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Experimental haplotyping of whole genomes is now feasible, enabling new studies aimed at linking sequence variation to human phenotypes and disease susceptibility.

Precision medicine requires a different type of clinical trial that focuses on individual, not average, responses to therapy, says Nicholas J. Schork.

This Opinion article argues that capturing phase information in human genomics studies is crucial for important aims such as understanding how genotype contributes to phenotypes. existing approaches for phasing will need to be improved in order to meet this goal.

Complete sequences of chromosomes telomere-to-telomere from chimpanzee, bonobo, gorilla, Bornean orangutan, Sumatran orangutan and siamang provide a comprehensive and valuable resource for future evolutionary comparisons.

Genome-wide analysis identifies 30 loci associated with bipolar disorder, allowing for comparisons of shared genes and pathways with other psychiatric disorders, including schizophrenia and depression.

How genetic variation contributes to brain morphology is still poorly understood. Here Chenet al. combine brain imaging with single-nucleotide polymorphism data to discover that a substantial degree of cortical variation is derived from underlying genetic differences.

Ken Ong and colleagues report meta-analysis of 32 genome-wide association studies for age at menarche. They identify 30 loci newly associated with age at menarche, including four that were previously associated with BMI.

The race is on to find interventions that improve health and promote longevity. The mechanisms behind and possible benefits of one such intervention, dietary restriction, are more complex than previously thought.

Individual genome-wide polygenic risk scores (GPSs) for assessing disease susceptibility have been shown to yield both reliable and clinically meaningful results. However, certain impediments and outdated ways of thinking about health maintenance must be overcome before GPSs are adopted in routine care streams.

Genome-wide analysis identifies variants associated with the volume of seven different subcortical brain regions defined by magnetic resonance imaging. Implicated genes are involved in neurodevelopmental and synaptic signaling pathways.

There is increasing interest in investigating the influence of rare variants on common diseases, aided by high-throughput sequencing. However, the statistical approaches that are essential for analysing associations between rare variants and traits of interest are urgently in need of evaluation and refinement.

The antiplatelet drug clopidogrel helps prevent stent-associated thrombosis, but the antiplatelet effects are quite variable and the clinical consequences can be serious. New findings show that the variability in clopidogrel efficacy is affected by the enzyme paraoxonase-1 (PON1), which is required for clopidogrel bioactivation (pages 110–116).

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.

Meta-analyses of genome-wide association studies for endometriosis identify 49 distinct association signals. Fine-mapping of causal variants explores functional effects across various tissues. Genetic correlations between endometriosis and other pain conditions are also highlighted.

Two new studies report improved statistics to predict whether an individual participated in a genome-wide association study based on aggregate allele or genotype frequency information. They demonstrate that it may be possible to release summary statistics for a subset of genetic markers in a study while maintaining individual privacy.

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.

Better analytical methods are needed to extract biological meaning from genome-wide association studies (GWAS) of psychiatric disorders. Here the authors take GWAS data from over 60,000 subjects, including patients with schizophrenia, bipolar disorder and major depression, and identify common etiological pathways shared amongst them.

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.

Integration of GWAS and single-cell transcriptomic data from the entire nervous system systematically identifies cell types underlying brain complex traits and provides insights into the etiology of Parkinson’s disease.

A population epigenomic analysis of wild Arabidopsis thaliana accessions is presented, obtained by sequencing their whole genomes, methylomes and transcriptomes; thousands of DNA methylation variants are identified, some of which are associated with methylation quantitative trait loci.

The authors use single-nucleus RNA-seq to identify 10 GABAergic interneuron subtypes in human cortex layer 1. Molecular, morphological, and physiological evidence points to an emerging human cell type, the rosehip cell, not found in other species.

Little is known about von Economo neurons, which have been described in a subset of mammals and appear to be selectively lost in several human neurological diseases. Here, authors reveal the gene expression profile of these cells and show that they are likely long-distance projection neurons.

Amalio Telenti, Craig Venter and colleagues report common, low-frequency and rare variants associated with blood metabolite levels using whole-genome sequencing and comprehensive metabolite profiling in 1,960 individuals. They identify 246 metabolites whose levels are associated with genetic variation at 101 loci.

Genome-wide analyses identify eight independent loci associated with anorexia nervosa. Genetic correlations implicate both psychiatric and metabolic components in the etiology of this disorder, even after adjusting for the effects of common variants associated with body mass index.

Genome-edited human pluripotent stem cells and genome-edited mouse models reveal that combinatorial genetic interactions contribute to the complex genetic heritability of human cardiomyopathy.

ALK is identified as a neuroblastoma predisposition gene. Germline mutations were found in ALK, a tryrosine kinase receptor, in affected families. In addition, somatic point mutations in ALK were found in sporadic cases of neuroblastomas. ALK mutations seem to lead to constitutive activation of its kinase activity and promote cell proliferation.

It is feared that reprogramming may introduce DNA mutations. Here Bhutani et al. take three different reprogramming methods and using comparative whole genome analyses do identify nucleotide variations that are different in reprogrammed cells from the original fibroblasts, but none convey oncogenic potential.

We consider the shift from broad, population-level medicine to ultra-precise, individualized medicine using emerging therapeutic constructs, AI, deep phenotyping, and individual-centered trials to optimize health across diverse individual genetic and physiological profiles.

Socioeconomic status is associated with cognitive development, but the extent to which this reflects neuroanatomical differences is unclear. In 1,099 children and adolescents, family income was nonlinearly associated with brain surface area, and this association was greatest among disadvantaged children. Further, surface area mediated links between income and executive functioning.

Endometriosis is a major cause of infertility. Molecular mechanisms underlying the disease involve genetic and environmental risk factors. In a meta-analysis of eleven GWA studies, Sapkota and colleagues identify five novel risk loci, implicating steroid sex hormone pathways in the pathogenesis.

Protein kinases are one of the largest gene families in humans. Through a comprehensive survey of kinase mutations the authors highlight the structure–function relationships that control the activities of these proteins and their contribution to a varied set of human diseases.

This protocol describes how to sequence the transcriptome from a single nucleus. It is particularly suited to cell types that are difficult to isolate as intact whole cells, such as neurons.

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.

Naomi Wray and colleagues report an analysis of genome-wide association data sets from the Psychiatric Genomics Consortium for five psychiatric disorders. They find that common variation explains 17–29% of the variance in liability and provide further support for a shared genetic etiology for these related psychiatric disorders.

The last few years have seen extensive efforts to catalogue human genetic variation and elucidate its relationship to phenotypes, especially disease. Important challenges lie ahead in this area, particularly in relation to the contribution of rare and copy number variants.