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Via an integrative modelling approach that combines population and clinical trial data, the authors find that polygenic risk score-based screening would reduce premature mortality across seven commonly screened conditions.

This report from the 1000 Genomes Project describes the genomes of 1,092 individuals from 14 human populations, providing a resource for common and low-frequency variant analysis in individuals from diverse populations; hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites, can be found in each individual.

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.

Gil McVean and colleagues present a new Bayesian analysis framework that exploits the hierarchical structure of diagnosis classifications to analyze genetic variants against UK Biobank disease phenotypes derived from self-reporting and hospital episode statistics. Their method displays increased power to detect genetic effects over other approaches and identifies novel associations between classical HLA alleles and common immune-mediated diseases.

Various host factors may impact within-host pathogen evolution. Here, the authors develop a Bayesian approach for identifying host-pathogen interactions using large data sets of pathogen diversity, and apply it to investigate HLA-induced selection in the HIV-1 genome.

Gil McVean and colleagues report algorithms for de novo assembly and genotyping of variants using colored de Bruijn graphs and provide these in a software implementation called Cortex. Their methods can detect and genotype both simple and complex genetic variants in either an individual or a population.

Gil McVean and colleagues examine recombination hot spots in the human genome, using new search methods and drawing on HapMap II to identify an extended family of hot spot–associated motifs. They report a common sequence motif estimated to be found in ∼40% of recombination hot spots.

Gil McVean and Iain Mathieson report an analysis of the differential effects of population stratification on rare and common variants within association studies. They find that rare variants may show stronger stratification in some situations and that this is not corrected for by current structure methods, suggesting the need for the development of new statistical methods.

Gil McVean and colleagues report a meta-analysis of Immunochip studies including over 17,000 multiple sclerosis cases and 30,000 controls, with imputation of classical HLA alleles. They find two interactions involving class II HLA alleles but no evidence for significant epistatic interactions or interactions between HLA and non-HLA risk variants.

Gil McVean, Alexander Dilthey and colleagues present a graphical model-based method for accurate genomic assembly that uses the diversity present in multiple reference sequences, as represented by a population reference graph. The method is applied to simulated and empirical data from the human MHC region to demonstrate the improved accuracy of genomic inference.

Isolated populations may empower genetic association studies of complex traits. Here, the authors identify a rare cardioprotective APOC3variant in a Greek population isolate and highlight the value of using population isolates to detect rare variants that confer disease risk.

Age-dependent topic modeling provides a low-rank representation of longitudinal disease records and identifies diseases with heterogeneous comorbidity profiles, defining subtypes that exhibit distinct genome-wide and locus-specific association patterns.

The goal of the 1000 Genomes Project is to provide in-depth information on variation in human genome sequences. In the pilot phase reported here, different strategies for genome-wide sequencing, using high-throughput sequencing platforms, were developed and compared. The resulting data set includes more than 95% of the currently accessible variants found in any individual, and can be used to inform association and functional studies.

A method to cluster genetic risk profiles applied to 3,025 loci across 19,155 disease codes from over 300,000 individuals in the UK Biobank identifies 339 distinct disease association profiles and links clusters to biological pathways.

There are challenges with transferring genetic risk scores from ancestry in which they were generated to another. Here, the authors investigate the use of multi-ancestry versus single-ancestry training sets to construct polygenic scores and find that the optimal strategy varies across traits.

A new study demonstrates that PRDM9 variation in humans leads to profound differences in the activity of hotspots for both allelic recombination and genomic instability. Although PRDM9 is found to play a role in many more human hotspots than previously suspected, the search remains for additional, undetermined factors involved in defining hotspot locations and intensities.

Genome-wide analyses of vaccine antibody responses in 2,499 infants from Uganda, South Africa and Burkina Faso identify associations between specific HLA genes and response to eight vaccines, providing insights that could be considered for population-adjusted vaccine design strategies.

Natural Killer cells regulate foetal growth. Here the authors use a humanized transgenic mouse to demonstrate that specific HLA-C KIR2DL interactions promote changes in maternal and foetal cell transcriptomes, resulting in modifications to placental vasculature, intercellular communications and foetal growth restriction.

Here, the authors design a multiplex serology platform to quantitatively measure antibodies against 20 infectious agents in UK Biobank participants and confirm associations of antibody responses with sociodemographic characteristics, HLA genetic variants, and disease outcomes.

Genome-wide association analysis of irritable bowel syndrome identifies genetic susceptibility loci and highlights shared pathways with mood and anxiety disorders.

A new method for inferring genealogical histories from large-scale genetic data is used to characterize population structure using data from the 1000 Genomes Project, the UK Biobank and the Simons Genome Diversity Project.

The global set of bacterial and viral sequences can be rapidly searched using a data structure inspired by web-search algorithms.

Deep phenotype and genome-wide genetic data from 500,000 individuals from the UK Biobank, describing population structure and relatedness in the cohort, and imputation to increase the number of testable variants to 96 million.

The clinical application of new sequencing techniques is expected to accelerate pathogen identification. Here, Bradley et al. present a clinician-friendly software package that uses sequencing data for quick and accurate prediction of antibiotic resistance profiles for S. aureus and M. tuberculosis.

Isolated populations can increase power to detect low frequency and rare risk variants associated with complex phenotypes. Here, the authors identify variants associated with haematological traits in two isolated Greek populations that would be difficult to detect in the general population, due to their low frequency.

HLA-C expression levels correlate with immune responses to pathogens and autoimmunity, and vary in an allele-specific manner across individuals. Here the authors identify factors that drive differential expression of HLA-C allomorphs at the cell surface, and influence the structure of the peptide-binding cleft and diversity of peptides bound by HLA-C molecules.

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.

Ian Henderson and colleagues report fine-scale mapping and characterization of recombination rates in Arabidopsis thaliana. They find an enrichment of recombination hot spots overlapping transcription start and termination sites, as well as that hot spot–associated promoter regions show elevated levels of chromatin marks, including high H2A.Z, high H3K4me3 and low nucleosome density.

Sequencing data from two large-scale studies show that most of the genetic variation influencing the risk of type 2 diabetes involves common alleles and is found in regions previously identified by genome-wide association studies, clarifying the genetic architecture of this disease.

The International Multiple Sclerosis Genetics Consortium reports the discovery of 48 new susceptibility variants for multiple sclerosis through targeted follow-up of immune-related loci. They also report fine mapping of association signals at established susceptibility loci and provide insights into the immune system processes underlying this disease.

Gerton Lunter and colleagues report Platypus software, which combines a haplotype-based multi-sample variant caller with local sequence assembly in a Bayesian statistical framework. They demonstrate applications to exome and whole-genome data sets, to the identification de novo mutations in parent-offspring trios and to the genotyping of HLA loci.

A deletion that removes 1.6 Mb of DNA and several genes from the Y chromosome increases its carriers' chance of infertility, yet is present in ∼2% of men. The Y chromosome can no longer be regarded as a neutral locus in evolutionary studies.

Joint likelihood mapping across six autoimmune diseases identifies shared and distinct association signals and improves fine-mapping resolution at loci with shared effects, yielding insights into the underlying biological mechanisms.

Four genome-wide associated loci are currently known for malaria susceptibility. Here, the authors expand on earlier work by combining data from 11 malaria-endemic countries and additional population sequencing informing an African-enriched imputation reference panel, with findings including a previously unreported association on chromosome 6.

Neuroinflammation is central in many neurological conditions, and 'big data' have the potential to elucidate the complexity of inflammatory processes. This Review considers how the drive to collect and analyse big data is increasing our understanding of neuroinflammation in disease, and how these data can be used to improve clinical management.

Bladder cancer is a complex genetic disease and a common cause of death due to malignancy. Here, the authors carry out whole-genome sequencing of 14 bladder cancers to characterize the genomic landscape of the disease and show that mutational burden is associated with tumour progression in these samples.

Here, the analysis of 'HapMap 3' is reported — a public data set of genomic variants in human populations. The resource integrates common and rare single nucleotide polymorphisms (SNPs) and copy number polymorphisms (CNPs) from 11 global populations, providing insights into population-specific differences among variants. It also demonstrates the feasibility of imputing newly discovered rare SNPs and CNPs.

1000 Genomes imputation can increase the power of genome-wide association studies to detect genetic variants associated with human traits and diseases. Here, the authors develop a method to integrate and analyse low-coverage sequence data and SNP array data, and show that it improves imputation performance.

Copy number variants (CNVs) account for a major proportion of human genetic diversity and may contribute to genetic susceptibility to disease. Here, a large, genome-wide study of association between common CNVs and eight common human diseases is presented. The study provides a wealth of technical insights that will inform future study design and analysis. The results also indicate that common CNVs that can be 'typed' on existing platforms are unlikely to contribute much to the genetic basis of common diseases.

Rajesh Thakker and colleagues show that missense mutations affecting codon 15 of AP2S1 cause familial hypocalciuric hypercalcemia type 3, a disorder of calcium homeostasis. AP2S1 encodes a protein involved in clathrin-mediated endocytosis, and the mutations probably cause disease by disrupting internalization of the calcium-sensing receptor CaSR.

Genome-wide association studies in combination with functional analyses identify a genetic variant that explains why anti-tumour necrosis factor therapy, used in several autoimmune diseases, exacerbates multiple sclerosis.