Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent patient populations. Furthermore, the combined effect of these variants showed generalizability across smokers and never-smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.

We assembled an ancestrally diverse collection of genome-wide association studies of type 2 diabetes (T2D) in 180,834 cases and 1,159,055 controls (48.9% non-European descent). We identified 277 loci at genome-wide significance (p<5x10-8), including 237 attaining a more stringent trans-ancestry threshold (p<5x10-9), which were delineated to 338 distinct association signals. Trans-ancestry meta-regression offered substantial enhancements to fine-mapping, with 58.6% of associations more precisely localised due to population diversity, and 54.4% of signals resolved to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying foundations for functional investigations. Trans-ancestry genetic risk scores enhanced transferability across diverse populations, providing a step towards more effective clinical translation to improve global health.

Heart failure (HF) is a leading cause of morbidity and mortality worldwide1. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained2–4. We report the largest GWAS meta-analysis of HF to-date, comprising 47,309 cases and 930,014 controls. We identify 12 independent variant associations with HF at 11 genomic loci, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function suggesting shared genetic aetiology. Expression quantitative trait analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homeostasis (BAG3), and cellular senescence (CDKN1A). Using Mendelian randomisation analysis we provide new evidence supporting previously equivocal causal roles for several HF risk factors identified in observational studies, and demonstrate CAD-independent effects for atrial fibrillation, body mass index, hypertension and triglycerides. These findings extend our knowledge of the genes and pathways underlying HF and may inform the development of new therapeutic approaches.

25Heterosis has been key to the development of maize breeding but describing its genetic basis has 26 been challenging. Previous studies of heterosis have shown the contribution of within-locus 27 complementation effects (dominance) and their differential importance across genomic regions. 28 However, they have generally considered panels of limited genetic diversity and have shown 29 little benefit to including dominance effects for predicting genotypic value in breeding 30 populations. This study examined within-locus complementation and enrichment of genetic 31 effects by functional classes in maize. We based our analyses on a diverse panel of inbred lines 32 crossed with two testers representative of the major heterotic groups in the United States (1,106 33 hybrids), as well as a collection of 24 biparental populations crossed with a single tester (1,640 34 hybrids). We assayed three agronomic traits: days to silking (DTS), plant height (PH) and grain 35 yield (GY). Our results point to the presence of dominance for all traits, but also among-locus 36 complementation (epistasis) for DTS and genotype-by-environment interactions for GY. 37Consistently, dominance improved genomic prediction for PH only. In addition, we assessed 38 enrichment of genetic effects in classes defined by genic regions (gene annotation), structural 39 features (recombination rate and chromatin openness), and evolutionary features (minor allele 40 frequency and evolutionary constraint). We found support for enrichment in genic regions and 41 subsequent improvement of genomic prediction for all traits. Our results point to mechanisms by 42 which heterosis arises through local complementation in proximal gene regions and suggest the 43