Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40–50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10–20% (14–24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.

We aimed to systematically assess the measurement properties of diabetes-specific patient-reported outcome measures (PROMs) for measuring physical functioning, one of the core outcomes, in adults with type 2 diabetes.We performed a systematic literature search for PROMs or subscales measuring physical function that were validated to at least some extent in EMBASE and MEDLINE. Measurement properties were evaluated according to the COSMIN guideline for systematic reviews of PROMs.In total 21 articles were included, describing 12 versions of 7 unique diabetes-specific PROMs or subscales measuring physical functioning. In general, there were few high-quality studies on measurement properties of PROMs measuring physical functioning in adults with type 2 diabetes. The Dependence/Daily Life subscale of the Diabetic Foot Ulcer Scale—Short Form (DFS-SF) and the Impact of Weight on Activities of Daily Living Questionnaire (IWADL) were most extensively evaluated. Both had sufficient ratings for aspects of content validity, although with mostly very low-quality evidence. Sufficient ratings for structural validity, internal consistency, and reliability were also found for both instruments, but responsiveness was rated inconsistent for both instruments. The other PROMs or subscales often had insufficient aspects of content validity, or their unidimensionality could not be confirmed.This systematic review showed that the Dependence/Daily Life subscale of the DFS-SF and the IWADL could be used to measure physical functioning in people with type 2 diabetes in research or clinical practice, while keeping the limitations of these instruments in mind. The measurement properties that have not been evaluated extensively for these PROMs should be evaluated in future studies.The study protocol was registered in the PROSPERO database, number CRD42021234890.

We identify biomarkers for disease progression in three type 2 diabetes cohorts encompassing 2,973 individuals across three molecular classes, metabolites, lipids and proteins. Homocitrulline, isoleucine and 2-aminoadipic acid, eight triacylglycerol species, and lowered sphingomyelin 42:2;2 levels are predictive of faster progression towards insulin requirement. Of ~1,300 proteins examined in two cohorts, levels of GDF15/MIC-1, IL-18Ra, CRELD1, NogoR, FAS, and ENPP7 are associated with faster progression, whilst SMAC/DIABLO, SPOCK1 and HEMK2 predict lower progression rates. In an external replication, proteins and lipids are associated with diabetes incidence and prevalence. NogoR/RTN4R injection improved glucose tolerance in high fat-fed male mice but impaired it in male db/db mice. High NogoR levels led to islet cell apoptosis, and IL-18R antagonised inflammatory IL-18 signalling towards nuclear factor kappa-B in vitro. This comprehensive, multi-disciplinary approach thus identifies biomarkers with potential prognostic utility, provides evidence for possible disease mechanisms, and identifies potential therapeutic avenues to slow diabetes progression.

We investigated the reliability of physical activity monitoring based on trunk accelerometry in older adults and assessed the number of measured days required to reliably assess physical activity. Seventy-nine older adults (mean age 79.1 ± 7.9) wore an accelerometer at the lower back during two nonconsecutive weeks. The duration of locomotion, lying, sitting, standing and shuffling, movement intensity, the number of locomotion bouts and transitions to standing, and the median and maximum duration of locomotion were determined per day. Using data of week 2 as reference, intraclass correlations and smallest detectable differences were calculated over an increasing number of consecutive days from week 1. Reliability was good to excellent when whole weeks were assessed. Our results indicate that a minimum of two days of observation are required to obtain an ICC ≥ 0.7 for most activities, except for lying and median duration of locomotion bouts, which required up to five days.