Purpose of Review Fractures are frequently encountered in paediatric practice. Although recurrent fractures in children usually unveil a monogenic syndrome, paediatric fracture risk could be shaped... Show morePurpose of Review Fractures are frequently encountered in paediatric practice. Although recurrent fractures in children usually unveil a monogenic syndrome, paediatric fracture risk could be shaped by the individual genetic background influencing the acquisition of bone mineral density, and therefore, the skeletal fragility as shown in adults. Here, we examine paediatric fractures from the perspective of monogenic and complex trait genetics.Recent Findings Large-scale genome-wide studies in children have identified similar to 44 genetic loci associated with fracture or bone traits whereas similar to 35 monogenic diseases characterized by paediatric fractures have been described.Genetic variation can predispose to paediatric fractures through monogenic risk variants with a large effect and polygenic risk involving many variants of small effects. Studying genetic factors influencing peak bone attainment might help in identifying individuals at higher risk of developing early-onset osteoporosis and discovering drug targets to be used as bone restorative pharmacotherapies to prevent, or even reverse, bone loss later in life. Show less
Ibi, D.; Noordam, R.; Klinken, J.B. van; Li-Gao, R.F.; Mutsert, R. de; Trompet, S.; ... ; Dijk, K.W. van 2020
Background: The increase in serum triglyceride (TG) concentrations in response to a meal is considered a risk factor for cardiovascular disease. We aimed to elucidate the genetics of the... Show moreBackground: The increase in serum triglyceride (TG) concentrations in response to a meal is considered a risk factor for cardiovascular disease. We aimed to elucidate the genetics of the postprandial TG response through genome-wide association studies (GWAS). Methods: Participants of the NEO (Netherlands Epidemiology of Obesity) study (n=5630) consumed a liquid mixed meal after an overnight fast. GWAS of fasting and postprandial serum TG at 150 minutes were performed. To identify genetic variation of postprandial TG independent of fasting TG, we calculated the TG response at 150 minutes by the residuals of a nonlinear regression that predicted TG at 150 minutes as a function of fasting TG. Association analyses were adjusted for age, sex, and principal components in a linear regression model. Next, using the identified variants as determinants, we performed linear regression analyses on the residuals of the postprandial response of 149 nuclear magnetic resonance-based metabolite measures. Results: GWAS of fasting TG and postprandial serum TG at 150 minutes resulted in completely overlapping loci, replicating previous GWAS. From GWAS of the TG response, we identified rs7350789-A (allele frequency=0.36), mapping to hepatic lipase (LIPC), to be associated with a smaller increase in TG concentrations at 150 minutes (beta=-0.11;P-value=5.1x10(-8)). Rs7350789-A was associated with responses of 33 metabolite measures (P-value <1.34x10(-3)), mainly smaller increases of the TG-component in almost all HDL (high-density lipoprotein) subparticles (HDL-TG), a smaller decrease of HDL diameter and smaller increases of most components of VLDL (very low density lipoprotein) subparticles. Conclusions: GWAS of the TG response identified a variant nearLIPCas a main contributor to postprandial TG metabolism independent of fasting TG concentrations, resulting in smaller increases of HDL-TG and VLDL subparticles. Show less
