Search

Isolated populations may empower genetic association studies of complex traits. Here, the authors identify a rare cardioprotective APOC3variant in a Greek population isolate and highlight the value of using population isolates to detect rare variants that confer disease risk.

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

Network expansion of trait-associated genes for 1,002 human phenotypes identifies pleiotropic gene modules and biological processes associated with multiple traits, and potential opportunities for drug repurposing and development.

A population-scale map of gene expression in primary human microglia provides a systematic exploration of microglia diversity and how age, sex, pathology, cortical anatomy and common germline genetic variation influence the microglia transcriptome.

Open Targets Genetics is a community resource that provides systematic fine mapping at human GWAS loci, enabling users to prioritize genes at disease-associated regions and assess their potential as drug targets.

Cerebro–costo–mandibular syndrome, CCMS, is a severe human multiple malformation disorder. Here, the authors report that mutations in SNRPBdisrupt the normal regulation of alternative splicing at this gene, and in so doing, may be responsible for the development of CCMS.

The role of the immune system in the pathogenesis of psychiatric disorders is unclear. Here, the authors show that genetic risk variants for multiple psychiatric disorders are enriched in regions of the genome active in the brain and in lymphoid cells, especially stimulated T cells, but not in myeloid cells.

A mouse mutagenesis screen identifies CYRI (FAM49B) as a host protection factor against Salmonella infection. CYRI negatively regulates RAC1 signalling to interfere with bacterial entry and dissemination.

Recurrent histone mutations are linked to paediatric glioblastoma multiforme, an aggressive type of brain tumour.

Nada Jabado and colleagues report identification of gain-of-function mutations in ACVR1, which encodes activin A receptor type I, in midline pediatric high-grade astrocytomas.

Isolated populations can provide useful information on low-frequency variants for dissecting genetic architecture of complex traits. Here, Zeggini and colleagues show enrichment of rare and low-frequency variants and 8 novel low-frequency variant signals for cardiometabolic traits in two Greek isolated populations

This study identifies regulatory variants in sensory neurons derived from induced pluripotent stem cells. Despite differentiation-induced variability, an allele-specific method allowed detection of loci influencing gene expression, chromatin accessibility and RNA splicing.

GASPACHO is a statistical method that identifies nonlinear dynamic genetic effects using single-cell RNA-seq data. Analysis of an antiviral response in human fibroblasts identifies 1,275 expression QTLs, many of which colocalize with risk loci for autoimmune and infectious diseases.

Kym Boycott, Mark O'Driscoll and colleagues report identification of mutations in STAMBP, a gene encoding the deubiquitinating isopeptidase STAMBP, in individuals with microcephaly–capillary malformation syndrome.

Rui Chen and colleagues identify mutations in NMNAT1 as a new cause of Leber congenital amaurosis. They further show that all examined individuals with NMNAT1 mutations have macular colobomas, a condition marked by severe degeneration of the central retina.

Genome-wide meta-analysis, fine-mapping and integrative prioritization using expression quantitative trait loci, protein interaction networks and tissue-specific expression implicate new candidate susceptibility genes for Alzheimer’s disease.

Loss-of-function mutations in the human CTP synthase 1 gene cause an immunodeficiency disease with impaired T cell proliferation after antigen stimulation, revealing a potential new target for immunosuppressive drugs.

In a mouse model and in human medulloblastoma patients, the metastases in an individual have similar genomic alterations and DNA methylation patterns, but these patterns are highly divergent from those of the primary tumour, indicating that therapies will need to be tailored to fit the molecular alterations present in the primary tumour and/or the metastases.

Stefan Pfister and the ICGC PedBrain Tumor Project report whole-genome sequencing of 96 pilocytic astrocytomas. They identify recurrent activating mutations in FGFR1 and PTPN11 and novel NTRK2 fusion genes.

William Dobyns and colleagues report de novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA in the sporadic overgrowth syndromes megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) and megalencephaly-capillary malformation (MCAP).

Nada Jabado, Jacek Majewski, Annie Huang and colleagues show that embryonal tumors with multilayered rosettes are characterized by a recurrent fusion of TTYH1 with the C19MC microRNA cluster. They further show that this fusion results in massive overexpression of a brain-specific isoform of DNMT3B, suggesting that this pediatric brain tumor is driven by epigenetic reactivation of an early developmental neurogenesis program.

Eamonn Sheridan, Elizabeth Ross and colleagues report discovery of a new megalencephaly syndrome caused by de novo missense mutations in CCND2. They show that these mutations lead to stabilization of cyclin D2, and they present evidence that cyclin D2 stabilization may be a common downstream mechanism in PI3K-AKT–associated megalencephaly syndromes.

Konstantinos Hatzikotoulas et al. report the largest genome-wide association study to date for developmental dysplasia of the hip using national clinical audit data from the UK. They find a significant association with the GDF5 locus and evidence for shared genetic architecture with hip osteoarthritis.