Recent studies have examined the genetic correlations of single‐nucleotide polymorphism (SNP) effect sizes across pairs of populations to better understand the genetic architectures of complex ...traits. These studies have estimated
ρ
g, the cross‐population correlation of joint‐fit effect sizes at genotyped SNPs. However, the value of
ρ
g depends both on the cross‐population correlation of true causal effect sizes (
ρ
b) and on the similarity in linkage disequilibrium (LD) patterns in the two populations, which drive tagging effects. Here, we derive the value of the ratio
ρ
g
/
ρ
b as a function of LD in each population. By applying existing methods to obtain estimates of
ρ
g, we can use this ratio to estimate
ρ
b. Our estimates of
ρ
b were equal to 0.55 (
SE = 0.14) between Europeans and East Asians averaged across nine traits in the Genetic Epidemiology Research on Adult Health and Aging data set, 0.54 (
SE = 0.18) between Europeans and South Asians averaged across 13 traits in the UK Biobank data set, and 0.48 (
SE = 0.06) and 0.65 (
SE = 0.09) between Europeans and East Asians in summary statistic data sets for type 2 diabetes and rheumatoid arthritis, respectively. These results implicate substantially different causal genetic architectures across continental populations.
Modern population-scale biobanks contain simultaneous measurements of many phenotypes, providing unprecedented opportunity to study the relationship between biomarkers and disease. However, inferring ...causal effects from observational data is notoriously challenging. Mendelian randomization (MR) has recently received increased attention as a class of methods for estimating causal effects using genetic associations. However, standard methods result in pervasive false positives when two traits share a heritable, unobserved common cause. This is the problem of correlated pleiotropy. Here, we introduce a flexible framework for simulating traits with a common genetic confounder that generalizes recently proposed models, as well as a simple approach we call Welch-weighted Egger regression (WWER) for estimating causal effects. We show in comprehensive simulations that our method substantially reduces false positives due to correlated pleiotropy while being fast enough to apply to hundreds of phenotypes. We apply our method first to a subset of the UK Biobank consisting of blood traits and inflammatory disease, and then to a broader set of 411 heritable phenotypes. We detect many effects with strong literature support, as well as numerous behavioral effects that appear to stem from physician advice given to people at high risk for disease. We conclude that WWER is a powerful tool for exploratory data analysis in ever-growing databases of genotypes and phenotypes.
There is mounting evidence that complex human phenotypes are highly polygenic, with many loci harboring multiple causal variants, yet most genetic association studies examine each SNP in isolation. ...While this has led to the discovery of thousands of disease associations, discovered variants account for only a small fraction of disease heritability. Alternative multi-SNP methods have been proposed, but issues such as multiple-testing correction, sensitivity to genotyping error, and optimization for the underlying genetic architectures remain. Here we describe a local joint-testing procedure, complete with multiple-testing correction, that leverages a genetic phenomenon we call linkage masking wherein linkage disequilibrium between SNPs hides their signal under standard association methods. We show that local joint testing on the original Wellcome Trust Case Control Consortium (WTCCC) data set leads to the discovery of 22 associated loci, 5 more than the marginal approach. These loci were later found in follow-up studies containing thousands of additional individuals. We find that these loci significantly increase the heritability explained by genome-wide significant associations in the WTCCC data set. Furthermore, we show that local joint testing in a cis-expression QTL (eQTL) study of the gEUVADIS data set increases the number of genes containing significant eQTL by 10.7% over marginal analyses. Our multiple-hypothesis correction and joint-testing framework are available in a python software package called Jester, available at github.com/brielin/Jester.
The increasing number of genetic association studies conducted in multiple populations provides an unprecedented opportunity to study how the genetic architecture of complex phenotypes varies between ...populations, a problem important for both medical and population genetics. Here, we have developed a method for estimating the transethnic genetic correlation: the correlation of causal-variant effect sizes at SNPs common in populations. This methods takes advantage of the entire spectrum of SNP associations and uses only summary-level data from genome-wide association studies. This avoids the computational costs and privacy concerns associated with genotype-level information while remaining scalable to hundreds of thousands of individuals and millions of SNPs. We applied our method to data on gene expression, rheumatoid arthritis, and type 2 diabetes and overwhelmingly found that the genetic correlation was significantly less than 1. Our method is implemented in a Python package called Popcorn.
Bulk-tissue molecular quantitative trait loci (QTLs) have been the starting point for interpreting disease-associated variants, and context-specific QTLs show particular relevance for disease. Here, ...we present the results of mapping interaction QTLs (iQTLs) for cell type, age, and other phenotypic variables in multi-omic, longitudinal data from the blood of individuals of diverse ancestries. By modeling the interaction between genotype and estimated cell-type proportions, we demonstrate that cell-type iQTLs could be considered as proxies for cell-type-specific QTL effects, particularly for the most abundant cell type in the tissue. The interpretation of age iQTLs, however, warrants caution because the moderation effect of age on the genotype and molecular phenotype association could be mediated by changes in cell-type composition. Finally, we show that cell-type iQTLs contribute to cell-type-specific enrichment of diseases that, in combination with additional functional data, could guide future functional studies. Overall, this study highlights the use of iQTLs to gain insights into the context specificity of regulatory effects.
To identify regulatory variants with plasticity in effect size, we performed interaction molecular quantitative trait loci (iQTL) mapping with cell-type abundance, age, sex, and smoking as the environmental factors. Our results highlight the usefulness of iQTLs for gaining insights into the context specificity of regulatory effects.
Multi-omics datasets are becoming more common, necessitating better integration methods to realize their revolutionary potential. Here, we introduce multi-set correlation and factor analysis (MCFA), ...an unsupervised integration method tailored to the unique challenges of high-dimensional genomics data that enables fast inference of shared and private factors. We used MCFA to integrate methylation markers, protein expression, RNA expression, and metabolite levels in 614 diverse samples from the Trans-Omics for Precision Medicine/Multi-Ethnic Study of Atherosclerosis multi-omics pilot. Samples cluster strongly by ancestry in the shared space, even in the absence of genetic information, while private spaces frequently capture dataset-specific technical variation. Finally, we integrated genetic data by conducting a genome-wide association study (GWAS) of our inferred factors, observing that several factors are enriched for GWAS hits and
-expression quantitative trait loci. Two of these factors appear to be related to metabolic disease. Our study provides a foundation and framework for further integrative analysis of ever larger multi-modal genomic datasets.
Schizophrenia is a debilitating psychiatric disorder with approximately 1% lifetime risk globally. Large-scale schizophrenia genetic studies have reported primarily on European ancestry samples, ...potentially missing important biological insights. Here, we report the largest study to date of East Asian participants (22,778 schizophrenia cases and 35,362 controls), identifying 21 genome-wide-significant associations in 19 genetic loci. Common genetic variants that confer risk for schizophrenia have highly similar effects between East Asian and European ancestries (genetic correlation = 0.98 ± 0.03), indicating that the genetic basis of schizophrenia and its biology are broadly shared across populations. A fixed-effect meta-analysis including individuals from East Asian and European ancestries identified 208 significant associations in 176 genetic loci (53 novel). Trans-ancestry fine-mapping reduced the sets of candidate causal variants in 44 loci. Polygenic risk scores had reduced performance when transferred across ancestries, highlighting the importance of including sufficient samples of major ancestral groups to ensure their generalizability across populations.
The most commonly implemented method of constructing a constrained Delaunay triangulation (CDT) in the plane is to first construct a Delaunay triangulation, then incrementally insert the input ...segments one by one. For typical implementations of segment insertion, this method has a Θ(kn2) worst-case running time, where n is the number of input vertices and k is the number of input segments.
We give a randomized algorithm for inserting a segment into a CDT in expected time linear in the number of edges the segment crosses. We demonstrate with a performance comparison that for segments that cross many edges, our algorithm is faster than gift-wrapping. We also show that a simple algorithm for segment location, which precedes segment insertion, is fast enough never to be a bottleneck in CDT construction. A result of Agarwal, Arge, and Yi implies that randomized incremental construction of CDTs by our segment insertion algorithm takes expected O(nlogn+nlog2k) time. We show that this bound is tight by deriving a matching lower bound. Although there are CDT construction algorithms guaranteed to run in O(nlogn) time, incremental CDT construction is easier to program and competitive in practice.
Lastly, we partly extend the analysis (albeit not the linear-time insertion algorithm) to randomized incremental CDT construction in three dimensions.
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