Genetic causes and underlying disease mechanisms in early-onset osteoporosis

Sammanfattning: Adult-onset osteoporosis is a disorder that affects a significant proportion of the elderly population worldwide and entails a substantial disease burden for the affected individuals. Childhood-onset osteoporosis is a rare condition often associating with a severe bone disease and recurrent fractures already in early childhood. Both childhood-onset and adult-onset osteoporosis have a large genetic component, but in children the disorder is usually genetically less complex and often caused by a single gene variant. This makes genetic studies a well-suited approach to explore primary osteoporosis in children, which is the focus of this thesis. Genetic studies can also be used to study bone metabolism in healthy children because of the dynamic stage of the skeleton during growth. Studies in children also have the advantage of involving less confounding environmental factors and other co-morbidities than studies in adults. Our genetic studies had two main goals. First of all, for individuals affected with a severe bone phenotype, a molecular diagnosis is important for several reasons, but particularly for prognostic purposes and for decisions related to treatment strategy. Secondly, the hope is that uncovering genetic regulators of bone metabolism in severely affected children will reveal universal mechanisms that are important also for the adult osteoporosis population. Paper I and Paper II had a monogenic focus and investigated individuals with childhood-onset osteoporosis or fracture propensity. In Paper I we identified two novel disease-causing variants in the PLS3 (Plastin 3) gene. The findings allowed us to conclude that PLS3 screening should be recommended in children with primary osteoporosis, especially if vertebral compression fractures are a dominant feature. In Paper II we showed for the first time that PLS3 gene deletions can cause osteoporosis in children. We also found evidence suggesting that PLS3 has an important role in bone matrix mineralization. Paper III and Paper IV approached bone health as a polygenic trait. In Paper III we explored, for the first time, the polygenic contribution to osteoporosis in children with presumed monogenic bone phenotypes. The study findings suggest that a proportion of the children with severe bone phenotypes and a suspected monogenic etiology for osteoporosis instead may have a polygenic cause underlying the disorder. Finally, in Paper IV we show that the genes GC and CYP2R1 are important determinants of the 25(OH)D concentration in 24-month-old healthy children. Using a Mendelian randomization approach, we also provide support for a causal relationship between 25(OH)D and bone strength in these 24-month-old children.