Mendelian randomization (MR), a method to infer causal relationships, is confounded by genetic correlations reflecting shared etiology. We developed a model in which a latent causal variable (LCV) mediates the genetic correlation; trait 1 is partially genetically causal for trait 2 if it is strongly genetically correlated with the LCV, quantified using the genetic causality proportion (gcp). We fit this model using mixed fourth moments E(α12α1α2) and E(α22α1α2) of marginal effect sizes for each trait; if trait 1 is causal for trait 2, then SNPs affecting trait 1 (large α12) will have correlated effects on trait 2 (large α1α2), but not vice versa. In simulations, our method avoided false positives due to genetic correlations, unlike MR. Across 52 traits (average N=331k), we identified 30 causal relationships with high gcp estimates. Novel findings included a causal effect of LDL on bone mineral density, consistent with clinical trials of statins in osteoporosis.

Fine-mapping aims to identify causal variants impacting complex traits. Several recent methods improve fine-mapping accuracy by prioritizing variants in enriched functional annotations. However, these methods can only use information at genome-wide significant loci (or a small number of functional annotations), severely limiting the benefit of functional data. We propose PolyFun, a computationally scalable framework to improve fine-mapping accuracy using genome-wide functional data for a broad set of coding, conserved, regulatory and LD-related annotations. PolyFun prioritizes variants in enriched functional annotations by specifying prior causal probabilities for fine-mapping methods such as SuSiE or FINEMAP, employing special procedures to ensure robustness to model misspecification and winner's curse. In simulations with in-sample LD, PolyFun + SuSiE and PolyFun + FINEMAP were well-calibrated and identified >20% more variants with posterior causal probability >0.95 than their non-functionally informed counterparts (and >33% more fine-mapped variants than previous functionally-informed fine-mapping methods). In simulations with mismatched reference LD, PolyFun + SuSiE remained well-calibrated when reducing the maximum number of assumed causal SNPs per locus, which reduces absolute power but still produces large relative improvements. In analyses of 49 UK Biobank traits (average N=318K) with insample LD, PolyFun + SuSiE identified 3,025 fine-mapped variant-trait pairs with posterior causal probability >0.95, a >32% improvement vs. SuSiE; 223 variants were fine-mapped for multiple genetically uncorrelated traits, indicating pervasive pleiotropy. We used posterior mean per-SNP heritabilities from PolyFun + SuSiE to perform polygenic localization, constructing minimal sets of common SNPs causally explaining 50% of common SNP heritability; these sets ranged in size from 28 (hair color) to 3,400 (height) to 2 million (number of children). In conclusion, PolyFun prioritizes variants for functional follow-up and provides insights into complex trait architectures..

Elevated serum urate levels cause gout, and correlate with cardio-metabolic diseases via poorly understood mechanisms. We performed a trans-ethnic genome-wide association study of serum urate among 457,690 individuals, identifying 183 loci (147 novel) that improve prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardio-metabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urateassociated loci and co-localization with gene expression in 47 tissues implicated kidney and liver as main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A trans-activated the promoter of the major urate transporter ABCG2 in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardio-metabolic traits.

Disease variants identified by genome-wide association studies (GWAS) tend to overlap with expression quantitative trait loci (eQTLs), but it remains unclear whether this overlap is driven by gene expression levels mediating genetic effects on disease. Here we introduce a new method, mediated expression score regression (MESC), to estimate disease heritability mediated by the cis-genetic component of gene expression levels. We applied MESC to GWAS summary statistics for 42 traits (average N = 323K) and cis-eQTL summary statistics for 48 tissues from the Genotype-Tissue Expression (GTEx) consortium. Averaging across traits, only 11±2% of heritability was mediated by assayed gene expression levels. Expression-mediated heritability was enriched in genes with evidence of selective constraint and genes with disease-appropriate annotations. Our results demonstrate that assayed bulk-tissue eQTLs, though disease relevant, cannot explain the majority of disease heritability.