Birth weight is positively associated with adult osteoporosis risk: observational and Mendelian randomization studies

Abstract

The relationship between birth weight and osteoporosis was inconsistent in previous observational studies. Therefore, we performed a systematic evaluation to determine the inconsistent relationship and further make causal inference based on the UK Biobank datasets ($500,000 individuals) and individual/summary-level genetic datasets. Observational analyses found consistent negative associations either between birth weight and estimated bone mineral density (eBMD) or between genetic risk score (GRS) of birth weight and eBMD in total subjects, and sex-stratified subgroups. Mediation analyses detected significant mediation effects of adult weight and height on associations between birth weight and eBMD. Birth weight was causally associated not only with three BMD phenotypes (eBMD, total body [TB]-BMD, and femoral neck [FN]-BMD) under two effect models (total and fetal effect), but also with the risk of fracture using different Mendelian randomization (MR) methods. Multivariable MR analyses detected the pleiotropic effects of some environmental factors (e.g., gestational duration, head circumference, hip circumference) on the associations between birth weight and BMD/fracture. Three BMD phenotypes (eBMD, TB-BMD, and FN-BMD) have significant mediation effects on the associations between birth weight and fracture by using a novel mediation MR analysis under the multivariable MR framework. This multistage systematic study found consistent causal associations between birth weight and osteoporosis risk, fetal origin of genetic effects underlying the associations, and several mediation factors on the detected associations. The results enhanced our understanding of the effects of fetal original phenotypes on outcomes in late adulthood and provided helpful clues for early prevention research on osteoporosis.

Emerging roles of circular RNAs in osteoporosis

“…[1][2][3][4] It is accompanied or asymptomatic by mild or serious symptoms, which is one cause of pathological fracture and also the high-risk factor influencing human health. [5][6][7] The incidence of osteoporosis is 70% in people over 80 years and 15% in people over 50 years old. 8,9 The osteoporosis patient's number exceeds 200 million worldwide at present, while the number may increase to 300 million as ageing population by 2023.…”

Exploring the association between birthweight and breast cancer using summary statistics from a perspective of genetic correlation, mediation, and causality

“…Unlike prior relevant studies [ 39 ], one of the remarkable strengths of our work is that we resolved the relative contributions of fetal and maternal genotypes on birthweight and employed fetal/maternal-specific effects of birthweight in our genetic overlap analysis as well as in our MR analysis, which provides us an unprecedented opportunity to untangle the origin of the relationship between birthweight and breast cancer [ 43 , 66 , 67 ]. For example, we discovered that fetal-specific birthweight was genetically correlated to breast cancer in a positive direction, while maternal-specific birthweight showed a negative genetic correlation to breast cancer.…”

“…We finally evaluated the causal association among the four traits using various MR methods. Following prior studies [ 43 , 66 , 67 ], we selected a set of independent birthweight-associated SNPs ( P < 6.60 × 10 –9 and r 2 < 0.10) as instruments. Specifically, the total of 104 instruments for fetal-specific birthweight included 63 fetal-effect specific SNPs, 26 SNPs exerting both fetal and maternal effects with the same effect direction and 15 SNPs exhibiting both fetal and maternal effects but with the opposite effect direction (Additional file 1 : Table S1); while the total of 72 instruments for maternal-specific birthweight included 31 maternal-effect specific SNPs, 26 SNPs exerting both fetal and maternal effects with the same effect direction, 15 SNPs exhibiting both fetal and maternal effects but with the opposite effect direction (Additional file 1 : Table S2).…”

Genetic Risk for Osteoporosis and the Benefit of Adherence to Healthy Lifestyles

“…We followed a similar quality control by Yu et al [ 24 ] in their osteoporosis study. A total of ∼92 million variants were generated by imputation, which was performed based on Haplotype Reference Consortium (HRC), UK10K and 1,000 Genomes reference panels.…”