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Here the authors conduct a multi-ancestry meta-analysis of telomere length, used diverse approaches to identify genes underlying association signals, and experimentally validated POP5 and KBTBD6 as regulators of telomere length in human cells.

Platelet aggregation is associated with myocardial infarction and stroke. Here, the authors have conducted a whole genome sequencing association study on platelet aggregation, discovering a locus in RGS18, where enhancer assays suggest an effect on activity of haematopoeitic lineage transcription factors.

MultiSTAAR provides a general and flexible statistical framework for functionally informed multi-trait rare variant analysis of biobank-scale sequencing studies by jointly analyzing multiple traits and incorporating annotation information.

Using data from a single time point, passenger-approximated clonal expansion rate (PACER) estimates the fitness of common driver mutations that lead to clonal haematopoiesis and identifies TCL1A activation as a mediator of clonal expansion.

STAARpipeline is a comprehensive framework for flexible and scalable rare-variant association analysis using whole-genome sequencing data and annotation information.

STAAR is a powerful rare variant association test that incorporates variant functional categories and complementary functional annotations using a dynamic weighting scheme based on annotation principal components. STAAR accounts for population structure and relatedness and is scalable for analyzing large whole-genome sequencing studies.

Here, the authors suggest that molecular dysregulation on three axes may play a critical role in asthma within the African Diaspora. RNASeq and DNA methylation data are generated from nasal epithelium including cases and controls from seven different geographic sites.

The Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) aims to better understand population genetics of the African diaspora. Here, it uses deeply sequenced whole-genomes to describe the impact of admixture and potential disease burden of deleterious variants.

Personalized medicine requires accurate and ethnicity-optimized reference genome panels. Here, the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) evaluates typical variant filters and existing genome databases against newly sequenced African-ancestry populations.

The burden of asthma varies between ancestries, but GWAS have so far focused on mainly European ancestry populations. Here, Daya et al. perform GWAS for asthma in 14,654 individuals of African ancestry and, besides confirming previously known loci, identify two potentially African ancestry-specific loci.

Analyses of genome and exome sequencing data identify rare coding and structural variants associated with atrial fibrillation and highlight genetic links between atrial fibrillation and cardiomyopathies.

Analysis of whole-genome sequences of 25,465 individuals of European ancestry shows that rare variants contribute substantially to the heritability of height and body mass index.

Here, the authors use passenger mutations to quantify expansion rate in ~6,000 people with mosaic chromosomal alterations in the NHLBI TOPMed cohort, finding associations between growth rate and blood counts along with germline genetic modulators of growth rate.

Michael Bamshad and colleagues report an exome sequencing study of extreme phenotypes to identify genetic variants that modify the risk for chronic Pseudomonas aeruginosa airway infection in individuals with cystic fibrosis.

Although the common genetic variants contributing to blood lipid levels have been studied, the contribution of rare variants is less understood. Here, the authors perform a rare coding and noncoding variant association study of blood lipid levels using whole genome sequencing data.

A method that allows for the detection of mosaic chromosomal alterations from blood whole-genome sequencing data highlights ancestry-specific differences in the distribution of common and rare germline susceptibility variants.

The authors perform meta-analysis of GWAS studies for asthma from multiancestral cohorts. They identify five new loci and find that the asthma-associated loci are enriched near enhancer marks in immune cells.

The goals, resources and design of the NHLBI Trans-Omics for Precision Medicine (TOPMed) programme are described, and analyses of rare variants detected in the first 53,831 samples provide insights into mutational processes and recent human evolutionary history.

Analysis of 97,691 high-coverage human blood DNA-derived whole-genome sequences enabled simultaneous identification of germline and somatic mutations that predispose individuals to clonal expansion of haematopoietic stem cells, indicating that both inherited and acquired mutations are linked to age-related cancers and coronary heart disease.

The influence of X chromosome genetic variation on blood lipids and coronary heart disease (CHD) is not well understood. Here, the authors analyse X chromosome sequencing data across 65,322 multi-ancestry individuals, identifying associations of the Xq23 locus with lipid changes and reduced risk of CHD and diabetes mellitus.

Common variants account for only a small amount of the heritable risk for developing asthma. Using a meta-analysis approach, Igartua et al. identify one low-frequency missense mutation and two genes with functional variants that are associated with asthma, but only in specific ethnic groups.

Most polygenic risk score (PRS) methods focus only on individuals with distinct primary continental ancestry, without accommodating recently-admixed individuals. Here, the authors develop a novel penalized regression-based PRS method specifically designed for admixed individuals.

Most genetic association studies have been done on single nucleotide polymorphisms and small indels, while other types of variants have been less studied. Here, the authors use whole genome sequencing in a diverse population to identify and provide experimental evidence for associations between structural variants and blood-cell traits.

Drugs targeting cardiovascular disease (CVD) can have negative consequences for liver function. Here, the authors combine genome wide analyses on 69,479 individuals to identify loss-of-function variants with beneficial effects on CVD-related traits without negative impacts on liver function.

Both rare and common variants contribute to the aetiology of complex traits such as type 2 diabetes (T2D). Here, the authors examine the effect of coding variation on glycaemic traits and T2D, and identify low-frequency variation in GLP1Rsignificantly associated with these traits.

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.

Exploring the clonal expansion of somatically mutated hematopoietic stem cells with aging, Mack, Raddatz et al. quantify rates of clonal expansion in 4,370 individuals in the Trans-Omics for Precision Medicine cohort, observing epigenetic and proteomic patterns associated with clonal hematopoiesis of indeterminate potential.

Louise Wain, Ian Hall, Martin Tobin and colleagues report genome-wide association analyses of lung function, identifying 43 new signals associated with one or more lung function traits. A genetic risk score derived from these results was significantly associated with risk for chronic obstructive pulmonary disease in independent populations.

Cathy Laurie and colleagues detect mosaicism for large chromosomal abnormalities in peripheral blood in a subset of healthy individuals. They show that the frequency of such events increases with age and is associated with elevated risk of developing a subsequent hematological cancer.

de Vries, Conomos, Singh and Nicholson et al. identify two additional loci associated with coronary artery calcification (ARSE and MMP16) via a genome-wide association study in 22,400 participants from multiple ancestral groups and prove that ARSE is a mediator of vascular smooth muscle cell calcification and phenotype switching.

A study shows that clonal haematopoiesis of indeterminate potential is associated with an increased risk of chronic liver disease specifically through the promotion of liver inflammation and injury.

John Novembre and colleagues present a new approach for constructing recombination maps based on ancestry switch points among individuals. They construct a high-resolution genome-wide recombination map based on admixed African-American and African-Caribbean individuals and compare this to previous recombination maps.

Most studies of the genetics of the metabolome have been done in individuals of European descent. Here, the authors integrate genomics and metabolomics in Black individuals, highlighting the value of whole genome sequencing in diverse populations and linking circulating metabolites to human disease.

Pooling participant-level genetic data into a single analysis can result in variance stratification, reducing statistical performance. Here, the authors develop variant-specific inflation factors to assess variance stratification and apply this to pooled individual-level data from whole genome sequencing.

Assembly of a pan-genome from 910 humans of African descent identifies 296.5 Mb of novel DNA mapping to 125,715 distinct contigs. This African pan-genome contains ~10% more DNA than the current human reference genome.

An analysis of 16 health-related quantitative traits in approximately 350,000 individuals reveals statistically significant associations between genome-wide homozygosity and four complex traits (height, lung function, cognitive ability and educational attainment); in each case increased homozygosity associates with a decreased trait value, but no evidence was seen of an influence on blood pressure, cholesterol, or ten other cardio-metabolic traits.

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.

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.

Dan Nicolae, Carole Ober and colleagues report a meta-analysis of genome-wide association studies for asthma in a collection of ethnically diverse North American populations. They identify a newly associated susceptibility locus at PYHIN1 in individuals of African descent.

Circulating lipoprotein(a) is an important risk factor for cardiovascular disease and shows variability between different ethnic groups. Here, Zekavat et al. perform whole-genome sequencing in individuals of European and African ancestries and find ancestry-specific genetic determinants for lipoprotein(a) levels.

Peter Visscher and colleagues report an analysis to partition the genetic variation for several complex traits onto chromosome segments and find that the variation explained is approximately proportional to the total length of genes included within a chromosome segment. They estimate that ~45%, ~17%, ~25% and ~21% of the phenotypic variation, respectively, for height, body mass index, von Willebrand factor and QT interval is tagged by common SNPs, and they partition this variation by chromosome and chromosome segments.

Common genetic variants associated with plasma lipids have been extensively studied for a better understanding of common diseases. Here, the authors use whole-genome sequencing of 16,324 individuals to analyze rare variant associations and to determine their monogenic and polygenic contribution to lipid traits.

MetaSTAAR enables functionally informed rare variant association analysis in biobank-scale cohorts using an efficient, sparse matrix approach for summary statistic storage.

A high-resolution reference panel based on whole-genome sequencing data enables accurate imputation of HLA alleles across diverse populations and fine-mapping of HLA association signals for HIV-1 host response.