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Atypical femur fractures (AFFs) are rare adverse events associated with bisphosphonate use, having unclear pathophysiology. AFFs also cluster in families and have occurred in patients with monogenetic bone diseases sometimes without bisphosphonate use, suggesting an underlying genetic susceptibility. Our aim was to identify a genetic cause for AFF in a Caucasian family with seven members affected by osteoporosis, including three siblings with bisphosphonate-associated AFFs. Using whole-exome sequencing, we identified a rare pathogenic variant c.G1063A (p.Gly355Ser) in lysyl oxidase like 4 (LOXL4) among 64 heterozygous rare, protein-altering variants shared by the three siblings with AFFs. The same variant was also found in a fourth sibling with a low-trauma femur fracture above the knee, not fulfilling all the ASBMR criteria of AFF and in one of 73 unrelated European AFF patients. LOXL4 is involved in collagen cross-linking and may be relevant for microcrack formation and bone repair mechanisms. Preliminary functional analysis showed that skin fibroblast-derived osteoblasts from the unrelated patient with the LOXL4 variant expressed less collagen type I and elastin, while osteogenic differentiation and mineralization were enhanced compared with two controls. In conclusion, this LOXL4 variant may underlie AFF susceptibility possibly due to abnormal collagen metabolism leading to increased formation of microdamage or compromised healing of microcracks in the femur., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Rationale: Research suggests that respiratory and cardiovascular drugs can ameliorate the rate of lung function decline. Objectives: To investigate the impact of respiratory and cardiovascular pharmacotherapy on lung function trajectories in the general population. Methods: Repeated spirometry was performed in the Rotterdam Study, a population-based cohort of adults aged ≥45 years. Exposure to long-acting beta2-agonists (LABA), long-acting muscarinic antagonists (LAMA), inhaled corticosteroids (ICS), cardioselective beta-blockers, calcium channel blockers, ACE-inhibitors, angiotensin-II receptor blockers, and statins was quantified from pharmacy records to account for therapy adherence. Propensity-score matching and multinomial logistic regression were performed to model medication effects on lung function trajectories, which were previously identified based on FEV 1 and FVC patterns. Models were additionally stratified by genetic variation in each drug target. Measurement and Main Results: Among 3,783 individuals, 2,974 (78.6%) were classified as normal lung function decliners, 432 (11.4%) as rapid decliners, and 377 (10.0%) as improvers. Exposure to LABA (odds ratio (OR) =1.09 [95%-CI: 1.03-1.16] per 10% increase in exposure), ICS (OR=1.08 [95%-CI: 1.02-1.14]), and statins (OR=1.04 [95%-CI: 1.02-1.06]) significantly increased the odds of being an improver compared to a normal decliner. Beta 1 -blocker use was associated with higher odds of being a rapid decliner (OR=1.04 [95%-CI: 1.00-1.09]), which was driven by incident users. Pharmacogenetic analysis suggests that the effects of LABA, ICS, and beta 1 -blockers are dependent on genetic variation in their drug targets. Conclusions: Our study suggests that LABA, ICS, and statins may favorably modulate lung function trajectories in adults, while initiation of beta 1 -blockers was associated with rapid lung function decline.

Objective: To discover new variants associated with low ovarian reserve after gonadotoxic treatment among adult female childhood cancer survivors using a genome-wide association study approach., Design: Genome-wide association study., Setting: Not applicable., Patients: A discovery cohort of adult female childhood cancer survivors from the pan-European PanCareLIFE cohort (n = 743; median age: 25.8 years), excluding those who received bilateral ovarian irradiation, bilateral oophorectomy, central nervous system or total body irradiation, or stem cell transplantation. Replication was attempted in the US-based St. Jude Lifetime Cohort (n = 391; median age: 31.3 years)., Exposure: Female childhood cancer survivors are at risk of therapy-related gonadal impairment. Alkylating agents are well-established risk factors, and the interindividual variability in gonadotoxicity may be explained by genetic polymorphisms. Data were collected in real-life conditions, and cyclophosphamide equivalent doses were used to quantify alkylation agent exposure., Main Outcome Measure: Anti-Müllerian hormone (AMH) levels served as a proxy for ovarian function, and the findings were combined in a meta-analysis., Results: Three genome-wide significant (<5.0 × 10 -8 ) and 16 genome-wide suggestive (<5.0 × 10 -6 ) loci were associated with log-transformed AMH levels, adjusted for cyclophosphamide equivalent dose of alkylating agents, age at diagnosis, and age at study in the PanCareLIFE cohort. On the basis of the effect allele frequency (EAF) (>0.01 if not genome-wide significant), and biologic relevance, 15 single nucleotide polymorphisms were selected for replication. None of the single nucleotide polymorphisms were statistically significantly associated with AMH levels. A meta-analysis indicated that rs78861946 was associated with borderline genome-wide statistical significance (reference/effect allele: C/T; effect allele frequency: 0.04, beta (SE): -0.484 (0.091)., Conclusion: This study found no genetic variants associated with a lower ovarian reserve after gonadotoxic treatment because the findings of this genome-wide association study were not statistically significant replicated in the replication cohort. Suggestive evidence for the potential importance of 1 variant is briefly discussed, but the lack of statistical significance calls for larger cohort sizes. Because the population of childhood cancer survivors is increasing, large-scale and systematic research is needed to identify genetic variants that could aid predictive risk models of gonadotoxicity as well as fertility preservation options for childhood cancer survivors., Competing Interests: Declaration of Interests M.E.M.v.d.P. reports funding from European Union’s Seventh Framework Programme for research (technological development, and demonstration funding), Dutch Cancer Society (grant no. VU 2006-3622), Princess Máxima Center Foundation, and Stichting Kinderoncologisch Centrum Rotterdam (sKOCR), DCOG-LATER VEVO study was funded by the Dutch Cancer Society (grant no. VU 2006-3622) and by the Children Cancer-Free Foundation (Project no. 20) and the St Jude Lifetime Cohort study by NCI U01 CA195547. L.B. has nothing to disclose. Y.Y. reports funding from National Cancer Institute (NCI) U01CA195547 (MPI: Hudson/Ness), St. Jude Lifetime Cohort Study (SJLIFE), NCI P30CA021765 (PI: Roberts) Cancer Center Support Grant (CCSG), and American Lebanese Syrian Associated Charities for the submitted work; funding from NCI U24CA055727 (PI: Armstrong) Childhood Cancer Survivor Study (CCSS), National Institutes of Health (NIH) R03DE029238 (PI: Li/Sun) Innovative Statistical Analysis for Genome-Wide Data with General Interval Censored Outcomes of Oral Health in Childhood Cancer Survivors, NCI R01CA216354 (MPI: Yasui/Zhang) Late Effects Prediction Using Clinical Phenotypes and Whole Genome Sequencing, St Jude Lifetime Cohort study by NCI U01 CA195547, NCI R01CA270157 (MPI: Bhakta/Yasui) Measuring Lifelong Multimorbidity with Patient Perspectives: Implementing and Visualizing the Cumulative Burden Methodology Across Cohorts, NCI R01CA258193 (MPI: Huang/Yasui) Patient-Generated Health Data to Predict Childhood Cancer Survivorship Outcomes (HEALTHSHARE), NIH &MD Anderson Cancer Center R01CA261750-01A1 (MPI: Howell/Mulrooney/Yasui) Personalized Risk Prediction to Reduce Cardiovascular Disease in Childhood Cancer Survivors, NCI &Northwestern University R01CA261898 (MPI: Burridge/Sapkota) Predicting and Preventing Chemotherapy-Induced Cardiotoxicity in African American Children, NC. J.S.E.L. has nothing to disclose. L.L.R. has nothing to disclose. W.J.E.T. has nothing to disclose. B.V. has nothing to disclose. B.V. has nothing to disclose. D.B. has nothing to disclose. G.J.L.K. has nothing to disclose. C.B.L. has nothing to disclose. A.O. has nothing to disclose. J.J.L. has nothing to disclose. C.C.M.B. has nothing to disclose. J.B. has nothing to disclose. C.B. has nothing to disclose. E.C. has nothing to disclose. E.v.D.-d.B. has nothing to disclose. U.D. has nothing to disclose. H.J.v.d.P. has nothing to disclose. A.C.H.d.V. has nothing to disclose. J.F.W. has nothing to disclose. A.R. has nothing to disclose. S.D.F. has nothing to disclose. D.G. has nothing to disclose. M.M. has nothing to disclose. M.K. has nothing to disclose. T.K. has nothing to disclose. J.K. has nothing to disclose. D.M.-M. has nothing to disclose. C.S. has nothing to disclose. O.Z. has nothing to disclose. P.K. has nothing to disclose. L.C.M.K. has nothing to disclose. R.J.B. has nothing to disclose. F.W. has nothing to disclose. J.L.B. has nothing to disclose. A.G.U. has nothing to disclose. A.M.E.B. has nothing to disclose. F.E.v.L. has nothing to disclose. K.K.N. has nothing to disclose. M.M.H. has nothing to disclose. A.-L.L.F.v.d.K. has nothing to disclose. M.M.v.d.H.E. has nothing to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Bone Health Index (BHI) has been proposed as a useful instrument for assessing bone health in children. However, its relationship with fracture risk remains unknown. We aimed to investigate whether BHI is associated with bone mineral density (BMD) and prevalent fracture odds in children from the Generation R Study. We also implemented genome-wide association study (GWAS) and polygenic score (PGS) approaches to improve our understanding of BHI and its potential. In total, 4150 children (49.4 % boys; aged 9.8 years) with genotyped data and bone assessments were included in this study. BMD was measured across the total body (less head following ISCD guidelines) using a GE-Lunar iDXA densitometer; and BHI was determined from the hand DXA scans using BoneXpert®. Fractures were self-reported collected with home questionnaires. The association of BHI with BMD and fractures was evaluated using linear models corrected for age, sex, ethnicity, height, and weight. We observed a positive correlation between BHI and BMD (ρ = 0.32, p-value<0.0001). Further, every SD decrease in BHI was associated with an 11 % increased risk of prevalent fractures (OR:1.11, 95 % CI 1.00-1.24, p-value = 0.05). Our BHI GWAS identified variants (lead SNP rs1404264-A, p-value = 2.61 × 10 -14 ) mapping to the ING3/CPED1/WNT16 locus. Children in the extreme tails of the BMD PGS presented a difference in BHI values of -0.10 standard deviations (95% CI -0.14 to -0.07; p-value<0.0001). On top of the demonstrated epidemiological association of BHI with both BMD and fracture risk, our results reveal a partially shared biological background between BHI and BMD. These findings highlight the potential value of using BHI to screen children at risk of fracture., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Desmosomes are dynamic complex protein structures involved in cellular adhesion. Disruption of these structures by loss-of-function variants in desmosomal genes leads to a variety of skin- and heart-related phenotypes. In this study, we report TUFT1 as a desmosome-associated protein, implicated in epidermal integrity. In two siblings with mild skin fragility, woolly hair, and mild palmoplantar keratoderma but without a cardiac phenotype, we identified a homozygous splice-site variant in the TUFT1 gene, leading to aberrant mRNA splicing and loss of TUFT1 protein. Patients' skin and keratinocytes showed acantholysis, perinuclear retraction of intermediate filaments, and reduced mechanical stress resistance. Immunolabeling and transfection studies showed that TUFT1 is positioned within the desmosome and that its location is dependent on the presence of the desmoplakin carboxy-terminal tail. A Tuft1-knockout mouse model mimicked the patients' phenotypes. Altogether, this study reveals TUFT1 as a desmosome-associated protein, whose absence causes skin fragility, woolly hair, and palmoplantar keratoderma., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases., (© 2024. The Author(s).)