Leveraging polygenic enrichments of gene features to predict genes underlying complex traits and diseases.

Genome-wide association studies (GWASs) are a valuable tool for understanding the biology of complex human traits and diseases, but associated variants rarely point directly to causal genes. In the present study, we introduce a new method, polygenic priority score (PoPS), that learns trait-relevant gene features, such as cell-type-specific expression, to prioritize genes at GWAS loci. Using a large evaluation set of genes with fine-mapped coding variants, we show that PoPS and the closest gene individually outperform other gene prioritization methods, but observe the best overall performance by combining PoPS with orthogonal methods. Using this combined approach, we prioritize 10,642 unique gene-trait pairs across 113 complex traits and diseases with high precision, finding not only well-established gene-trait relationships but nominating new genes at unresolved loci, such as LGR4 for estimated glomerular filtration rate and CCR7 for deep vein thrombosis. Overall, we demonstrate that PoPS provides a powerful addition to the gene prioritization toolbox.

A saturated map of common genetic variants associated with human height.

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.

Variance-quantitative trait loci enable systematic discovery of gene-environment interactions for cardiometabolic serum biomarkers.

Gene-environment interactions represent the modification of genetic effects by environmental exposures and are critical for understanding disease and informing personalized medicine. These often induce differential phenotypic variance across genotypes; these variance-quantitative trait loci can be prioritized in a two-stage interaction detection strategy to greatly reduce the computational and statistical burden and enable testing of a broader range of exposures. We perform genome-wide variance-quantitative trait locus analysis for 20 serum cardiometabolic biomarkers by multi-ancestry meta-analysis of 350,016 unrelated participants in the UK Biobank, identifying 182 independent locus-biomarker pairs (p < 4.5×10-9). Most are concentrated in a small subset (4%) of loci with genome-wide significant main effects, and 44% replicate (p < 0.05) in the Women's Genome Health Study (N = 23,294). Next, we test each locus-biomarker pair for interaction across 2380 exposures, identifying 847 significant interactions (p < 2.4×10-7), of which 132 are independent (p < 0.05) after accounting for correlation between exposures. Specific examples demonstrate interaction of triglyceride-associated variants with distinct body mass- versus body fat-related exposures as well as genotype-specific associations between alcohol consumption and liver stress at the ADH1B gene. Our catalog of variance-quantitative trait loci and gene-environment interactions is publicly available in an online portal.

Genome-wide gene-diet interaction analysis in the UK Biobank identifies novel effects on hemoglobin A1c.

Diet is a significant modifiable risk factor for type 2 diabetes (T2D), and its effect on disease risk is under partial genetic control. Identification of specific gene-diet interactions (GDIs) influencing risk biomarkers such as glycated hemoglobin (HbA1c) is a critical step towards precision nutrition for T2D prevention, but progress has been slow due to limitations in sample size and accuracy of dietary exposure measurement. We leveraged the large UK Biobank (UKB) cohort and a diverse group of dietary exposures, including 30 individual dietary traits and 8 empirical dietary patterns, to conduct genome-wide interaction studies in ~340 000 European-ancestry participants to identify novel GDIs influencing HbA1c. We identified five variant-dietary trait pairs reaching genome-wide significance (P < 5 × 10-8): two involved dietary patterns (meat pattern with rs147678157 and a fruit & vegetable-based pattern with rs3010439) and three involved individual dietary traits (bread consumption with rs62218803, dried fruit consumption with rs140270534 and milk type [dairy vs. other] with 4:131148078_TAGAA_T). These were affected minimally by adjustment for geographical and lifestyle-related confounders, and four of the five variants lacked genetic main effects that would have allowed their detection in a traditional genome-wide association study for HbA1c. Notably, multiple loci near transient receptor potential subfamily M genes (TRPM2 and TRPM3) interacted with carbohydrate-containing food groups. These interactions were further characterized using non-European UKB subsets and alternative measures of glycaemia (fasting glucose and follow-up HbA1c measurements). Our results highlight GDIs influencing HbA1c for future investigation, while reinforcing known challenges in detecting and replicating GDIs.