Integrative Analysis Confirmed the Association between Osteoprotegerin and Osteoporosis / 中国医学科学杂志(英文版)

Objective This study aimed to verify the association between osteoprotegerin gene () and its variants with osteoporosis (OP) by performing integrative analysis.Methods We used the KGG software to perform gene-based association analysis, which integrated all publicly available single-nucleotide polymorphism (SNP)-based values and obtained an overall value for the . The significant SNPs were screened for expression quantitative trait loci (eQTLs). Meta-analysis was used to combine the associations between the variants of and bone mineral density (BMD) reported in the literatures. Then we performed dual-luciferase reporter gene systems for the functional verification of the variants of .Results In the gene-based association analysis, the over all value of was 6.24×10 for BMD at femoral neck (FN) and 7.37×10 for BMD at lumbar spine (LS), indicating the importance of for OP. The publicly available eQTL database identified 5 eQTLs which exert cis-regulation effects on at FN and LS. Literature searching found that rs2073617 (known as T950C) was the hot spot SNP. There were 13 relevant studies on rs2073617 besides the GEFOS-2 study identified from the PubMed. Significant differences among TT, TC and CC genotypes at FN (= 0.047) and LS (= 0.025) were shown by meta-analysis, demonstrating the associations between T950C polymorphism and BMD. Luciferase gene expression was significantly higher at the presence of allele C than allele T in the 293T cells (=-9.47, <0.01). Conclusion The integrative analysis further confirmed the importance of in OP and the correlation of T950C polymorphism with BMD of OP. The strategy can be used as a reference for functional interpretation of other disease-related genes.

Susceptibility Genes for Multiple Sclerosis Identified in a Gene-Based Genome-Wide Association Study

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) is a demyelinating and inflammatory disease of the central nervous system. The aim of this study was to identify more genes associated with MS. METHODS: Based on the publicly available data of the single-nucleotide polymorphism-based genome-wide association study (GWAS) from the database of Genotypes and Phenotypes, we conducted a powerful gene-based GWAS in an initial sample with 931 family trios, and a replication study sample with 978 cases and 883 controls. For interesting genes, gene expression in MS-related cells between MS cases and controls was examined by using publicly available datasets. RESULTS: A total of 58 genes was identified, including 20 "novel" genes significantly associated with MS (p<1.40x10(-4)). In the replication study, 44 of the 58 identified genes had been genotyped and 35 replicated the association. In the gene-expression study, 21 of the 58 identified genes exhibited differential expressions in MS-related cells. Thus, 15 novel genes were supported by replicated association and/or differential expression. In particular, four of the novel genes, those encoding myelin oligodendrocyte glycoprotein (MOG), coiled-coil alpha-helical rod protein 1 (CCHCR1), human leukocyte antigen complex group 22 (HCG22), and major histocompatibility complex, class II, DM alpha (HLA-DMA), were supported by the evidence of both. CONCLUSIONS: The results of this study emphasize the high power of gene-based GWAS in detecting the susceptibility genes of MS. The novel genes identified herein may provide new insights into the molecular genetic mechanisms underlying MS.

ANKRD7 and CYTL1 are novel risk genes for alcohol drinking behavior / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Alcohol dependence (AD) is a complex disorder characterized by impaired control over drinking. It is determined by both genetic and environmental factors. The recent approach of genome-wide association study (GWAS) is a powerful tool for identifying complex disease-associated susceptibility alleles, however, a few GWASs have been conducted for AD, and their results are largely inconsistent. The present study aimed to screen the loci associated with alcohol-related phenotypes using GWAS technology.</p><p><b>METHODS</b>A genome-wide association study with the behavior of regular alcohol drinking and alcohol consumption was performed to identify susceptibility genes associated with AD, using the Affymetrix 500K SNP array in an initial sample consisting of 904 unrelated Caucasian subjects. Then, the initial results in GWAS were replicated in three independent samples: 1972 Caucasians in 593 nuclear families, 761 unrelated Caucasian subjects, and 2955 unrelated Chinese Hans.</p><p><b>RESULTS</b>Several genes were associated with the alcohol-related phenotypes at the genome-wide significance level, with the ankyrin repeat domain 7 gene (ANKRD7) showing the strongest statistical evidence for regular alcohol drinking and suggestive statistical evidence for alcohol consumption. In addition, certain haplotypes within the ANKRD7 and cytokine-like1 (CYTL1) genes were significantly associated with regular drinking behavior, such as one ANKRD7 block composed of the SNPs rs6466686-rs4295599-rs12531086 (P = 6.51 × 10(-8)). The association of alcohol consumption was successfully replicated with rs4295599 in ANKRD7 gene in independent Caucasian nuclear families and independent unrelated Chinese Hans, and with rs16836497 in CYTL1 gene in independent unrelated Caucasians. Meta-analyses based on both the GWAS and replication samples further supported the observed significant associations between the ANKRD7 or CYTL1 gene and alcohol consumption.</p><p><b>CONCLUSION</b>The evidence suggests that ANKRD7 and CYTL1 genes may play an important role in the variance in AD risk.</p>

Contribution of genotype and ethnicity to bone mineral density variation in Caucasians and Chinese: a test for five candidate genes for bone mass / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Ethnicity is shown to be one of important factors affecting bone mineral density (BMD). The present study was performed to compare the association of six markers for five candidate genes with BMD variation in two populations of different ethnicity, Caucasian and Chinese, and the contribution of genotype and ethnicity to this variation in the populations.</p><p><b>METHODS</b>The studied restriction fragment length polymorphisms were BsaH I of the calcium-sensing receptor gene, SacI of the alpha2HS-glycoprotein (AHSG) gene, PvuII and XbaI of the oestrogen receptor alpha gene, ApaI of the vitamin D receptor (VDR) gene and BstBI of the parathyroid hormone gene. The association of these markers with BMD was analysed by one-way and two-way ANOVA with adjustment for covariates.</p><p><b>RESULTS</b>Two polymorphisms, AHSG-SacI and VDR-ApaI, showed no association with BMD, while the others were associated with BMD variation at some skeletal sites in either males or females. The polymorphisms indicated clear distinctions between the associations depending on ethnicity, gender and skeletal site. Similar patterns were observed in their contribution to the total population BMD variation. Ethnicity appears to have a larger effect on the total population BMD variation in females than in males. It may account, on the average, for about 2% total population BMD variation at the spine of females and about 1% at the hip of males and females.</p><p><b>CONCLUSION</b>The results of the present study suggest that significant interethnic differentiation at some loci may contribute to the significant interethnic difference in BMD. However, this contribution apparently is not large.</p>