Abstract
Recent genome-wide (GW) scans have identified several independent loci affecting human stature, but their contribution through the different skeletal components of height is still poorly understood. We carried out a genome-wide scan in 12,611 participants, followed by replication in an additional 7,187 individuals, and identified 17 genomic regions with GW-significant association with height. Of these, two are entirely novel (rs11809207 in CATSPER4, combined P-value = 6.1×10−8 and rs910316 in TMED10, P-value = 1.4×10−7) and two had previously been described with weak statistical support (rs10472828 in NPR3, P-value = 3×10−7 and rs849141 in JAZF1, P-value = 3.2×10−11). One locus (rs1182188 at GNA12) identifies the first height eQTL. We also assessed the contribution of height loci to the upper- (trunk) and lower-body (hip axis and femur) skeletal components of height. We find evidence for several loci associated with trunk length (including rs6570507 in GPR126, P-value = 4×10−5 and rs6817306 in LCORL, P-value = 4×10−4), hip axis length (including rs6830062 at LCORL, P-value = 4.8×10−4 and rs4911494 at UQCC, P-value = 1.9×10−4), and femur length (including rs710841 at PRKG2, P-value = 2.4×10−5 and rs10946808 at HIST1H1D, P-value = 6.4×10−6). Finally, we used conditional analyses to explore a possible differential contribution of the height loci to these different skeletal size measurements. In addition to validating four novel loci controlling adult stature, our study represents the first effort to assess the contribution of genetic loci to three skeletal components of height. Further statistical tests in larger numbers of individuals will be required to verify if the height loci affect height preferentially through these subcomponents of height.
Highlights
Body height is determined by several biological processes that occur throughout the life of an individual and involve both normal and pathological growth
The first genetic association studies of adult height have confirmed a role of many common variants in influencing human height, but to date, the genetic basis of differences between different skeletal components of height have not been addressed
By examining nearly 20,000 individuals from the UK and the Netherlands, we provide statistically significant evidence that 17 genomic regions are associated with height, including four novel regions
Summary
Body height is determined by several biological processes that occur throughout the life of an individual and involve both normal and pathological growth. Epidemiological studies have revealed marked differences in the growth patterns for the lower and upper portions of the body. Both trunk and lower limb length are associated with parental height, birth weight and weight at age 4 years [1]. Trunk length is not correlated with nutrient intake in children, and has been shown to be negatively correlated with psychophysical stress [1]. This evidence suggests that independent growth pathways might be in part responsible for final upper and lower body size
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