3 min readNew Study Begins to Uncover the Skeletal Basis of Variation in Height

A new study has delved deeper than ever before into understanding the genetic basis of adult human height. The study using exploratory statistical analyses to uncover how 17 genetic variants that are implicated in human height affect the length of particular skeletal components of the body, used as a proxy for height subcomponents.

 
Hinxton, UK – A new study has delved deeper than ever before into understanding the genetic basis of adult human height. The study using exploratory statistical analyses to uncover how 17 genetic variants that are implicated in human height affect the length of particular skeletal components of the body, used as a proxy for height subcomponents.
The research opens the door to a better understanding of the developmental pathways that contribute to human height. Four of the variants that the team described as associated with height had not previously been identified.
According to the report from the Wellcome Trust Sanger Institute, researchers at the institute led an international consortium of investigators from Canada, Israel, the Netherlands and UK to study approximately 20,000 individuals, searching for regions in the genome that were associated with differences in height. By looking through 300,000 known SNPs – single letter changes in genetic code – the team found 17 regions that contributed to human height. To understand better how variation at these regions contributed to height, the team took skeletal measurements of the spine, leg and hip-axis, to determine the specific effects of these genetic markers on the length of skeletal size measurements.
“The statistical analysis of height subcomponents poses challenges due to the high correlation among the different traits,” explains Dr Nicole Soranzo, Sanger Institute researcher and lead author on the study. “There have been a handful of genome-wide association studies that have concentrated on height in the past, but the impact of variants on the different skeletal subcomponents of height has never been investigated. The study begins to clear a path for research that goes beyond looking at associations, to look at biological processes involved in differential height components.”
Genetic regions that play a role in increased human height have, in the past, been uncovered in genome-wide association studies. Height is relatively easy to measure simply and accurately. However, to look at the contribution of individual skeletal components is considerably more complicated.
“Overall height can mask differences in the skeletal components: researchers need to tease apart the contribution of genetic loci to each of these components. Our study is a first attempt towards this goal but much larger samples will be needed to accomplish it,” explains Dr Panos Deloukas, senior investigator at the Sanger Institute and coordinator of the consortium. “The final upper or lower body size of humans might be the result of independent growth pathways that need to be understood.”
The team wanted to elucidate how the 17 variants strongly associated with adult height impacted on the length of individual skeletal components. To measure the length of the skeletal components the team used data from high-resolution densitometric scans of human bones. Nine of the variants were associated with increased trunk length; approximately 5% of the variance in femur length was explained by a combination of all of the variants. Seven of the variants influenced hip-axis length, which is a known predictor for osteoporosis in humans.
The height of an individual is composite of many genetic influences and each genetic region identified so far adds less than half a centimetre to the height of the individual carrying the underlying variant. In total the 17 regions, reported in this study, account for approximately 2-3% of the variance in height of the sample. The four novel height loci discovered bring the total number of genes implicated in human height to 47. These genes appear to be involved in a variety of processes: from DNA replication to intercellular signalling, cell division and skeletal development.
“The array of gene functions underlying the determination of human height are already starting to show links to several human diseases,” says Dr Fernando Rivadeneira, Assistant Professor at the Erasmus MC and co-lead author on the study. “For instance, our current finding on GDF5 – one of the genes associated with hip-axis length – provides further understanding to our previous finding, where we found GDF5 associated with osteoarthritis and bone fracture susceptibility. Similarly, many other height loci with demonstrated overgrowth functions have a known role in human cancers. In-depth analysis of the way in which common variants in genes have modest effects on people’s height can provide important insights into understanding the causes of human diseases.”
As well as developing new methodological principles for study in this area, the researchers’ findings could lead to the discovery of medically important genetic regions for several human diseases. More research and replication using larger samples will strengthen the results and might lead to a more developed understanding of clinical effects.
“This exciting area of research is ripe for further investigation,” explains Professor Tim Spector, Director of the TwinsUK project at Kings College London. “We are beginning to understand the genetic basis, not just of human height, but of how individual bones develop. This research underscores the importance of using highly characterised human populations and will help understand musculoskeletal disease in humans.”

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