Quantitative Trait Loci for Bone Lengths on Chromosome 5 Using Dual Energy X-Ray Absorptiometry Imaging in the Twins UK Cohort

Human height is a highly heritable and complex trait but finding important genes has proven more difficult than expected. One reason might be the composite measure of height which may add heterogeneity and noise. The aim of this study was to conduct a genome-wide linkage scan to identify quantitative trait loci (QTL) for lengths of spine, femur, tibia, humerus and radius. These were investigated as alternative measures for height in a large, population–based twin sample with the potential to find genes underlying bone size and bone diseases. 3,782 normal Caucasian females, 18–80 years old, with whole body dual energy X-ray absorptiometry (DXA) images were used. A novel and reproducible method, linear pixel count (LPC) was used to measure skeletal sizes on DXA images. Intraclass correlations and heritability estimates were calculated for lengths of spine, femur, tibia, humerus and radius on monozygotic (MZ; n = 1,157) and dizygotic (DZ; n = 2,594) twins. A genome-wide linkage scan was performed on 2000 DZ twin subjects. All skeletal sites excluding spine were highly correlated. Intraclass correlations showed results for MZ twins to be significantly higher than DZ twins for all traits. Heritability results were as follows: spine, 66%; femur, 73%; tibia, 65%; humerus, 57%; radius, 68%. Results showed reliable evidence of highly suggestive linkage on chromosome 5 for spine (LOD score  =  3.0) and suggestive linkage for femur (LOD score  =  2.19) in the regions of 105cM and 155cM respectively. We have shown strong heritability of all skeletal sizes measured in this study and provide preliminary evidence that spine length is linked to the chromosomal region 5q15-5q23.1. Bone size phenotype appears to be more useful than traditional height measures to uncover novel genes. Replication and further fine mapping of this region is ongoing to determine potential genes influencing bone size and diseases affecting bone

A Polymorphism in a Gene Encoding Perilipin 4 Is Associated with Height but not with Bone Measures in Individuals from the Framingham Osteoporosis Study

There is increasing interest in identifying new pathways and candidate genes that confer susceptibility to osteoporosis. There is evidence that adipogenesis and osteogenesis may be related, including a common bone marrow progenitor cell for both adipocytes and osteoblasts. Perilipin 1 (PLIN1) and Perilipin 4 (PLIN4) are members of the PATS family of genes and are involved in lipolysis of intracellular lipid deposits. A previous study reported gender-specific associations between one polymorphism of PLIN1 and bone mineral density (BMD) in a Japanese population. We hypothesized that polymorphisms in PLIN1 and PLIN4 would be associated with bone measures in adult Caucasian participants of the Framingham Osteoporosis Study (FOS). We genotyped 1,206 male and 1,445 female participants of the FOS for four single-nucleotide polymorphism (SNPs) in PLIN1 and seven SNPs in PLIN4 and tested for associations with measures of BMD, bone ultrasound, hip geometry, and height. We found several gender-specific significant associations with the measured traits. The association of PLIN4 SNP rs8887, G>A with height in females trended toward significance after simulation testing (adjusted P = 0.07) and remained significant after simulation testing in the combined-sex model (adjusted P = 0.033). In a large study sample of men and women, we found a significant association between one SNP in PLIN4 and height but not with bone traits, suggesting that PATS family genes are not important in the regulation of bone. Identification of genes that influence human height may lead to a better understanding of the processes involved in growth and development

Meta-analysis of genome-wide scans for human adult stature identifies novel Loci and associations with measures of skeletal frame size.

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 = 6.1x10(-8) and rs910316 in TMED10, P-value = 1.4x10(-7)) and two had previously been described with weak statistical support (rs10472828 in NPR3, P-value = 3x10(-7) and rs849141 in JAZF1, P-value = 3.2x10(-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 = 4x10(-5) and rs6817306 in LCORL, P-value = 4x10(-4)), hip axis length (including rs6830062 at LCORL, P-value = 4.8x10(-4) and rs4911494 at UQCC, P-value = 1.9x10(-4)), and femur length (including rs710841 at PRKG2, P-value = 2.4x10(-5) and rs10946808 at HIST1H1D, P-value = 6.4x10(-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