Volume 54 Issue 9, September 2022

Across >150,000 individuals, we identified hundreds of genes associated with autism spectrum disorder (ASD) and atypical neurodevelopment. Most ASD-related genes were also associated with developmental delay. However, increased mutation rates in ASD and shared genetic risk with schizophrenia was observed for some genes, many of which are enriched in developing neurons.

Migration can increase regional differences in both DNA variants and environmental factors that are associated with socio-economic status. Without controlling for geography, associations between genes and complex traits will therefore include effects of environmental differences between high-income and low-income regions.

We comprehensively define the genomic landscape of pediatric acute lymphoblastic leukemia (ALL) in the largest cohort assembled to date, and identify new driver genes and biological pathways that are targeted by genetic alteration. These findings serve as a road map to improve our understanding of disease development and identify therapeutic targets in pediatric ALL.

In our study of 83 tissue samples from 31 patients with pancreatic cancer receiving different treatment regimens, we directly identified normal cells transitioning to a tumor state. Single-cell technologies enabled us to observe how the tumor and the surrounding environment work together to create a treatment-resistant niche.

The genetic landscape of human induced pluripotent stem cells (iPSCs) is strongly influenced by the somatic cells of origin, and mutational signatures directly reflect pre-reprogramming and post-reprogramming mutagenic processes. BCOR mutations are recurrent and have functional consequences for the differentiation capacity of iPSCs.

We generated a cattle genotype–tissue expression atlas (CattleGTEx) as part of the farm animal GTEx project. Analysis of 7,180 public RNA-sequencing samples revealed genetic variants that regulate the transcriptome across 23 distinct bovine tissues. Integrating these data with GWAS advances our understanding of the fundamental molecular mechanisms that underpin complex traits in cattle.

Large-scale sequence-based analyses identify novel risk variants and susceptibility genes for Crohn’s disease, and implicate mesenchymal cell-mediated intestinal homeostasis in disease etiology.

Integrated analyses in a large collection of families provide insights into the combined effects of rare variants and polygenic risk on autism spectrum disorder.

Comprehensive factor analysis of core diagnostic features provides insights into the complex genetic architecture underlying phenotypic heterogeneity in autism.

An integrated analysis of de novo and inherited coding variants in 42,607 individuals with autism spectrum disorder identifies 60 risk genes of which five have not previously been associated with neurodevelopmental disorders.

Analysis of rare protein-truncating, damaging missense and copy number variants from exome sequencing of 63,237 individuals identifies 72 genes associated with autism spectrum disorder.

Multi-ancestry meta-analyses of genome-wide association studies for self-reported physical activity during leisure time, leisure screen time, sedentary commuting and sedentary behavior at work identify 99 loci associated with at least one of these traits.

Analyses of gene–environment correlations across geographic regions for 56 complex traits in UK Biobank suggest that both passive and active sources of gene–environment correlation affect genetic association signals.

A powerful method for splicing quantitative trait loci (sQTL) mapping, THISTLE, is presented and applied to a collection of 2,865 brain samples. Integration with GWAS identifies 244 genes associated via cis-sQTLs, of which 61% were not identified using expression QTLs.

Cistrome-wide association study (CWAS) is an approach for nominating variants that impact traits through effects on chromatin state. CWAS performed on 307 prostate cistromes identifies candidate loci for prostate cancer and androgen-related traits.

A genomic and transcriptomic analysis of 2,754 childhood acute lymphoblastic leukemias identifies 376 putative driver genes, and associations between disease subtypes and prognosis.

A multi-omic analysis of pancreatic cancer identifies spatially resolved, heterogeneous cell populations including transitional cell types. Analysis of primary samples identifies treatment-related changes in cross-talk between tumor and stromal cells.

Sequencing of human induced pluripotent stem cell lines highlights pervasive mutagenesis, heterogeneity between clones derived from the same individual during a single reprogramming experiment and positive selection for acquired mutations in BCOR.

HIC2 regulates the fetal-to-adult hemoglobin switch. It inactivates an enhancer of the BCL11A gene, a fetal globin repressor, by reducing chromatin accessibility and displacing the transcription factor GATA1.

METTL3-dependent RNA N⁶-methyladenosine (m⁶A) deposition can lead to DNA demethylation. The m⁶A reader FXR1 recruits DNA 5-methylcytosine dioxygenase TET1 to chromatin, which is linked to chromatin accessibility and gene transcription.

The cattle Genotype–Tissue Expression atlas of expression and splicing QTLs is generated from 7,180 uniformly re-processed RNA-seq samples. Integration with GWAS identifies candidate genes and variants associated with economically important traits.