhaps during in utero development when IGF-II is known to be one of the determinants of fetal growth. Independent of its effect on methylated DNA, ZBTB38 also regulates transcription of TH, the gene encoding tyrosine hydroxylase, the rate-limiting step in catecholamine synthesis. Other commonly identified gene candidates were HMGA2 encoding a chromatin architectural factor and CDK6 encoding a cyclin dependent kinase regulator of the cell cycle.

While each of these candidate genes has only a small effect upon adult height (estimated 0.4 cm), collectively they can exert significant influence and account for only approximately 4% of adult stature. The more “tall” alleles one has, the taller the individual (Figure). In the study of Weedon et al, there was a 5 cm difference in adult stature between subjects with 17 or fewer “tall” alleles compared to those with 27 or more.

Gudbjartsson DF, Walters GB, Thorleifsson G, et al. Many sequence variants affecting diversity of adult human height. Nat Genet. 2008;40:609-15.

Lettre G, Jackson AU, Gieger C, et al. Identification of 10 loci associated with height highlights new biological pathways in human growth. Nat Genet. 2008;40:489-90.

Weedon MN, Lango H, Lindgren CM, et al. Genome-wide association analysis identifies 20 loci that influence adult height. Nat Genet. 2008;40:573-83.

First Editor’s Comment

These reports are of great interest as they dramatically illustrate just how many genes must be involved in the determination of adult stature. They also illustrate the quantitative problem that the clinician will face in identifying the “cause” of genetic short stature in a specific patient. However, it was difficult to critically examine the data because some of it was derived by meta-analysis of previously published reports. Thus, it was unclear whether or not there may have been some overlap between analytical data utilized in the 3 reports. The reports are also difficult to interpret because the investigators employed different probes for similar or related SNP sites. For example, ZBTB38 was identified as SNP rs724016 in the report of Lettre et al, as SNP rs6440003 in the report of Weedon et al, and as SNP rs6763931 in the report of Gudbjartsson et al. [A brief expository review of genome-wide association studies and SNPs has been written by Christensen and Murray.³]

Allen W. Root, MD

Second Editor’s Comment

Fisher proposed in 1918 that many genetic factors, each having an individually small effect, explain the heritability of height.⁴ Much attention has been devoted since that time to identifying these factors. For instance, numerous genes have been identified that harbor mutations responsible for the osteochondrodysplasias and other syndromes associated with severe short stature, but in general these genes do not seem to influence the normal continuous variation in stature. Although linkage studies have elucidated chromosomal regions that affect height variation, they have not identified specific gene loci that influence height in the general population. It has not been until the recent application of genome-wide association (GWA) studies that significant headway has been made. This approach takes advantage of high-throughput analysis of single nucleotide polymorphisms (SNPs) identified through the so called HapMap project, a growing number of patient groups for whom DNA is available for analysis and advances in computational methods that enable such analysis and permit datasets to be combined. Indeed, one of the first GWA investigations of height was reviewed in GGH.⁵ This reviewed study has now been expanded substantially and joined by 3 other large GWA studies as reported in the May 2008 Nature Genetics. The new investigations have utilized more rigorous multi-stage experimental designs to analyze hundreds of thousands of SNP markers in ~63,000 individuals measured for adult height.

The report by Weedon et al identified 20 genetic variants which, in the aggregate, account for ~3% of height variation in adults of European ancestry. The identified SNP markers do not influence height per se, but they implicate genes within which or nearby to which they reside. One can envision how most of the candidate genes implicated in this manner could influence growth as they encompass growth factors and their receptors, proteins that interact with or alter the extracellular milieu of growth factors and proteins that modulate intracellular signaling or are linked to cell cycle regulation or cancer. Most notable here are Indian hedgehog (IHH), Hedgehog interacting protein (HHIP) and Patched 1 (PTCH1), which belong to the Hedgehog pathway, growth and differentiation factor 5 (GDF5), suppressor of cytokine signaling 2 (SOCS2) and cyclin-dependent kinase-6 (CDK6). The previous association with a marker near the high mobility group-A2 (HMGA2) gene locus was confirmed.

The report by Lettre et al identified 10 loci associated with height variation also in adults of European ancestry, 4 of which were the same as in the Weedon report including HHIP. These authors emphasized that 3 of the candidate genes—HMGA2, the histone methyltransferase DOT1L and the methyl-DNA-binding transcriptional repressor gene ZBT38—are involved in chromatin remodeling. They note that the 3’ untranslated region of HMGA2 contains the largest number of let-7 microRNA binding sites and that 3 of the other implicated genes, CDK6, DOT1L and LIN28B, a gene upregulated in hepatocellular carcinoma, are considered targets of let-7. MicroRNAs, such as let-7, are small, nontranslated RNAs that down regulate expression of target genes.

The report by Gudbjartsson et al detected 27 genomic regions in which SNP variants were associated with adult height. Their data came from individuals with Icelandic, Dutch, European- and African-American ancestries and results accounted for 3.7% variation in adult height. Several of the implicated genes were the same as in the other 2 reports, but a few additional genes were indentified including BMP2, BMP6 and the TGF-β and BMP inhibitor, Noggin (NOG).

In contrast to the GGH abstract⁵ describing a single SNP association with adult height published in May 2008, these new reports identify 54 gene loci that influence variation in height in adults primarily of European descent. As noted in the accompanying editorial by Visscher,⁶ it is reassuring that SNPs previously observed to associate with height were confirmed, SNPs in 3 genes were found associated with height in all 3 studies, and 7 genes were implicated in 2 of the 3 investigations. It is not surprising that variation in genes involving growth factors or modulation of growth factor signaling pathways influence height. More intriguing and novel is the implication of genes involved in chromatin remodeling and in microRNA regulation of gene expression. The papers illustrated the power of GWA studies and also the necessity of very large sample sizes creating consortia of research groups and even consortia of consortia as stated by Visscher.⁶

William A. Horton, MD