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Abstract An increasing number of epidemiological studies have suggested that birth weight (BW) may be a determinant of bone health later in life, although the underlying genetic mechanism remains unclear. Here, we applied a pleiotropic conditional false discovery rate (cFDR) approach to the genome-wide association study (GWAS) summary statistics for lumbar spine bone mineral density (LS BMD) and BW, aiming to identify novel susceptibility variants shared between these two traits. We detected 5 novel potential pleiotropic loci which are located at or near 7 different genes (NTAN1, PDXDC1, CACNA1G, JAG1, FAT1P1, CCDC170, ESR1), among which PDXDC1 and FAT1P1 have not previously been linked to these phenotypes. To partially validate the findings, we demonstrated that the expression of PDXDC1 was dramatically reduced in ovariectomized (OVX) mice in comparison with sham-operated (SHAM) mice in both the growth plate and trabecula bone. Furthermore, immunohistochemistry assay with serial sections showed that both osteoclasts and osteoblasts express PDXDC1, supporting its potential role in bone metabolism. In conclusion, our study provides insights into some shared genetic mechanisms for BMD and BW as well as a novel potential therapeutic target for the prevention of OP in the early stages of the disease development. Key messages We investigated pleiotropy-informed enrichment between LS BMD and BW. We identified genetic variants related to both LS BMD and BW by utilizing a cFDR approach. PDXDC1 is a novel pleiotropic gene which may be related to both LS BMD and BW. Elevated expression of PDXDC1 is related to higher BMD and lower ratio n-6/n-3 PUFA indicating a bone protective effect of PDXDC1.

An increasing number of epidemiological studies have suggested that birth weight (BW) may be a determinant of bone health later in life, although the underlying genetic mechanism remains unclear. Here, we applied a pleiotropic conditional false discovery rate (cFDR) approach to the genome-wide association study (GWAS) summary statistics for lumbar spine bone mineral density (LS BMD) and BW, aiming to identify novel susceptibility variants shared between these two traits. We detected 5 novel potential pleiotropic loci which are located at or near 7 different genes (NTAN1, PDXDC1, CACNA1G, JAG1, FAT1P1, CCDC170, ESR1), among which PDXDC1 and FAT1P1 have not previously been linked to these phenotypes. To partially validate the findings, we demonstrated that the expression of PDXDC1 was dramatically reduced in ovariectomized (OVX) mice in comparison with sham-operated (SHAM) mice in both the growth plate and trabecula bone. Furthermore, immunohistochemistry assay with serial sections showed that both osteoclasts and osteoblasts express PDXDC1, supporting its potential role in bone metabolism. In conclusion, our study provides insights into some shared genetic mechanisms for BMD and BW as well as a novel potential therapeutic target for the prevention of OP in the early stages of the disease development.

Strong relationships have been found between appendicular lean mass (ALM) and bone mineral density (BMD). It may be due to a shared genetic basis, termed pleiotropy. By leveraging the pleiotropy with BMD, the aim of this study was to detect more potential genetic variants for ALM. Using the conditional false discovery rate (cFDR) methodology, a combined analysis of the summary statistics of two large independent genome wide association studies (GWAS) of ALM (n = 73,420) and BMD (n = 10,414) was conducted. Strong pleiotropic enrichment and 26 novel potential pleiotropic SNPs were found for ALM and BMD. We identified 156 SNPs for ALM (cFDR

Context Although metabolic profiles appear to play an important role in menopausal bone loss, the functional mechanisms by which metabolites influence bone mineral density (BMD) during menopause are largely unknown. Objective We aimed to systematically identify metabolites associated with BMD variation and their potential functional mechanisms in peri- and postmenopausal women. Design and Methods We performed serum metabolomic profiling and whole-genome sequencing for 517 perimenopausal (16%) and early postmenopausal (84%) women aged 41 to 64 years in this cross-sectional study. Partial least squares regression and general linear regression analysis were applied to identify BMD-associated metabolites, and weighted gene co-expression network analysis was performed to construct co-functional metabolite modules. Furthermore, we performed Mendelian randomization analysis to identify causal relationships between BMD-associated metabolites and BMD variation. Finally, we explored the effects of a novel prominent BMD-associated metabolite on bone metabolism through both in vivo/in vitro experiments. Results Twenty metabolites and a co-functional metabolite module (consisting of fatty acids) were significantly associated with BMD variation. We found dodecanoic acid (DA), within the identified module causally decreased total hip BMD. Subsequently, the in vivo experiments might support that dietary supplementation with DA could promote bone loss, as well as increase the osteoblast and osteoclast numbers in normal/ovariectomized mice. Dodecanoic acid treatment differentially promoted osteoblast and osteoclast differentiation, especially for osteoclast differentiation at higher concentrations in vitro (eg,10, 100 μM). Conclusions This study sheds light on metabolomic profiles associated with postmenopausal osteoporosis risk, highlighting the potential importance of fatty acids, as exemplified by DA, in regulating BMD.

As the major cause of female anovulatory infertility, polycystic ovary syndrome (PCOS) affects a great proportion of women at childbearing age. Although glucagon-like peptide 1 receptor agonists (GLP-IRAs) show therapeutic effects for PCOS, its target and underlying mechanism remains elusive. In the present study, we identified that, both in vivo and in vitro, GLP-1 functioned as the regulator of proliferation and antiapoptosis of MGCs of follicle in PCOS mouse ovary. Furthermore, forkhead box protein O1 (FoxO1) plays an important role in the courses. Regarding the importance of granulosa cells (GCs) in oocyte development and function, the results from the current study could provide a more detailed illustration on the already known beneficial effects of GLP-1RAs on PCOS and support the future efforts to develop more efficient GLP-1RAs for PCOS treatment.

OBJECTIVE: To establish a new method for rapid and quantitative measurement of orbital fat volume based on magnetic resonance imaging (MRI) data. METHODS: We collected MRI data from normalized mold and patients with the diagnosis of thyroid-associated ophthalmopathy (TAO). The cross-sectional areas of the orbital fat on each MR image slice were measured to calculate the fat volume on each slice and then the total orbital fat volume. We recorded the time for completing the measurement and assessed the precision, reliability, repeatability and interoperator variations of the results. RESULTS: This MRI data-based method allowed precise measurement of the orbital fat volumes with an absolute value of the mean percentage difference < 1%. This method was fast and the results showed a good repeatability (with CVs < 1%), a high reliability (ICC=0.996, 95% CI: 0.985-0.999) and a high interoperator concordance (95% CI of the Bland-Altman: -0.54-0.90). CONCLUSION: The novel method we established for orbital fat volume measurement is rapid, accurate, reliable and reproducible with a low learning cost for clinical use.

OBJECTIVE: To analyze the relationship between orbital fat volume and the progression and prognosis of thyroidassociated ophthalmopathy (TAO) and determine the optimal treatment timing for TAO. METHODS: The clinical data were collected from 35 patients (70 orbits) with a definite diagnosis of TAO between January, 2016 and December, 2016. The correlation between orbital fat volume and the clinical parameters was evaluated. We also analyzed the correlation of the signal intensity ratio (SIR) of the extraocular muscles with the clinical parameters. The orbital fat volume was compared between patients with TAO and 12 control subjects. RESULTS: The orbital fat volume was significantly correlated with the duration of TAO (r=0.480, P < 0.01), but showed no significant difference between patients with a disease course within 6 months and those with a disease course of 6 to 12 months (P=0.084). The patients with a disease course beyond 12 months had a significantly greater orbital fat volume than those with a disease course of 6 months (P < 0.01) or 6 to 12 months (P < 0.05). The orbital fat volume was correlated with the degree of proptosis (r=0.622, P < 0.01), and an increase of exophthalmos by 1 mm was associated with a total orbital volume increment of 0.88 mL. The clinical activity score was correlated with the SIR of the extraorbital muscles (r=0.536, P < 0.01) and levels of anti-thyroid-stimulating hormone receptor antibody (r=0.416, P < 0.01). The orbital fat volume was significantly greater in TAO patients than in the healthy individuals (P < 0.01). CONCLUSION: In patients with TAO, the peak increase of orbital fat volume occurs one year after the disease onset. Measurement of the orbital fat volume combined with SIR of the extraorbital muscles can serve as an indicator for determining the optimal timing for intervention of TAO and helps in the evaluation of prognosis of the patients.

Objective Effective management of thyroid-associated ophthalmopathy (TAO) requires precise identification of the disease activity period as it is responsive to immunosuppressive treatment. Quantitative evaluations of orbital soft tissue are useful for analysing disease stages. We aimed to establish a method for orbital soft tissue volume calculation based on magnetic resonance imaging (MRI) data using 3D reconstruction technology. Furthermore, we validated the accuracy and precision of this method and investigated volume differences between patients with TAO and healthy individuals. Materials and methods Using Mimics software for 3D reconstruction based on orbital MRI data, we quantitatively measured orbital fat volume (FV) and extraocular muscle volume (MV) using a manual phantom, and in patients with TAO and healthy volunteers (n = 10 each). The phantom was made using a combination of butter and chicken muscle and 2 observers measured its volume. Volume calculations were compared to a previously established standard volume. One observer measured a typical TAO case 10 times to calculate intra-observer variability while 3 observers independently measured 10 patients with TAO each to calculate interobserver variability. Orbital soft tissue volumes between 10 patients with TAO and 10 healthy individuals were compared. Results The precision of calculations for the phantom between the 2 observers varied from -4.60% to -2.78% for FV and between -4.13% to 0.71% for MV. Mean differences among repetitive calculations were lower than 4%, except during measurement of MV, which was 5.84%. The intraclass correlation coefficient varied from 0.976 to 0.996. FV was 15.53 ± 3.06 mL in patients with TAO and 11.32 ± 1.68 mL(P = .001)in healthy individuals, while MV was 3.19 ± 0.82 mL in patients with TAO and 2.45 ± 0.57 mL(P = .030)in healthy individuals. Conclusions This method of calculating orbital soft tissue volumes based on MRI data and 3D reconstruction is both reliable and accurate as it yielded significant differences in tissue volume between patients with TAO and healthy individuals.