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Genome-wide association studies incorporating data for populations of African ancestry provide an expanded view of the genetic basis of schizophrenia, which has previously been studied mainly in European and East Asian cohorts.

Steven McCarroll, Giulio Genovese and colleagues report a new approach to help complete maps of the human genome reference sequence. They use a population-based admixture mapping approach and report the successful mapping of ~4 Mb of unplaced human euchromatic sequences.

Variants in two neighbouring genes,APOL1 and MYH9, have previously been associated with kidney disease. Here, using 1000 genomes data, the authors reason by exclusion that the APOL1variants are in fact the most likely causal variants involved in kidney disease, and that this genomic region should be targeted in future studies to determine function.

Therapeutic options for patients with renal medullary carcinoma (RMC) are limited. Here the authors report the results of a phase II clinical trial of anti-PD1 nivolumab plus anti-CTLA4 ipilimumab in RMC, associating the activation of a myeloid mimicry program in tumor cells to the rapid disease progression and hyper-progression observed in treated patients.

A large-scale meta-analysis across eight biobank datasets identifies common genetic variants associated with mosaic loss of the X chromosome in female participants.

Using large-scale analysis of protein interactions and bioinformatics, Li et al. describe the organization of the core-scaffold machinery of the postsynaptic density and its assembly in protein-interaction networks. The authors show how mutations associated with complex brain disorders are distributed along spatiotemporal protein complexes and modulate their protein interactions.

Using genetically engineered models, Genovese and colleagues study patterns of convergent evolution in renal cancer, and pinpoint dysregulation of interferon signaling as a means of adaptation to chromosomal instability in metastatic progression.

Analysis of genotyping data for more than 150,000 individuals from the UK Biobank using long-range phase information sheds light on mechanisms of clonal haematopoiesis.

Rare genetic mutations that disrupt the functionality of important genes increase the risk of psychiatric and neurodevelopmental disorder. This study found that, in the general population not diagnosed with such disorders, these same mutations affect the average educational level. Carriers of these mutations have on average half a semester less of education than noncarriers.

The burden of mosaic chromosomal alterations in blood-derived DNA, a type of clonal hematopoiesis, is associated with an increased risk for diverse types of infections, including sepsis and pneumonia.

Analysis of blood-derived DNA from participants in the UK Biobank demonstrates that clonal expansions of acquired copy-neutral loss of heterozygosity mutations act on inherited alleles along a chromosome arm by modifying their allelic dosages.

Malignant cells with mesenchymal features display increased chromatin accessibility, particularly in the pericentromeric and centromeric regions, in turn resulting in delayed mitosis and catastrophic cell division.

A genome-wide association study including over 76,000 individuals with schizophrenia and over 243,000 control individuals identifies common variant associations at 287 genomic loci, and further fine-mapping analyses highlight the importance of genes involved in synaptic processes.

Using whole-exome sequencing, the authors identified 244,246 coding-sequence and splice-site ultra-rare variants (URVs) and found that gene-disruptive and putatively protein-damaging URVs were significantly more abundant in schizophrenia cases than in controls. The excess of protein-compromising URVs was concentrated in brain-specific genes, particularly in neuronally expressed genes whose proteins are located at the synapse.

The authors surveyed whole-exome and RNA-sequencing data from 252 unique pluripotent stem cell lines, some of which are in the pipeline for clinical use, and found that approximately 5% of cell lines had acquired mutations in the TP53 gene that allow mutant cells to rapidly outcompete non-mutant cells, but do not prevent differentiation.

Cancer cells can be dependent on mitochondrial respiration to survive. Here, in pancreatic cancer cells, the authors show that monounsaturated fatty acids-linked ether lipids maintain mitochondrial redox homeostasis and modulate sensitivity to inhibition to electron transport chain complex I.

A synaptic neuron and astrocyte program (SNAP) varies among healthy humans, may shape interindividual differences in synapses and plasticity, and is undermined in schizophrenia and with advancing age.

Whole-exome sequencing identifies ten risk genes for schizophrenia implicated by rare protein-coding variants, a subset of which overlap with risk genes in other neurodevelopmental disorders.

KRAS mutations are a driver event of pancreatic ductal adenocarcinoma; here, a subpopulation of dormant tumour cells, relying on oxidative phosphorylation for survival, is shown to be responsible for tumour relapse after treatment targeting the KRAS pathway.

Mosaic loss of chromosome Y (mLOY) is associated with age and smoking but also genetic factors play a role. Here, Terao et al. perform GWAS for mLOY in 95,380 Japanese men and identify 46 loci that overlap with hematopoietic stem cell enhancers and transcription factor binding sites critical for hematopoiesis.

In this study of protein-coding de novo mutations in schizophrenia, researchers found only a small contribution toward overall risk, coming predominantly from genes under negative selection and highly expressed in the brain.

This report from the 1000 Genomes Project describes the genomes of 1,092 individuals from 14 human populations, providing a resource for common and low-frequency variant analysis in individuals from diverse populations; hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites, can be found in each individual.

Exome sequence analysis of more than 5,000 schizophrenia cases and controls identifies a polygenic burden primarily arising from rare, disruptive mutations distributed across many genes, among which are those encoding voltage-gated calcium ion channels and the signalling complex formed by the ARC protein of the postsynaptic density; as in autism, mutations were also found in homologues of known targets of the fragile X mental retardation protein.

WebSchizophrenia is associated with genetic variation at the major histocompatibility complex locus; this study reveals that alleles at this locus associate with schizophrenia in proportion to their tendency to generate greater expression of complement component 4 (C4A) genes and that C4 promotes the elimination of synpases.

How the 22q11.2 deletion predisposes to psychiatric disease is unclear. Here, the authors examine living human neuronal cells and show that 22q11.2 regulates the expression of genes linked to autism during early development, and genes linked to schizophrenia and synaptic biology in neurons.

Arginine methylation by PRMTs is dysregulated in cancer. Here, the authors use functional genomics screens and identify PRMT1 as a vulnerability in pancreatic ductal adenocarcinoma, and further show that PRMT1 regulates RNA metabolism and coordinates expression of genes in cell cycle progression, maintaining genomic stability and tumour growth.

Sherman et al. describe the contribution of mosaic copy number variants (mCNVs) to the risk of autism spectrum disorder (ASD). Probands with ASD carry a significant burden of mCNVs relative to their unaffected siblings.

A new approach called liquid biopsy integration site sequencing enables monitoring of genetically modified cells in solid tissues of patients receiving gene therapy.

A genome-wide association study of mosaic loss of chromosome Y (LOY) in UK Biobank participants identifies 156 genetic determinants of LOY, showing that LOY is associated with cancer and non-haematological health outcomes.

In chromosomally unstable tumour cells, rupture of micronuclei exposes genomic DNA and activates the cGAS–STING cytosolic DNA-sensing pathway, thereby promoting metastasis.

Results for the final phase of the 1000 Genomes Project are presented including whole-genome sequencing, targeted exome sequencing, and genotyping on high-density SNP arrays for 2,504 individuals across 26 populations, providing a global reference data set to support biomedical genetics.

The CNV analysis group of the Psychiatric Genomic Consortium analyzes a large schizophrenia cohort to examine genomic copy number variants (CNVs) and disease risk. They find an enrichment of CNV burden in cases versus controls and identify 8 genome-wide significant loci as well as novel suggestive loci conferring either risk or protection to schizophrenia.

Stratified medicine promises to tailor treatment for individual patients, however it remains a major challenge to leverage genetic risk data to aid patient stratification. Here the authors introduce an approach to stratify individuals based on the aggregated impact of their genetic risk factor profiles on tissue-specific gene expression levels, and highlight its ability to identify biologically meaningful and clinically actionable patient subgroups, supporting the notion of different patient ‘biotypes’ characterized by partially distinct disease mechanisms.

This study uses gene expression predictors for the dorsolateral prefrontal cortex and other brain regions to perform a transcriptomic imputation analysis of schizophrenia, identifying 413 genic associations across 13 brain regions and 36 significantly enriched pathways.

Sexual dimorphism in genetic vulnerability to schizophrenia, systemic lupus erythematosus and Sjögren’s syndrome is linked to differential protein abundance from alleles of complement component 4.

Relatives of patients with amyotrophic lateral sclerosis have an unexpectedly high incidence of schizophrenia. Here, the authors show a genetic link between the two conditions, suggesting shared neurobiological mechanisms.

The authors defined a roadmap for investigating the genetic covariance between structural or functional brain phenotypes and risk for psychiatric disorders. Their proof-of-concept study using the largest available common variant data sets for schizophrenia and volumes of several (mainly subcortical) brain structures did not find evidence of genetic overlap.

1000 Genomes imputation can increase the power of genome-wide association studies to detect genetic variants associated with human traits and diseases. Here, the authors develop a method to integrate and analyse low-coverage sequence data and SNP array data, and show that it improves imputation performance.

Schizophrenia is a highly heritable genetic disorder, however, identification of specific genetic risk variants has proven difficult because of its complex polygenic nature—a large multi-stage genome-wide association study identifies 128 independent associations in over 100 loci (83 of which are new); key findings include identification of genes involved in glutamergic neurotransmission and support for a link between the immune system and schizophrenia.

Depletion of malic enzyme 3 in pancreatic cancer cells that have a deletion of the gene for malic enzyme 2 selectively kills the cells, suggesting that the enzyme might represent a therapeutic target for this subset of cancers.

Depletion of Smarcb1 activates the Myc network of signalling cascades, increasing protein metabolism and activation of survival pathways allowing highly aggressive Kras-independent pancreatic cancer cells to develop.

A new method tests whether disease heritability is enriched near genes with high tissue-specific expression. The authors use gene expression data together with GWAS summary statistics for 48 diseases and traits to identify disease-relevant tissues.

Steven McCarroll and colleagues report an analysis of multiallelic copy number variants (mCNVs). They characterize mCNVs in 849 whole-genome sequences from the 1000 Genomes Project and find that mCNVs give rise to most gene dosage variation in humans.