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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.

Harnessing information from whole genome sequencing in 185 individuals, this study generates a high-resolution map of copy number variants. Nucleotide resolution of the map facilitates analysis of structural variant distribution and identification of the mechanisms of their origin. The study provides a resource for sequence-based association studies.

Steven McCarroll and colleagues present a detailed study of copy number variation of exons within the human HP (haptoglobin) gene. They show that HP exons undergo recurring deletions that, together with local SNP variation, influence LDL and total cholesterol levels in human populations.

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.

Steven McCarroll and colleagues examine common gene deletions in individuals that have undergone bone marrow transplantation. They find that risk of acute graft-versus-host disease is greater when the donor and recipient are mismatched for a homozygous deletion of UGT2B17.

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.

Structural variants (SVs) in human genomes contribute diversity and diseases. Here, the authors use a multi-platform strategy to generate haplotype-resolved SVs for three human parent–child trios.

Integrative anatomical, molecular, behavioral, and modeling evidence suggests that higher dopamine D1 receptor expression in prefrontal cortical parvalbumin neurons in marmosets likely contributes to their higher distractibility relative to macaques.

Using single-nucleus RNA sequencing data from patients with sporadic amyotrophic lateral sclerosis (ALS) cortices, the authors find that higher expression of ALS risk genes is accompanied by upregulation of stress responses in groups of extratelencephalic neurons. Analyses of glial nuclei revealed a downregulation of myelination genes in oligodendrocytes and upregulation of reactive state genes in microglia.

Transcriptome-wide analysis of differential expression (TRADE) is a broadly applicable tool for characterizing patterns of differential expression across the genome.

Steven McCarroll and colleagues use a population genetics approach to identify nine different structural forms of the 17q21.31 inversion region. They show that duplications have arisen independently on both ancestral forms of the inversion and have reached high frequencies in Europeans.

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.

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.

Steven McCarroll and colleagues report an analytical framework for characterizing genome deletion polymorphism in populations, applied here to the low coverage genome sequences of 168 individuals from the 1000 Genomes Project. Their population-aware analysis enables structural inference with greater accuracy than previous methods.

Steven McCarroll, Joel Hirschhorn and colleagues identify eight common structural forms of the human amylase locus. They measured amylase gene copy number in ~3,500 individuals and detected no association with BMI and obesity.

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.

A study shows that clonal haematopoiesis of indeterminate potential is associated with an increased risk of chronic liver disease specifically through the promotion of liver inflammation and injury.

The authors used deep metric learning to characterize 650 neuroactive compounds by zebrafish behavioral profiles. After redesigning a large screen to overcome AI/ML shortcut learning, zebrafish behavioral similarity found compounds acting on the same human receptors as structurally dissimilar drugs.

Duplicated genomic regions are accurately resolved using an optimized algorithm for mapping reads from next-generation sequencers.

Thousands of sperm genomes have been analysed with a new method called Sperm-seq, revealing interconnected meiotic variation at the single-cell and person-to-person levels, and suggesting chromosome compaction as a way to explain the relationships between diverse recombination phenotypes.

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.

Calcium-permeable AMPA receptors are identified to have a role in maintaining low feature selectivity in a specific population of inhibitory interneurons, and this function is conserved across ferrets, rodents, marmosets and humans.

Genome-wide association analyses of 41,917 bipolar disorder cases and 371,549 controls of European ancestry provide new insights into the etiology of this disorder and identify novel therapeutic leads and potential opportunities for drug repurposing.

Phenotypic selection analysis is used to estimate the type and strength of selection that acts on more than 15,000 transcripts in rice (Oryza sativa), which provides insight into the adaptive evolutionary role of selection on gene expression.

Genome-wide meta-analysis with individuals of East Asian or European ancestry identifies 176 loci associated with schizophrenia. Despite consistent genetic effects across populations, polygenic risk models trained in one population have reduced performance in the other population.

A genome-wide association study and Metabochip meta-analysis of body mass index (BMI) detects 97 BMI-associated loci, of which 56 were novel, and many loci have effects on other metabolic phenotypes; pathway analyses implicate the central nervous system in obesity susceptibility and new pathways such as those related to synaptic function, energy metabolism, lipid biology and adipogenesis.

Maps of human genome copy number variation (CNV) are maturing into useful resources for complex disease genetics. Four new studies increase the resolution of CNV maps and seek to locate human phenotypic variation on these maps.

A strategy for inferring phase for rare variant pairs is applied to exome sequencing data for 125,748 individuals from the Genome Aggregation Database (gnomAD). This resource will aid interpretation of rare co-occurring variants in the context of recessive disease.

A genomic constraint map for the human genome constructed using data from 76,156 human genomes from the Genome Aggregation Database shows that non-coding constrained regions are enriched for regulatory elements and variants associated with complex diseases and traits.

In this largest whole-exome sequencing study of epilepsies to date, the Epi25 Collaborative identified extremely rare variants that confer risk for diverse epilepsy subtypes, highlighting roles in synaptic transmission and neuronal excitability.

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

Overexpression of complement C4A is associated with schizophrenia risk. Using a novel mouse model, Yilmaz et al. find that increased expression of C4A leads to abnormal synaptic pruning and behavior, suggesting its importance as a therapeutic target.

David Altshuler and colleagues report the design of a hybrid SNP-CNV genotyping array (Affymetrix SNP 6.0 Array) allowing for integrated SNP and CNV detection. They describe its application to 270 HapMap samples to compile a high-resolution map of over 1,500 copy number polymorphisms, and related population-genetic analyses.

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.

Incorporating protein-altering copy number variants ascertained from UK Biobank whole-exome sequencing data into analyses of rare predicted loss-of-function variants identifies complex trait associations not detectable using standard analysis methods.

Synaptic connections are critical for brain function but are hard to measure systematically. Here, authors present a method which uses rabies virus barcoding and single-cell RNAseq to parallelize monosynaptic network reconstruction from molecularly-profiled single cells.

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.

A single-cell multiomics analysis of over 200,000 cells of the primary motor cortex of human, macaque, marmoset and mouse shows that divergence of transcription factor expression corresponds to species-specific epigenome landscapes, and conserved and divergent gene regulatory features are reflected in the evolution of the three-dimensional genome.

David Altshuler and colleagues describe analysis for integrating genotype calling of SNPs, common copy number polymorphisms and rare CNVs, implemented in a suite of software programs collectively named Birdsuite.

Characterizing how genetic variation impacts cell morphology can provide an important links between disease association and cellular function. Here the authors identified the morphological impacts of genomic variants by generating high-throughput morphological profiling and whole genome sequencing data on iPSCs from 297 donors.

Single-nucleus RNA-sequencing analyses of brain from humans, macaques, marmosets, mice and ferrets reveal diverse ways that interneuron populations have changed during evolution.

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.

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.

Circulating lipoprotein(a) is an important risk factor for cardiovascular disease and shows variability between different ethnic groups. Here, Zekavat et al. perform whole-genome sequencing in individuals of European and African ancestries and find ancestry-specific genetic determinants for lipoprotein(a) levels.

A catalogue of predicted loss-of-function variants in 125,748 whole-exome and 15,708 whole-genome sequencing datasets from the Genome Aggregation Database (gnomAD) reveals the spectrum of mutational constraints that affect these human protein-coding genes.