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Regulation of gene expression and splicing are thought to be tissue-specific. Here, the authors obtain genomic and transcriptomic data from putamen and substantia nigra of 117 neurologically healthy human brains and find that splicing eQTLs are enriched for neuron-specific regulatory information.

3’ untranslated regions (3’UTRs) play a crucial role in regulating gene expression, but our 3’UTR catalogue is incomplete. Here, the authors develop a machine learning-based framework to predict previously unannotated 3’UTRs in 39 human tissues.

Zarkali and colleagues studied brain connectivity in 108 people with Lewy body disease. They found distinct structural cortical reorganisation linked to cognitive, not motor symptoms and implicated excitatory RORB4 neurons in dementia-associated changes.

Expression quantitative trait loci (eQTLs) are genomic regions that regulate gene expression. Here the authors provide a publicly available data set of exon-level eQTLs across the human brain. This includes many genome-wide association study (GWAS) hits for neurological and psychiatric disorders.

An optical detection and analysis platform quantifies aggregate density, distribution and size in fluorescently labelled post-mortem human brain tissue.

Knowledge of genomic features specific to humans may be important for understanding disease. Here the authors demonstrate a potential role for these human-lineage-specific sequences in brain development and neurological disease.

Men and women differ in terms of their neurochemistry, behaviour and susceptibility to disease. Here the authors show that sex differences in gene expression and splicing are widespread in adult human brain, and that sex-biased expression is likely to have functional consequences.

A rare variant burden analytical framework for Mendelian diseases was developed and applied to data from the 100,000 Genomes Project, identifying 69 probable new disease–gene associations.

Here, the authors describe a noncoding genetic variant in GBA1 specific to people of African ancestry that increases the risk of neurodegenerative diseases by interfering with the splicing of mRNA, resulting in lowered protein levels and activity.

Fairbrother-Browne and collaborators analyze the relationship between nuclear and mitochondrial gene expression across the human brain and find correlation profiles that are governed by regional patterns. They show that these correlations are disrupted in neurodegenerative diseases, suggesting the relevance of mito-nuclear interactions for normal brain function.

The landscape of RNA isoforms in human cortex is revealed by deep long-read RNA sequencing.

REM-sleep behavior disorder often precedes Parkinson’s disease or dementia. Here, the authors perform a genome-wide association study for REM-sleep behavior disorder, and discover how it potentially affects gene expression in the brain.

The natural antisense transcript MAPT-AS1 interferes with translation of mRNA transcript into tau protein in the brain and may represent a general mechanism for controlling levels of intrinsically disordered proteins, with particular relevance for neurodegeneration.

Whole-genome sequence analysis identifies five independent risk loci for Lewy body dementia and demonstrates overlapping genetic architecture with Alzheimer’s and Parkinson’s diseases.

The hippocampus in mammalian brain varies in size across individuals. Here, Hibar and colleagues perform a genome-wide association meta-analysis to find six genetic loci with significant association to hippocampus volume.

Whole-exome sequencing reveals that a rare variant of phospholipase D3 (PLD3(V232M)) segregates with Alzheimer’s disease status in two independent families and doubles risk for the disease in case–control series, and that several other PLD3 variants increase risk for Alzheimer’s disease in African Americans and people of European descent.

In a GWAS study of 32,438 adults, the authors discovered five novel loci for intracranial volume and confirmed two known signals. Variants for intracranial volume were also related to childhood and adult cognitive function and to Parkinson's disease, and enriched near genes involved in growth pathways, including PI3K-AKT signaling.

Pluripotent stem cells can be generated from the somatic cells of humans and are a useful model to study disease. Here, pluripotent stem cells are made from a patient with familial Parkinson's disease, and the resulting neurons exhibit elevated levels of α-synuclein, recapitulating the molecular features of the patient's disease.

Paul Thompson and colleagues report a genome-wide association study for hippocampal, intracranial and total brain volume. They identify a locus at 12q24 associated with hippocampal volume and a locus at 12q14 associated with intracranial volume.

There is currently no disease-modifying treatment for Parkinson’s disease, a common neurodegenerative disorder. Here, the authors use genetic variation associated with gene and protein expression to find putative drug targets for Parkinson’s disease using Mendelian randomization of the druggable genome.

Developmental disorders (DDs) are more prevalent in males, thought to be due to X-linked genetic variation. Here, the authors investigate the burden of X-linked coding variants in 11,044 DD patients, showing that this contributes to ~6% of both male and female cases and therefore does not solely explain male bias in DDs.

By integrating healthcare and exome-sequencing data from parent–offspring trios of patients with developmental disorders, 28 genes that had not previously been associated with developmental disorders were identified.

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.

Ageing increases the risk of many diseases. Here the authors compare blood cell transcriptomes of over 14,000 individuals and identify a set of about 1,500 genes that are differently expressed with age, shedding light on transcriptional programs linked to the ageing process and age-associated diseases.

Genome-wide association studies are used to identify common genetic variants that affect the structure of selected subcortical regions of the human brain; their identification provides insight into the causes of variability in brain development and may help to determine mechanisms of neuropsychiatric dysfunction.

Highly conserved recursive splice sites are identified in vertebrates, particularly within long genes encoding proteins that are involved in neuronal development; analysis of the splicing mechanism reveals that such recursive splicing sites can be used to dictate different mRNA isoforms.

Nik-Zainal and colleagues leverage CRISPR–Cas9 and whole-genome sequencing to examine mutational patterns following knockout of 42 human DNA repair genes. They further develop and validate a clinically relevant tool to detect mismatch repair-deficient tumors.

Sérgio Sousa and colleagues show that Lenz-Majewski syndrome, a disorder featuring generalized craniotubular hyperostosis, results from de novo gain-of-function mutations in PTDSS1. The mutations lead to increased phophatidylserine synthesis, suggesting a link between phosphatidylserine production and bone metabolism.

Comprehensive analysis of existing GWAS summary statistic and gene expression data illustrate significant regional correlations between different neurodegenerative diseases and single-cell immune-related eQTLs.