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The authors present the largest genome-wide association study to date for a rare Parkinsonian disorder, progressive supranuclear palsy (PSP). They include follow-up investigations of the identified susceptibility loci, functional consequences, and cell-specific pathologies, providing insights into genetic and molecular mechanisms underlying PSP.

Meta-analysis of genome-wide association studies on Alzheimer’s disease and related dementias identifies new loci and enables generation of a new genetic risk score associated with the risk of future Alzheimer’s disease and dementia.

The heterogeneity of whole-exome sequencing (WES) data generation methods presents a challenge to joint analysis. Here, the authors present a bioinformatics strategy to generate high-quality data from processing diversely generated WES samples, as applied in the Alzheimer’s Disease Sequencing Project.

Polygenic risk scores for Alzheimer’s disease derived from individuals of European ancestry can show improved performance in multiancestry settings after incorporating genome-wide association summary statistics from diverse populations.

Known genetic loci account for only a fraction of the genetic contribution to Alzheimer’s disease. Here, the authors have performed a large genome-wide meta-analysis comprising 409,435 individuals to discover 6 new loci and demonstrate the efficacy of an Alzheimer’s disease polygenic risk score.

Large genome-wide meta-analysis of clinically diagnosed late-onset Alzheimer’s disease (LOAD) from 94,437 individuals identifies new LOAD risk loci and implicates Aβ formation, tau protein binding, immune response and lipid metabolism.

Multi-omic profiling of brain tissue from patients with Alzheimer’s disease (AD) identifies gains in H3K27ac and H3K9ac linked to transcription and disease pathways. Increasing H3K27ac and H3K9ac in a fly model of AD exacerbates neurodegeneration.

APOE is the major genetic risk factor for Alzheimer’s disease. In a large number of neuropathologically confirmed cases and controls, the impact of different APOE genotypes on Alzheimer’s dementia risk was greater than previously thought and APOE2 homozygotes had an exceptionally low risk.

Whole-exome sequencing in a large autism study identifies over 100 autosomal genes that are likely to affect risk for the disorder; these genes, which show unusual evolutionary constraint against mutations, carry de novo loss-of-function mutations in over 5% of autistic subjects and many function in synaptic, transcriptional and chromatin-remodelling pathways.

Corticobasal degeneration is a rare neurodegenerative disorder that can only be definitively diagnosed by autopsy. Here, Kouri et al. conduct a genome-wide-association study and identify two genetic susceptibility loci 17q21 (MAPT) and 3p12 (MOBP), and a novel susceptibility locus at 8p12.

Sven van der Lee, Julie Williams, Gerard Schellenberg and colleagues identify rare coding variants in PLCG2, ABI3 and TREM2 associated with Alzheimer's disease. These genes are highly expressed in microglia and provide additional evidence that the microglia-mediated immune response contributes to the development of Alzheimer's disease.

By comparing the genome-wide profile of H4K16ac in AD with younger and elder controls, the authors propose a mechanism for how age is a risk factor for AD: a histone modification, whose accumulation is associated with aging, is dysregulated in AD.

Genome-wide analyses identify common variants associated with 11 distinct neuropathology endophenotypes, providing insights into the mechanisms underlying the genetic risk of Alzheimer’s disease and related dementias.

Multistage gene burden analysis in exome sequencing data from 32,558 individuals identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease.

The conserved microRNA miR-34 regulates age-associated events and long-term brain integrity in Drosophila, providing a molecular link between ageing and neurodegeneration.

Gerard Schellenberg and colleagues report a genome-wide association study of late-onset Alzheimer's disease (LOAD), as part of the Alzheimer Disease Genetics Consortium. They identify common variants in MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 associated with LOAD.

On antigen stimulation, CD8 T cells undergo a developmental program characterized by expansion and then contraction of antigen-specific effector (T_E) populations, followed by the persistence of long-lived memory (T_M) cells. During this transition, CD8 T cells are now shown to switch from glucose metabolism to fatty acid metabolism by a TRAF6-dependent mechanism.

Philippe Amouyel, Julie Williams, Gerard Schellenberg, Sudha Seshadri and colleagues report a meta-analysis of genome-wide association studies for late-onset Alzheimer's disease in 17,008 cases and 37,154 controls with replication in an additional 8,572 cases and 11,312 controls. They identify 11 loci newly associated with Alzheimer's disease.

Exome sequencing of 175 autism spectrum disorder parent–child trios reveals that few de novo point mutations have a role in autism spectrum disorder and those that do are distributed across many genes and are incompletely penetrant, further supporting extreme genetic heterogeneity of this spectrum disorder.

Gerard Schellenberg and colleagues report a genome-wide association study for progressive supranuclear palsy, a movement disorder with prominent tau neuropathology. They identified three new risk loci and confirmed the known risk locus at MAPT.

Vivianna Van Deerlin and colleagues report that common variants at 7p21 are associated with a subtype of frontotemporal lobar degeneration marked by TDP-43 inclusions. They further show that the risk alleles are associated with elevated brain expression of TMEM106B, which resides at the peak of association on 7p21.

David Whitcomb, Bernie Devlin and colleagues report the results of a genome-wide association study of pancreatitis. They identify common variants at two loci associated with risk of this disease, including one on the X chromosome that shows strong evidence of interaction with alcohol consumption.