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Background: Bone size is an important determinant of bone strength and is under strong genetic control. Objective: To identify quantitative trait loci (QTL) for areal bone size variation, a large-scale genomewide linkage scan was carried out in 451 Caucasian families. Participants and methods: Of 4124 people with phenotypes, 3899 were genotyped with 410 microsatellite markers. Multipoint linkage analyses were carried out in the entire sample, as well as in men and women separately. Potential epistatic interactions between identified genomic regions were also assessed. Results: Several potentially important genomic regions were identified, such as 8q24 for hip bone size (logarithm of the ratio of the odds that two loci are linked (LOD) 3.27) and 2p24 (LOD 2.04) for spine bone size. 8q24 may also interact with 19p13 to affect hip bone size. Several sex-specific QTL were also detected, such as 14q21 (LOD 2.94) for wrist bone size in women and 16q12 (LOD 2.19) for hip bone size in men. Conclusions: Together with previous findings, this study has further delineated the genetic basis of bone size and laid a foundation for future studies to eventually elucidate the mechanisms of bone size regulation and associated fracture risks. [ABSTRACT FROM AUTHOR]

This article presents information about a study which determines the importance of oestrogen receptor α (ESR1) gene for the onset of menstruation. In the study, the sample was composed of 939 female offspring from 304 white families. There were two to eight female offspring in each family, giving a total of 1140 sister pairs. Subsequently results show that two single nucleotide polymorphisms in the ESR1 gene, rs3778082 and rs2228480, were associated with menarcheal age. According to the results of the linkage and association studies, the ESR1 gene may have an effect on menarcheal age.

Background: The vitamin D receptor (VDR) gene is important to human stature, as it mediates metabolic pathways, calcium homeostasis, and phosphate homeostasis, which influence growth. Methods: We examined the relationship between VDR and adult height in 1873 white subjects from 406 nuclear families. Four SNPs, namely -4817A/G at intron 1, Fokl C/T at exon 2 start codon, Bsml A/G at intron 8, and Taql T/C at exon 9 in VDR were tested for linkage and association with adult height variation by the program QTDT (quantitative transmission disequilibrium test). The bT haplotype of the Bsml and Taql loci was further tested far its association with height in unrelated samples randomly chosen from the 406 nuclear families by traditional population association methods. Results: All four tested SNPs were linked to adult height. Within family associations with height were detected at Bsml and Taql loci (p=0.048 and 0.039, respectively). Analyses based on Bsml/Taql haplotypes also revealed evidence for linkage (p = 0.05) and association (p = 0.001) with height. The bT haplotype was significantly associated with higher adult height (p = 0.033, within family association test). Such an association might be female specific and influenced by menstrual status. Conclusions: Our results strongly suggest that VDR may be linked to and associated with adult height variation in white popuations. [ABSTRACT FROM AUTHOR]

Background: The haplotype based association method offers a powerful approach to complex disease gene mapping. In this method, a few common haplotypes that account for the vast majority of chromosomes in the populations are usually examined for association with disease phenotypes. This brings us to a critical question of whether rare haplotypes play an important role in influencing disease susceptibility and thus should not be ignored in the design and execution of association studies. Methods: To address this question we surveyed, in a large sample of 1873 white subjects, six candidate genes for osteoporosis (a common late onset bone disorder), which had 29 SNPs, an average marker density of 13 kb, and covered a total of 377 kb of the DNA sequence. Results: Our empirical data demonstrated that two rare haptotypes of the parathyroid hormone (PTH)/PTH related peptide receptor type 1 and vitamin D receptor genes (PTHR 1 and VDR) with frequencies of 1.1% and 2.9%, respectively, had significant effects on osteoporosis phenotypes (p = 4.2 × 10-6 and p = 1.6 × 10-4, respectively). Large phenotypic differences (4.0sim;5.0%) were observed between carriers of these rare haplotypes and non-carriers. Carriers of the two rare haplotypes showed quantitatively continuous variation in the population and were derived from a wide spectrum rather than from one extreme tail of the population phenotype distribution. Conclusions: These findings indicate that rare haplotypes/variants are important for disease susceptibility and cannot be ignored in genetics studies of complex diseases. The study has profound implications for association studies and applications of the HapMap project. [ABSTRACT FROM AUTHOR]

Background: Osteoporosis is a major public health problem, mainly quantified by low bone mineral density (BMD). The majority of BMD variation is determined by genetic effects. A pilot whole genome linkage scan (WGS) was previously reported in 53 white pedigrees with 630 subjects. Several genomic regions were suggested to be linked to BMD variation. Objective: To substantiate these previous findings and detect new genomic regions. Methods: A WGS was conducted on an extended sample where the size was almost tripled (1816 subjects from 79 pedigrees). All the subjects were genotyped with 451 microsatellite markers spaced -8.1 cM apart across the human genome. Two point and multipoint linkage analyses were carried out using the variance component method. Results: The strongest linkage signal was obtained on Xq27 with two point 100 scores of 4.30 for wrist BMD, and 2.57 for hip BMD, respectively. Another important region was 11 q23, which achieved a maximum LOD score of 3.13 for spine BMD in multipoint analyses, confirming the results on this region in Iwo earlier independent studies. Suggestive linkage evidence was also found on 7p14 and 20p12. Conclusions: Together with the findings from other studies, the current study has further delineated the genetic basis of bone mass and highlights the importance of increasing sample size to confirm linkage findings and to identify new regions of linkage. [ABSTRACT FROM AUTHOR]

Tests the linkage and association of two genes with obesity phenotypes by investigating single nucleotide polymorphisms. Involvement of apolipoprotein E and transforming growth factor beta in lipid metabolism and adipocyte differentiation; Use of the quantitative transmission disequilibrium test; Body mass index; Percentage fat mass; Use of dual energy X-ray absorptiometry.