title: Linkage and association analyses using families identified a locus affecting an osteoporosis-related trait.
abstract: Osteoporosis is a common disorder characterized by low bone mass and microarchitectural deterioration of bone tissue, resulting in an increase in bone fragility and in susceptibility to fractures. The genetic basis of osteoporosis is complex and involves multiple genes and environmental factors. Here we introduce a family-based study of the genetics of osteoporosis - the Genetic Analysis of Osteoporosis (GAO) Project - to discover genetic variants affecting osteoporosis-related phenotypes. The GAO Project involved 11 extended families from Barcelona, Spain selected through a proband with osteoporosis (N=367). We performed spine, femur and whole body densitometry for all participants and also analyzed strength and geometrical properties of the hip. Our study focused on 23 densitometric phenotypes that we considered of high clinical relevance and four definitions of low bone mass and fracture status. Pedigree validation was carried out through microsatellite genotyping. The same microsatellites were used to interrogate our data (i) for the replication of previous linkage signals and (ii) for the potential discovery of new linkage signals. The linkage analysis identified one region marked by microsatellite D17S787 showing a strong and significant signal of linkage with femoral shaft cross-sectional moment of inertia (CSMI; LOD=3.18; p=6.5×10(-5)). The chromosomal location marked by microsatellite D17S787 includes several genes, among which two are of particular interest: COL1A1 and SOST, coding for collagen alpha-1 (I) chain and sclerostin, respectively. Follow-up association analysis resulted in only one significant result for rs4792909 from the SOST genomic region (p=0.00248). As a result, we provide strong and significant evidence from both linkage and association analyses that the SOST gene may affect the strength of the femoral shaft. Future investigations should study the relationship between bone mass formation and strength properties of the bones.
authors: Unit of Genomics of Complex Diseases, Research Institute, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors: Georgios
authors: G
authors: Athanasiadis
authors: Department of Internal Medicine, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors: Jorge
authors: J
authors: Malouf
authors: Department of Internal Medicine, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors: Nerea
authors: N
authors: Hernandez-Sosa
authors: Unit of Genomics of Complex Diseases, Research Institute, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors: Laura
authors: L
authors: Martin-Fernandez
authors: Unit of Genomics of Complex Diseases, Research Institute, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors: Marta
authors: M
authors: Catalan
authors: Department of Internal Medicine, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors: Jordi
authors: J
authors: Casademont
authors: Unit of Genomics of Complex Diseases, Research Institute, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. Electronic address: jsoria@santpau.cat.
authors: Jose Manuel
authors: JM
authors: Soria
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D005190:Family; D005260:Female; D056726:Genetic Association Studies; D008040:Genetic Linkage; D056426:Genetic Loci / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D010024:Osteoporosis / Q000235:genetics*; D010641:Phenotype; D020161:Physical Chromosome Mapping; D019655:Quantitative Trait, Heritable; D015203:Reproducibility of Results; D055815:Young Adult
keywords: Association; Bone mineral density; Dual energy X-ray absorptiometry; Linkage; Osteoporosis