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Plasma proteomic analysis of presymptomatic individuals with amyotrophic lateral sclerosis identifies novel disease-associated proteins and enables the development of an accurate diagnostic biomarker panel.

Chronic Kidney Disease affects 1 in 10 people worldwide with prevalence continuing to rise, thus there is a need to identify novel biomarkers that can add value to existing clinical and biochemical risk predictors. Here the authors identify miR190a-5p as potential indicator of kidney health and disease progression in patients with chronic kidney disease.

Chesi et al. use exome sequencing of trios consisting of subjects with amyotrophic lateral sclerosis and their parents to find de novo variants in 25 genes, one of which is the chromatin regulator SS18L1 (CREST).

Zhao et al. generated models from whole blood gene expression to predict amyotrophic lateral sclerosis case-control status and combined gene features with clinical variables to predict survival, both validated in an external independent dataset.

The socioeconomic burden of amyotrophic lateral sclerosis (ALS) is high, but the projected number of cases in the upcoming years is unclear. Here, the authors estimate the number and distribution of ALS cases to 2040, and show that cases are projected to increase, particularly in developing nations.

The authors find that TDP-43 loss of function—the pathology defining the neurodegenerative conditions ALS and FTD—induces novel mRNA polyadenylation events, which have different effects, including an increase in RNA stability, leading to higher protein levels.

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.

Cross-species transcriptomics on vulnerable neuronal populations unravels the transcription factor CREB3 and its regulatory network as resilience markers of ALS. Genetics and epidemiology further identify the protective rare variant CREB3R119G.

The past year has seen some extraordinary activity in clinical amyotrophic lateral sclerosis (ALS) research. Two trials were completed, with negative results, but the discovery of novel ALS-associated genes, and body fluid and imaging biomarkers warrants cautious optimism. Here, we provide a snapshot of some of the main findings in 2014.

This study identifies a fluid biomarker of TDP-43 dysfunction, a central pathological feature of the ALS–FTD disease spectrum, and demonstrates that such loss of TDP-43 splicing repression occurs presymptomatically.

A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology.

This work introduces a wet lab and computational pipeline, Napu, for small variant calling and de novo assembly of Nanopore sequencing data, which leads to comparable performances to short-read sequencing and allows for large-scale long-read sequencing projects.

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.

A report detailing genotype data for over 500,000 markers in the human genome by examining 29 populations in the Human Genome Diversity Project.

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.

The identification of pathogenic mutations within prion-like domains (PrLDs) of the RNA-binding proteins hnRNPA2B1 and hnRNPA1 add to our understanding of how mutations in these proteins lead to degenerative disease, and highlight the potential importance of PrLDs in degenerative diseases of the nervous system, muscle and bone.

DNA sequencing of 3,864 individuals with ALS and 7,839 controls identified a novel disease gene, DNAJC7, which encodes a heat-shock protein. As DNAJC7 is an essential part of cell maintenance, mutations in DNAJC7 may lead to neurodegeneration.

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.

The authors identify mutations in the MATR3 gene as a cause of ALS and dementia in several families. MATR3 is known to bind the ALS-associated protein TDP-43, and at least one of these mutations alters the efficiency of this binding.

Two studies highlight the evolution of antisense oligonucleotide therapy for amyotrophic lateral sclerosis, offering hope for an effective treatment.

In this Review, the authors discuss our growing knowledge of the underlying genetics of amyotrophic lateral sclerosis (ALS; also known as motor neuron disease). They discuss how this information provides insight into causal disease mechanisms and translational opportunities for developing clinical therapeutics.

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.

Verneri Anttila and colleagues report meta-analysis of 29 genome-wide association studies for migraine. They identify five loci newly associated with migraine, three of which are associated with specific subtypes of migraine with or without aura.

Andrew Singleton, Thomas Gasser and colleagues report results of a genome-wide association study of Parkinson's disease among individuals of European ancestry. They find genome-wide significant associations at two loci, SNCA and MAPT, and provide supporting evidence for a new risk locus on 1q32.

In this review, the authors examine how the identification and analysis of genes associated with ALS have begun to provide insight into the onset and pathology of this motor disease. In addition, they discuss some emerging themes that are poised to inform future efforts to identify further gene targets.

An epigenome-wide association study of dementia with Lewy bodies discovers differentially methylated probes, genomic regions and pathways associated with this disease.

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.