As much as 90 percent of variation in adult height may be caused by genetic inheritance, but a multitude of genes are involved. Most of these have yet to be discovered.
Now a new meta-analysis of data from more than 100,000 people has identified variants in over two dozen genes that were not previously associated with height. The study also confirmed genetic associations in more than 30 previously known height genes. "Although the discoveries may not have immediate clinical use, the approach we used will undoubtedly be helpful in discovering genes that influence other traits and diseases," said the co-study leader, Hakon Hakonarson, M.D., Ph.D., director of the Center for Applied Genomics at The Children's Hospital of Philadelphia.
Using an existing gene chip customized to include approximately 50,000 SNPs (single-base changes in one letter of DNA's genetic code) in genes having a high likelihood of association with cardiovascular disease, the study team searched variants for SNPs linked to adult height. This study, said Hakonarson, which used height as a lead phenotype for a gene-rich SNP chip enhanced in rare variant coverage, suggests that such platforms will succeed in identifying genetic variants that contribute to multiple other cardiovascular diseases, and potentially to other complex traits.
"This is a proof-of-concept that more dense genotyping of selected gene-rich datasets allows us to find additional genes that have gone undetected in studies using conventional SNP arrays," said Hakonarson. Hakonarson and co-study leader Brendan J. Keating, D.Phil., also from the Center for Applied Genomics, led the large, international collaborative group whose study appeared online Dec. 30 in the American Journal of Human Genetics.
Many of the variants are in locations with interesting functional roles—in energy metabolism, growth hormones, circadian rhythm and cellular growth—of possible relevance to the biology of growth. The study team identified 64 height-associated genes, 27 of which had not been previously associated with height.
The meta-analysis included DNA from over 114,000 adults from six ethnic groups. The researchers used the IBC array, also called the CardioChip, previously designed by Keating to study genes identified or postulated to play a role in cardiovascular disease. The chip includes some 50,000 SNPs from 2,000 gene regions—about 10 percent of known human genes.
The researchers chose height as an easy-to-measure trait that is highly heritable, usually stable over adult life, and routinely recorded in large population-based studies. The CHOP scientists analyzed gene data from over 65,000 individuals, and Keating collaborated with researchers at dozens of centers throughout the world who genotyped samples from another 48,000 additional study subjects. In all, 47 studies contributed to this meta-analysis.
The specialized gene array provided very dense coverage in known and putative cardiovascular disease regions. The array's design allowed the researchers to capture richer genetic diversity from many resequencing studies and to detect SNPs with low frequency in many diverse human populations. Two of the novel uncommon SNP findings were in genes with compelling evidence of a biological role in determining height. The IL-11 gene is essential to normal bone development and the SMAD3 gene is made active by a growth factor involved with height. Many of the low-frequency SNPs, said the researchers, have strong effects, and may point the way to functional genes.
The researchers used a gene-centric approach, employing an array enriched with specific genes and avoiding non-coding sections of the genome. "The chip we used has high-density genetic coverage in a range of highly prioritized genes, and similar high-density chips may be useful in studying other complex genetic traits," said Hakonarson.
He added that "This discovery method is currently much less expensive than full-genome sequencing, which, as the technology advances, is becoming increasingly prevalent in identifying lower-frequency, disease-related genes. The near future may offer a window of opportunity for this type of technique, using large samples and dense genetic coverage, until whole-genome sequencing becomes more affordable."
Keating said that these results suggest that if the sample sizes are large enough, genotyping arrays with SNP content of less than 5 percent frequency in the population have the ability to capture new disease- and trait-associated variants that common SNP arrays have missed. These low-frequency variants also confer greater effect sizes in this study and may be a lot closer to disease causality.
"Meta-Analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height," American Journal of Human Genetics, published online Dec. 30, 2010, to publish in January 2011 print edition. doi: 10.1016/j.ajhg.2010.11.007
About The Children's Hospital of Philadelphia: The Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals and pioneering major research initiatives, Children's Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country, ranking third in National Institutes of Health funding. In addition, its unique family-centered care and public service programs have brought the 460-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit http://www.chop.edu.
John Ascenzi | EurekAlert!
Nanoparticle Exposure Can Awaken Dormant Viruses in the Lungs
16.01.2017 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt
Cholera bacteria infect more effectively with a simple twist of shape
13.01.2017 | Princeton University
Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales
Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...
Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.
As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...
At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).
Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...
Many pathogens use certain sugar compounds from their host to help conceal themselves against the immune system. Scientists at the University of Bonn have now, in cooperation with researchers at the University of York in the United Kingdom, analyzed the dynamics of a bacterial molecule that is involved in this process. They demonstrate that the protein grabs onto the sugar molecule with a Pac Man-like chewing motion and holds it until it can be used. Their results could help design therapeutics that could make the protein poorer at grabbing and holding and hence compromise the pathogen in the host. The study has now been published in “Biophysical Journal”.
The cells of the mouth, nose and intestinal mucosa produce large quantities of a chemical called sialic acid. Many bacteria possess a special transport system...
UMD, NOAA collaboration demonstrates suitability of in-orbit datasets for weather satellite calibration
"Traffic and weather, together on the hour!" blasts your local radio station, while your smartphone knows the weather halfway across the world. A network of...
10.01.2017 | Event News
09.01.2017 | Event News
05.01.2017 | Event News
17.01.2017 | Machine Engineering
17.01.2017 | Physics and Astronomy
16.01.2017 | Power and Electrical Engineering