title: Meta-analysis of gene-based genome-wide association studies of bone mineral density in Chinese and European subjects.
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.
  
  
  BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicine, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, China. lung1212@hku.hk
authors.forename: C-L
authors.initials: CL
authors.lastname: Cheung
authors.forename: P-C
authors.initials: PC
authors.lastname: Sham
authors.forename: S-M
authors.initials: SM
authors.lastname: Xiao
authors.forename: C H
authors.initials: CH
authors.lastname: Bow
authors.forename: A W-C
authors.initials: AW
authors.lastname: Kung
mesh_terms: D000328:Adult; D000368:Aged; D044466:Asian People / Q000235:genetics*; D015519:Bone Density / Q000235:genetics*; D005260:Female; D005272:Femur Neck / Q000502:physiology; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006723:Hong Kong / Q000453:epidemiology; D006801:Humans; D007055:Iceland / Q000453:epidemiology; D008159:Lumbar Vertebrae / Q000502:physiology; D008875:Middle Aged; D010024:Osteoporosis / Q000208:ethnology / Q000235:genetics* / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics*