Mapping variants in thyroid hormone transporter MCT8 to disease severity by genomic, phenotypic, functional, structural and deep learning integration.

Predicting and quantifying phenotypic consequences of genetic variants in rare disorders is a major challenge, particularly pertinent for 'actionable' genes such as thyroid hormone transporter MCT8 (encoded by the X-linked SLC16A2 gene), where loss-of-function (LoF) variants cause a rare neurodevelopmental and (treatable) metabolic disorder in males. The combination of deep phenotyping data with functional and computational tests and with outcomes in population cohorts, enabled us to: (i) identify the genetic aetiology of divergent clinical phenotypes of MCT8 deficiency with genotype-phenotype relationships present across survival and 24 out of 32 disease features; (ii) demonstrate a mild phenocopy in ~400,000 individuals with common genetic variants in MCT8; (iii) assess therapeutic effectiveness, which did not differ among LoF-categories; (iv) advance structural insights in normal and mutated MCT8 by delineating seven critical functional domains; (v) create a pathogenicity-severity MCT8 variant classifier that accurately predicted pathogenicity (AUC:0.91) and severity (AUC:0.

The association of gut microbiome composition with musculoskeletal features in middle-aged and older adults: a two-cohort joint study.

Background: Bones and muscles are connected anatomically, and functionally. Preliminary evidence has shown the gut microbiome influences the aging process of bone and muscle in animal studies. However, such evidence in humans is still scarce.

Rheumatoid arthritis and subsequent fracture risk: an individual person meta-analysis to update FRAX.

Unlabelled: The relationship between rheumatoid arthritis (RA) and fracture risk was estimated in an international meta-analysis of individual-level data from 29 prospective cohorts. RA was associated with an increased fracture risk in men and women, and these data will be used to update FRAX®.

Introduction: RA is a well-documented risk factor for subsequent fracture that is incorporated into the FRAX algorithm.

Associations of fetal and infant growth with pubertal timing.

Objective: Impaired fetal and infant growth may cause alterations in developmental programming of the hypothalamic-pituitary-gonadal axis and subsequently pubertal development. We aimed to assess associations between fetal and infant growth and pubertal development.

Design: Population-based prospective birth cohort.

Association between gut microbiome profiles and host metabolic health across the life course: a population-based study.

Background: The human gut microbiome changes considerably over time. Previous studies have shown that gut microbiome profiles correlate with multiple metabolic traits. As disease development is likely a lifelong process, evidence gathered at different life stages would help gain a better understanding of this correlation.