Epigenetic Regulation of Human Height — New Insight from a Rare Disorder

The height of an adult is under tight genetic control — therefore it is possible to guess the likely adult height of a child based on the parents’ heights. The proportion of the genetic effect has been estimated at 80-90%. However, the average height in Finland and many other countries is slowly increasing: we grow taller than the previous generations. As genes do not change that rapidly, it was hypothesized that epigenetic effects, such as regulation of gene expression by DNA methylation, might have an influence on human height.

 

In collaboration with the Children’s Hospital at the Helsinki University Hospital, the Group Kere has for many years been studying a rare disorder called Silver-Russell Syndrome (SRS). SRS is primarily a growth-affecting disorder, and studies of its causes have implicated epigenetic mechanisms at two positions in the genome: some patients have hypomethylation at the non-coding RNA gene H19, others may have inherited two copies of chromosome 7 from their mother (and none from the father), a very rare phenomenon known as uniparental disomy. Three groups of SRS patients were studied: those with H19 hypomethylation, those with uniparental disomy, and a third group of clinically similar patients with neither molecular cause. Surprisingly, it was found that a gene on chromosome 7, generally implicated in body patterning, was abnormally methylated in most patients belonging to any of the three groups.

Next, it was studied if the methylation pattern of this gene called HOXA4 (homeobox A4) correlated with height not only in SRS patients, but also in a cohort of 39 growth-retarded children without known cause, and it was found HOXA4 hypomethylation in 44% of them. Finally, it was found out that in a cohort of 227 healthy Swedish children, HOXA4 methylation correlated loosely with height, but might explain over 4 cm of height variation at age 8. This effect was stronger than any of the best growth-associated gene variants that were studied for comparison. It was also detected that the methylation of the HOXA4 gene correlated with its expression in blood samples.

It can be concluded that the epigenetic mechanisms involving HOXA4 have a major effect on human growth. The study emphasizes that the study of rare patients may reveal common biological regulatory mechanisms.

This study is part of Mari Muurinen’s thesis to be presented 2018.

Original Study: Muurinen M, Hannula-Jouppi K, Reinius LE, Söderhäll C, Kebede Merid S, Bergström A, Melén E, Pershagen G, Lipsanen-Nyman M, Greco D, Kere J. Hypomethylation of HOXA4 promoter is common in Silver-Russell syndrome and growth restriction and associates with stature in healthy children. Sci Rep 7: 15693, 2017