Identification of two sex-specific quantitative trait loci in chromosome 11q for hip bone mineral density in Chinese.

Department of Medicine, The University of Hong Kong, Hong Kong, SAR, China.
Human Heredity (Impact Factor: 1.57). 02/2006; 61(4):237-43. DOI: 10.1159/000095216
Source: PubMed

ABSTRACT Chromosome 11q has not only been found to contain mutations responsible for the several Mendelian disorders of the skeleton, but it has also been linked to bone mineral density (BMD) variation in several genome-wide linkage studies. Furthermore, quantitative trait loci (QTL) affecting BMD in inbred mice and baboons have been mapped to a region syntenic to human chromosome 11q. The aim of the present study is to determine whether there is a QTL for BMD variation on chromosome 11q in the Chinese population.
Nineteen microsatellite markers were genotyped for a 75 cM region on 11q13-25 in 306 Chinese families with 1,459 subjects. BMD (g/cm(2)) was measured by DXA. Linkage analyses were performed using the variance component linkage analysis method implemented in Merlin software.
For women, a maximum LOD score of 1.62 was achieved at 90.8 cM on 11q21 near the marker D11S4175 for femoral neck BMD; LOD scores greater than 1.0 were observed on 11q13 for trochanter BMD. For men, a maximum LOD score of 1.57 was achieved at 135.8 cM on 11q24 near the marker D11S4126 for total hip BMD.
We have not only replicated the previous linkage finding on chromosome 11q but also identified two sex-specific QTL that contribute to BMD variation in Chinese women and men.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Genome-wide linkage scans have identified a number of quantitative trait loci (QTLs) affecting bone mineral density (BMD), mainly in the Caucasian population. In this study, we aim to determine whether seven well-replicated QTLs also contribute to BMD variation in the southern Han Chinese population. Thirty-three microsatellite markers in the proximity of seven QTLs were genotyped in 1,459 subjects from 306 families ascertained through a proband with BMD Z-score equal to or less than -1.3 at either the lumbar spine or hip. Regression-based multipoint linkage analysis was performed. In the entire study population, good linkage evidence of total hip BMD to 7p14 [maximum log of odds (LOD) score (MLS) = 2.75; nominal P = 0.0002] and 1p36 (MLS = 1.6, P = 0.003) was revealed. In the subgroup analysis of 1,166 female subjects, MLS of 3.42, 2.65, 2.42, and 1.54 were obtained on 7p12 for total hip, lumbar spine, trochanter, and femoral neck BMD, respectively. A suggestive linkage signal was achieved at 7p14-15 with a MLS of 3.38 and 3.15 for trochanter and total hip BMD in the 678 premenopausal women, and at 7p12 for femoral neck and total hip BMD with MLS of 2.22 and 3.04 in postmenopausal women. Subgroup analysis of premenopausal women also provided additional evidence of suggestive linkage of total hip BMD to 1p36, with a MLS of 2.84 at 17.07 cM. Thus, linkage of BMD to 1p36 and 7p15-13 is confirmed in southern Chinese. Computational prioritization strategy and published genome-wide association studies suggested RERE and SFRP4 as two promising candidate genes in which variants responsible for the linkage signal may be identified by follow-up gene-wide association studies.
    Journal of Bone and Mineral Metabolism 01/2011; 29(1):80-7. · 2.22 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Gene-based association approach could be regarded as a complementary analysis to the single SNP association analysis. We meta-analyzed the findings from the gene-based association approach using the genome-wide association studies (GWAS) data from Chinese and European subjects, confirmed several well established bone mineral density (BMD) genes, and suggested several novel BMD genes. The introduction of GWAS has greatly increased the number of genes that are known to be associated with common diseases. Nonetheless, such a single SNP GWAS has a lower power to detect genes with multiple causal variants. We aimed to assess the association of each gene with BMD variation at the spine and hip using gene-based GWAS approach. We studied 778 Hong Kong Southern Chinese (HKSC) women and 5,858 Northern Europeans (dCG); age, sex, and weight were adjusted in the model. The main outcome measure was BMD at the spine and hip. Nine genes showed suggestive p value in HKSC, while 4 and 17 genes showed significant and suggestive p values respectively in dCG. Meta-analysis using weighted Z-transformed test confirmed several known BMD genes and suggested some novel ones at 1q21.3, 9q22, 9q33.2, 20p13, and 20q12. Top BMD genes were significantly associated with connective tissue, skeletal, and muscular system development and function (p < 0.05). Gene network inference revealed that a large number of these genes were significantly connected with each other to form a functional gene network, and several signaling pathways were strongly connected with these gene networks. Our gene-based GWAS confirmed several BMD genes and suggested several novel BMD genes. Genetic contribution to BMD variation may operate through multiple genes identified in this study in functional gene networks. This finding may be useful in identifying and prioritizing candidate genes/loci for further study.
    Osteoporosis International 09/2011; 23(1):131-42. · 4.04 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Low bone mineral density (BMD) is a risk factor for osteoporotic fracture with a high heritability. Previous large scale linkage study in Northern Chinese has identified four significant quantitative trait loci (QTL) for BMD variation on chromosome 2q24, 5q21, 7p21 and 13q21. We performed a replication study of these four QTL in 1,459 Southern Chinese from 306 pedigrees. Successful replication was observed on chromosome 5q21 for femoral neck BMD with a LOD score of 1.38 (nominal p value = 0.006). We have previously identified this locus in a genome scan meta-analysis of BMD variation in a white population. Subsequent QTL-wide gene-based association analysis in 800 subjects with extreme BMD identified CAST and ERAP1 as novel BMD candidate genes (empirical p value of 0.032 and 0.014, respectively). The associations were independently replicated in a Northern European population (empirical p value of 0.01 and 0.004 for CAST and ERAP1, respectively). These findings provide further evidence that 5q21 is a BMD QTL, and CAST and ERAP1 may be associated with femoral neck BMD variation.
    Human Genetics 03/2011; 130(4):539-46. · 4.63 Impact Factor