title: Genome-wide Survey of Runs of Homozygosity Identifies Recessive Loci for Bone Mineral Density in Caucasian and Chinese Populations.
abstract: Runs of homozygosity (ROHs), in which both parental alleles are identical, have been proposed to have recessive effects on multiple human complex diseases. Osteoporosis is a common complex disease characterized by low bone mineral density (BMD), which is highly heritable. And recessive loci that contribute to BMD variations have been identified. In this study, we performed a genome-wide ROHs association study using our SNP array data from three GWAS samples including 4,900 subjects from Caucasian and Chinese populations. Significant results were further subjected to replication in 3,747 additional subjects. ROHs associated with BMD were also tested for associations with osteoporotic fractures in a GWAS fracture sample. Combining results from all the samples, we identified 697 autosomal regions with ROHs. Among these, we detected genome-wide significant associations between BMD and 6 ROHs, including ROH1q31.3, 1p31.1, 3q26.1, 11q12.1, 21q22.1 and 15q22.3 (combined P = 6.29 × 10(-5)-3.17 × 10(-8)). Especially, ROH1p31.1 was found to be associated with increased risk of osteoporotic hip fractures (odds ratio [OR] = 3.71, P = 0.032). To investigate the functional relevance of the identified ROHs, we performed cis-expression quantitative trait locus (eQTL) analysis in lymphoblast cell lines. Three ROHs, including ROH1p31.1, 11q12.1, and 15q22.3, were found to be significantly associated with mRNA expression levels of their nearby genes (PeQTL < 0.05). In summary, our findings reveal that ROHs could play as recessive-acting determinants contributing to the pathogenesis of osteoporosis. Further molecular and functional studies are needed to explore and clarify the potential mechanism.
authors.affiliation: Key Laboratory of Biomedical Information Engineering of Ministry of Education and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Republic of China.
authors.forename: Tie-Lin
authors.initials: TL
authors.lastname: Yang
authors.affiliation: Key Laboratory of Biomedical Information Engineering of Ministry of Education and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Guo
authors.affiliation: School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, USA.
authors.forename: Ji-Gang
authors.initials: JG
authors.lastname: Zhang
authors.affiliation: School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Xu
authors.affiliation: School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Tian
authors.affiliation: School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, USA.
authors.forename: Hong-Wen
authors.initials: HW
authors.lastname: Deng
mesh_terms: D000368:Aged; D044466:Asian People / Q000235:genetics*; D015519:Bone Density / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006620:Hip Fractures / Q000235:genetics; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D058977:Molecular Sequence Annotation; D058866:Osteoporotic Fractures / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics; D044465:White People / Q000235:genetics*
keywords: ASSOCIATION; BMD; FRACTURES; ROHs