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Mutations in the costimulatory molecule CTLA-4 in six families are associated with immune dysregulation.

Juvenile myelomonocytic leukemia (JMML) is an aggressive disease with limited options for treatment. Here, the authors analyse the DNA methylome and mutational profile of JMML to define three subgroups with unique molecular and clinical characteristics.

Promoter capture Hi-C maps in human pancreatic islets identify more than 1,300 three-dimensional regulatory hubs, linking diabetes-associated enhancers to their target genes. Genetic variation in hubs impacts insulin secretion heritability.

tRNAs are linked with their cognate amino acid by aminoacyl tRNA synthetases (ARS). Here, the authors report a developmental encephalopathy associated with biallelic VARS variants (valyl-tRNA synthetase) that lead to loss of function, as determined by several in vitro assays and a vars knockout zebrafish model.

Fjell et al. analysed multiple large-scale longitudinal MRI datasets and found no evidence for an association of sleep duration and brain atrophy, suggesting that normal brains promote adequate sleep.

Prostate-specific antigen is used as a biomarker of prostate cancer, but levels can be affected by other factors not related to cancer. Here, the authors find genes associated with prostate specific antigen levels in healthy men, which could be used to reduce over-diagnosis and over-treatment.

Cardiac rehabilitation, in most developed countries, is a proven means of reducing mortality but it is grossly underutilized owing to factors involving both the health system and patients. These issues have not been investigated concurrently. In this paper the authors describe a prospective study with a multilevel design to show that the most relevant physician perceptions of such programs are program quality and perceived benefit. For patients, they are barriers to cardiac rehabilitation, which might be conveyed during pre-referral discussions. Work to improve physicians' perceptions and patients' understanding of rehabilitation services might improve use.

Honey bee workers take on different tasks for the colony as they age. Here, the authors develop a method to extract a descriptor of the individuals’ social networks and show that interaction patterns predict task allocation and distinguish different developmental trajectories.

Noninvasively monitoring immune function by positron emission tomography could affect the diagnosis and treatment evaluation of immunological disorders. Progress, however, has been hampered by the lack of probes with distinct biodistribution patterns. Radu et al. exploit the fact that many immune cells utilize a salvage pathway for nucleotide generation during DNA synthesis to develop [¹⁸F]FAC (1-(2′-deoxy-2′[¹⁸F]fluoroarabinofuranosyl) cytosine), a new probe with increased accumulation in proliferating T cells. Studies in mice show it has advantages over commonly used probes and may be clinically useful.

Prostate cancer often does not progress to invasive disease and thus markers predicting the course of the disease progression are critical for optimal treatment choices. Here the authors show that variants at two genetic loci correlate with the aggressiveness of prostate cancer.

Using whole-genome data for single-nucleotide polymorphism and results from genome-wide association studies, the authors show that people’s preference for pairing with those with similar phenotypic traits has genetic causes and consequences.

The differentiation of spinal motor neurons (MNs) from mouse and human embryonic stem cells provides opportunities to model MN development and disease, but most protocols produce only a subset of the MN subtypes found in vivo. Here the authors show that limb projecting lateral motor column MNs can be efficiently generated though the expression of Foxp1.

Kathy Sivils and colleagues report results of a large-scale association study of Sjögren's syndrome, a common autoimmune disease. They confirm strong associations with the HLA region and establish genome-wide significant associations at several non-HLA loci implicated in both innate and adaptive immunity.

In this study, He et al. find that the CHARGE syndrome–related chromatin remodeler Chd7 regulates the initiation of myelination and remyelination in the CNS. Chd7 interacts with Sox10 to orchestrate the transcriptional state of myelinogenic genes and serves as a molecular nexus of the regulatory networks that contribute to white matter pathogenesis in CHARGE syndrome.

Naomi Wray and colleagues report an analysis of genome-wide association data sets from the Psychiatric Genomics Consortium for five psychiatric disorders. They find that common variation explains 17–29% of the variance in liability and provide further support for a shared genetic etiology for these related psychiatric disorders.

This large-scale genome-wide association analysis of subjects with asthma, hay fever or eczema provides insights into the shared genetic basis of these allergic diseases. The findings suggest that these diseases partly co-occur because they share many genetic risk variants that dysregulate the expression of immune-related genes.

Systemic sclerosis (SSc) is a heterogeneous chronic autoimmune disease that affects the connective tissue. Here, López-Isac et al. identify 13 new risk loci for SSc as well as loci specific for limited cutaneous and diffuse SSc and, defining credible sets and performing functional annotation, highlight key pathways and cell types for SSc.

Integration of a global temporal transcriptional module with cell-type-specific transcription factors influences neuronal wiring in the fly visual system.

Rosalind Eeles, Christopher Haiman and colleagues report genome-wide association and meta-analyses of prostate cancer in populations of European, African, Japanese and Latino ancestry. They identify 23 new susceptibility loci, including one associated with early-onset prostate cancer.

Keri Monda, Kari North, Christopher Haiman and colleagues report a meta-analysis of GWAS for body mass index that is composed of 39,144 individuals of African ancestry, followed by further genotyping in 32,268 individuals of African ancestry. The study also includes analysis of publicly available data from the GIANT consortium of ~124,000 individuals of European ancestry. The paper reports evidence for two new loci near GALNT10 and MIR148A.

Flexible decision-making tools are needed to support action plans for plastics and other pollutants. Reproducible Analytical Pipelines (RAPs) and technological readiness levels (TRLs) will enable systematic validation and global harmonization of plastic pollution monitoring methods.

Emerging evidence suggests that the prolonged therapeutic use of androgen receptor (AR)-targeting agents in patients with prostate cancer induces histological dedifferentiation and lineage alterations. Roubaud and colleagues propose that AR suppression creates a checkpoint by which potent therapies exert a selective pressure on prostate cancer cells, favouring dedifferentiated and/or treatment-resistant cell lineages. The authors present a new clinical trial strategy in which rapid drug cycling is used to delay the onset of resistance and treatment-induced lineage crisis in patients with prostate cancer.