article: For many complex traits, gene regulation is likely to play a crucial mechanistic role. How the genetic architectures of complex traits vary between populations and subsequent effects on genetic prediction are not well understood, in part due to the historical paucity of GWAS in populations of non-European ancestry. We used data from the MESA (Multi-Ethnic Study of Atherosclerosis) cohort to characterize the genetic architecture of gene expression within and between diverse populations. Genotype and monocyte gene expression were available in individuals with African American (AFA, n = 233), Hispanic (HIS, n = 352), and European (CAU, n = 578) ancestry. We performed expression quantitative trait loci (eQTL) mapping in each population and show genetic correlation of gene expression depends on shared ancestry proportions. Using elastic net modeling with cross validation to optimize genotypic predictors of gene expression in each population, we show the genetic architecture of gene expression for most predictable genes is sparse. We found the best predicted gene in each population, TACSTD2 in AFA and CHURC1 in CAU and HIS, had similar prediction performance across populations with R2 > 0. 8 in each population. However, we identified a subset of genes that are well-predicted in one population, but poorly predicted in another. We show these differences in predictive performance are due to allele frequency differences between populations. Using genotype weights trained in MESA to predict gene expression in independent populations showed that a training set with ancestry similar to the test set is better at predicting gene expression in test populations, demonstrating an urgent need for diverse population sampling in genomics. Our predictive models and performance statistics in diverse cohorts are made publicly available for use in transcriptome mapping methods at https: //github. com/WheelerLab/DivPop.
  For over a decade, genome-wide association studies (GWAS) have facilitated the discovery of thousands of genetic variants associated with complex traits and new insights into the biology of these traits [1]. Most of these studies involved individuals of primarily European descent, which can lead to disparities when attempting to apply this information across populations [2–4]. Continued increases in GWAS sample sizes and new integrative methods will lead to more clinically relevant and applicable results. A recent study shows that the lack of diversity in large GWAS skew the prediction accuracy across non-European populations [5]. This discrepancy in predictive accuracy demonstrates that adding ethnically diverse populations is critical for the success of precision medicine, genetic research, and understanding the biology behind genetic variation [5–8]. Gene regulation is likely to play a critical role for many complex traits as trait-associated variants are enriched in regulatory, not protein-coding, regions [9–13]. Numerous expression quantitative trait loci (eQTLs) studies have provided insight into how genetic variation affects gene expression [14–17]. While eQTLs can act at a great distance, or in trans, the largest effect sizes are consistently found near the transcription start sites of genes [14–17]. Because gene expression shows a more sparse genetic architecture than many other complex traits, gene expression is amenable to genetic prediction with relatively modest sample sizes [18,19]. This has led to new mechanistic methods for gene mapping that integrate transcriptome prediction, including PrediXcan [20] and TWAS [21]. These methods have provided useful tools for understanding the genetics of complex traits; however, most of the models have been built using predominantly European populations. How the key variants involved in gene regulation differ among populations has not been fully explored. While the vast majority of eQTL mapping studies have been performed in populations of European descent, increasing numbers of transcriptome studies in non-European populations make the necessary comparisons between populations feasible [14,22,23]. An eQTL study across eight diverse HapMap populations (∼100 individuals/population) showed that the directions of effect sizes were usually consistent when an eQTL was present in two populations [14]. However, the impact of a particular genetic variant on population gene expression differentiation is also dependent on allele frequencies, which often vary between populations. A better understanding of the degree of transferability of gene expression prediction models across populations is essential for broad application of methods like PrediXcan in the study of the genetic architecture of complex diseases and traits in diverse populations. Here, in order to better define the genetic architecture of gene expression across populations, we combine genotype [24] and monocyte gene expression [25] data from the Multi-Ethnic Study of Atherosclerosis (MESA) for the first time. We perform eQTL mapping and optimize multi-SNP predictors of gene expression in three diverse populations. The MESA populations studied herein comprise 233 African American (AFA), 352 Hispanic (HIS), and 578 European (CAU) self-reported ancestry individuals. Using elastic net regularization and Bayesian sparse linear mixed modeling, we show sparse models outperform polygenic models in each population. We show the genetic correlation of SNP effects and the predictive performance correlation is highest between populations with the most overlapping admixture proportions. We found a subset of genes that are well predicted in the AFA and/or HIS cohorts that are poorly predicted, if predicted at all, in the CAU cohort. We also test our predictive models trained in MESA cohorts in independent cohorts from the HapMap Project [14], Geuvadis Consortium [26], and Framingham Heart Study [18,27] and show the correlation between predicted and observed gene expression is highest when the ancestry of the test set is similar to that of the training set. By diversifying our model-building populations, new genes may be implicated in complex trait mapping studies that were not previously interrogated. Models built here have been added to PredictDB for use in PrediXcan [20] and other studies, links at https: //github. com/WheelerLab/DivPop.
  We surveyed each MESA population (AFA, HIS, CAU) and two combined populations (AFHI, ALL) for cis-eQTLs. SNPs within 1Mb of each of 10,143 genes were tested for association with monocyte gene expression levels using a linear additive model. The MESA HIS cohort includes many individuals with recent African admixture (S1 Fig). We compared models that included a range of genotypic principal components (0,3, 5,10) and PEER factors (0,10,20,30) to adjust for hidden confounders in the expression data [28]. Genotypic principal components (PCs) and PEER factors were computed within each population prior to cis-eQTL mapping. While 3 genotypic PCs controlled for inflation due to population stratification compared to 0 PCs, especially in HIS, the cis-eQTLs discovered with 3,5, or 10 PCs were nearly the same (S2 Fig). We calculated the true positive rates (π1) of top cis-eQTLs (FDR < 0. 05) from our MESA discovery cohorts by examining their P value distributions in several replication cohorts: Framingham Heart Study (FHS, n = 4838 European ancestry individuals, whole blood expression microarray) [27], Geuvadis (GEU, n = 344 European and 77 African ancestry individuals, lympoblastoid cell line (LCL) RNA-Seq) [26], Yoruba from Ibadan, Nigeria (YRI, n = 107, LCL expression microarray) [14], and Mexican ancestry from Los Angeles (MXL, n = 45, LCL expression microarray) [14]. True positive rates were similar across PEER factors except for models with 0 PEER factors, which were either higher or lower depending on the replication population (Fig 1). Because the FHS replication population is the largest, true positive rates were higher across discovery populations. True positive rates for eQTLs discovered in AFA were higher compared to the other MESA populations in replication populations that include African ancestry individuals (GEU and YRI). eQTLs discovered in AFA and HIS yielded higher true positive rates in both YRI and MXL compared to eQTLs discovered in CAU (Fig 1). A full pairwise comparison of π1 statistics across all discovery and replication population PEER factor combinations showed similar trends (S3 Fig). As expected, the sample size of the discovery population influences the number of eQTLs mapped (Table 1). Hundreds of thousands to millions of SNPs were found to associate with gene expression (eSNPs) and most genes had at least one associated variant (eGenes) at FDR < 0. 05, with the absolute numbers correlating with sample size (Table 1). Cis-eQTL summary statistics for each population are available at https: //github. com/WheelerLab/DivPop. We estimated the local (cis-region SNPs) heritability (h2) for each gene and the genetic correlation (rG) between genes in each MESA population. We used the average information-REML algorithm implemented in GCTA [30,31] to estimate rG, which is constrained between -1 and 1 for each gene (See Methods). As in Brown et al. [32], the sample sizes for gene expression data are too small for obtaining accurate point estimates of rG for each gene. However, the large number of genes allow us to obtain accurate estimation of the global mean rG between populations. The population pair with the highest mean rG was CAU and HIS, followed by AFA and HIS, and the least correlated pair was AFA and CAU (Table 2). Genes with larger h2 estimates in at least one population tended to have larger rG estimates with lower standard errors (Fig 2A, S4 Fig). As the h2 threshold for inclusion increases, the mean rG between populations also increases (Fig 2B). The same pattern is observed when the h2 estimates are normalized by the number of SNPs in the gene (S4 Fig). To verify that our rG analysis did not contain any small sample-size biases, we simulated gene expression phenotypes in each population with the same local h2 distributions as the real data. For ten sets of simulated gene expression phenotypes, we estimated rG between populations and compared the simulated results to the observed results. While the mean rG ranged from 0. 46-0. 62 in the observed data, the mean rG in the simulated data was near zero with similar numbers of genes at -1 and 1 (Fig 2C). We examined the prediction performance of a range of models using elastic net regularization [33] to characterize the genetic architecture of gene expression in each population. The mixing parameter (α) of elastic net ranges from 0-1. Models with α near 0 assume a more polygenic architecture and models with α near 1 assume a more sparse architecture. We used nested cross-validation to compute the coefficient of determination R2 as our measure of model performance across three mixing parameters (α = 0. 05,0. 5,1). The model with α = 1 is equivalent to least absolute shrinkage and selection operator (lasso) regression [34]. When we compared the R2 values for each gene between models, more genes had a higher R2 with the lasso model (α = 1) than the most polygenic model tested (α = 0. 05) in each population (Table 3, Fig 3). The lasso model performed similarly to the mixture model (α = 0. 5), indicating elastic net is somewhat robust to α choice as long as a sparse component is included (Table 3, Fig 3). In addition to elastic net, we used Bayesian Sparse Linear Mixed Modeling (BSLMM) [35] to estimate if the local genetic contribution to gene expression is more polygenic or sparse. This approach models the genetic contribution of the trait as the sum of a sparse component and a polygenic component. BSLMM estimates the total percent variance explained (PVE) and the parameter PGE, which represents the proportion of the genetic variance explained by sparse effects. We found that for highly heritable genes (high PVE), the sparse component (PGE) is large; however, for genes with low PVE, we are unable to determine whether the sparse or polygenic component is predominant (S5 Fig). We also estimated heritability (h2) using a linear mixed model (LMM) [30] and Bayesian variable selection regression (BVSR) [36], which assume a polygenic and sparse architecture, respectively. It has previously been shown that BVSR performs similarly to BSLMM when the simulated architecture is sparse, but BVSR performs poorly compared to BSLMM when the simulated architecture includes a polygenic component [35]. BSLMM outperforms both LMM and BVSR in each population (S5 Fig). However, BSLMM and BVSR show greater correlation, providing further support that the sparse component dominates in the MESA cohorts (S5 Fig). We then compared each population’s gene expression predictive performance as measured by cross-validated coefficient of determination (R2). We first fit elastic net models (α = 0. 5) using 3 genotypic PCs and gene expression levels adjusted by 0,10,20 or 30 PEER factors in each population. Predictive performance was higher when we used 10 PEER factors compared to no PEER factor adjustment (S6 Fig). Seeing little difference between models with 10 or more PEER factors within populations (S6 Fig), we compared predictive performance between populations using the elastic net models with 10 PEER factors. The Spearman correlation (ρ) between CAU and HIS model performance is highest (ρ = 0. 778), followed by AFA and HIS (ρ = 0. 663). The lowest correlation between two populations was AFA and CAU with ρ = 0. 586 (Fig 4A). These correlation relationships mirror the European and African admixture proportions in the MESA HIS and AFA cohorts (S1 Fig). Because the sample sizes between MESA populations differed (Table 1), we randomly selected 233 individuals from CAU and HIS and fit elastic net models with these downsampled populations to match the AFA sample size. Predictive performance R2 is highly correlated between the full and downsampled populations (ρ > 0. 8). A handful of genes are better predicted with the full sample size (S7 Fig). Also, the between population correlations showed the same trend when all populations had the same sample size, with CAU and HIS the most correlated, followed by AFA and HIS (S7 Fig). There are many genes that are well predicted in both populations and poorly predicted in both populations. For example, TACSTD2, was well predicted across populations with an R2 > 0. 84 in each population. On the other hand, there are some genes that are well predicted in one population, but poorly predicted in the other and vice versa (Fig 4A). To test the hypothesis that allele frequency differences between populations are influencing predictive power, we performed a fixation index (FST) analysis. For each population pair, we calculated the mean FST for SNPs in each gene expression prediction model. Gene models with an absolute value R2 difference between populations greater than 0. 05 had significantly higher mean FST distribution than those with a smaller difference (Wilcoxon P = 2. 7 × 10−66). The significant increase in mean FST was robust across R2 difference thresholds (Fig 4B). Similar significant differences were observed when the SNP FST values were weighted by elastic net model betas across R2 difference thresholds from 0. 05-0. 3 (S8 Fig). In order to further compare gene expression prediction model performance between populations, using the models built in each MESA population, we predicted gene expression in our replication populations: FHS, GEU, MXL, and YRI. We calculated the true positive rates (π1 statistics) [29] for predicted vs. observed expression in each replication cohort when different numbers of gene models were included based on MESA predictive performance (Table 4, Fig 5). As expected, true positive rates were higher across model training populations for the largest replication population, FHS. For GEU, which includes European and African ancestry individuals, the best performing models were trained using all the MESA individuals (ALL, Fig 5). Prediction in YRI was best using AFA or AFHI models and prediction in MXL was optimal using the CAU models (Fig 5). These results demonstrate that when comparing predicted expression levels to the observed, a balance of the training population with ancestry most similar to the test population and total sample size leads to optimal predicted gene expression. Gene-based association methods like PrediXcan, TWAS, and S-PrediXcan have been developed to use genotype data to discover genes whose predicted expression is associated with a phenotype of interest [20,21,37]. To date, most predicted expression models available for these methods were trained in European ancestry cohorts. We used the five MESA models with S-PrediXcan [37] and publicly available multiancestry GWAS summary statistics from a large asthma study by the Trans-National Asthma Genetic Consortium (TAGC) [38]. While all MESA models performed similarly, the top genes differed across models (Fig 6, S1 Table). Many genes identified by S-PrediXcan were not previously implicated in the TAGC GWAS [38] (Table 5, S1 Table). Two of the genes that associated with asthma using the ALL models were not predicted in CAU and thus not even tested, demonstrating the additional information non-European populations may add to studies. They include C2 (complement C2) and BLOC1S1 (biogenesis of lysosomal organelles complex 1 subunit 1), which are on different chromosomes. Neither gene has been implicated in asthma GWAS before, but both are associated with age-related macular degeneration, another inflammation-related disease [39]. All summary statistics from our S-PrediXcan analyses are in S2 Table.
  We compared three MESA populations (AFA, HIS, and CAU) to better understand the genetic architecture of gene expression in diverse populations. We optimized predictors of gene expression using elastic net regularization and found that models with a sparse component outperform polygenic models. Between populations, the genetic correlation of gene expression is higher when continental ancestry proportions are more similar. We identified genes that are better predicted in one population and poorly predicted in another due to allele frequency differences. We tested our predictors developed in MESA in independent cohorts and found that the best prediction of gene expression occurred when the training set included individuals with similar ancestry to the test set. As seen in other studies [18,21,40], we show models with a sparse component outperform polygenic only models for gene expression prediction across populations. Thus, the genetic architecture of gene expression for many genes has a substantial sparse component. Notably, some genes do perform better in more polygenic models as shown here (genes below the horizontal zero line in Fig 3 and S5 Fig) and in Zeng et al. [41]. Larger sample sizes may reveal an additional polygenic component that may improve prediction for some genes. However, the population with the largest sample size (CAU) showed the least variability between models (Fig 3), suggesting that a more polygenic model does not add much to the predictive performance of a sparse model with fewer predictors. Thus, to balance these observations, we recommend using models that include a mixture of polygenic and sparse components like elastic net (α ≃ 0. 5) [33], BSLMM [35], and latent Dirichlet process regression [41]. We estimated the genetic correlation between each population pair for each gene. Populations with more shared ancestry as defined by clustering of genotypic principal components showed higher mean correlation across genes (S1 Fig, Table 2). As estimated heritability of genes increase, the mean genetic correlation between populations also increases (Fig 2B), which indicates the genetic architecture underlying gene expression is similar for the most heritable genes. However, even though prediction across populations is possible for some of the most heritable genes, we define a class of genes where predictive performance drops substantially between populations. We show this drop is due to allele frequency differences (larger FST) between populations. We tested our predictive gene expression models built in the MESA populations in several replication populations. As expected, the YRI gene expression prediction was best when using the AFA, AFHI, or ALL training sets, which each include individuals with African-ancestry admixture (Fig 5). The best gene expression prediction for MXL was with the CAU training set, which may reflect the lack of recent African ancestry in MXL [6] compared to the MESA HIS population (S1 Fig). For GEU, the best MESA prediction population was ALL, which indicates that multi-ethnic cohorts like GEU benefit from a pooled training set containing individuals of diverse ancestries. Thus, it may be beneficial to build gene expression models using training populations with a similar allele frequency spectrum to that of the test cohort taking into account SNPs that are interrogated in both populations. A similar cohort-specific strategy was used to increase power to detect genes associated with warfarin dose using PrediXcan in African Americans [42]. We applied S-PrediXcan using our MESA models to summary statistics from a multiancestry GWAS of asthma [38]. We found several novel and previously reported genes significantly associated with asthma (Table 5, S1 Table). Of the genes not implicated in the Demenais et al. GWAS [38], most were associated with inflammation-related diseases in the GWAS Catalog [1]. We found increased predicted ADORA1 expression significantly associated with increased asthma risk in 4/5 MESA models tested (S2 Table). While ADORA1 was not significant in Demenais et. al. [38], the gene has previously been reported to associate with asthma in a study investigating the relationships between phenotypes, which also found that immune-related disease associations cluster together [43]. Similar inflammation mechanisms could explain why two genes (C2 and BLOC1S1) previously associated with age-related macular degeneration [39] might also be implicated in asthma as shown here. Predictive models of gene expression developed in this study and performance statistics are made publicly available at https: //github. com/WheelerLab/DivPop for use in future studies of complex trait genetics across diverse populations. As in our S-PrediXcan analysis of asthma, multiancestry transcriptome integration may reveal new genes not implicated in European only studies. Inclusion of diverse populations in complex trait genetics is crucial for equitable implementation of precision medicine.
  This work was approved by the Loyola University Chicago Institutional Review Board (Project numbers 2014 and 2310). All data were previous collected and analyzed anonymously. We imputed genotypes in the MESA populations using the Michigan Imputation Server and 1000 genomes phase 3 v5 reference panel and Eagle v2. 3. Reference populations were EUR for CAU and mixed population for AFA and HIS [44–46]. The results were filtered by R2 < 0. 8, MAF > 0. 01, and ambiguous strand SNPs were removed. This left 9,352,383 SNPs in AFA, 7,201,805 SNPs in HIS, and 5,559,636 SNPs in CAU for further analysis. Quality control and cleaning of the genotype data was done using PLINK (https: //www. cog-genomics. org/plink2). SNPs were filtered by call rates less than 99%. Prior to IBD and principal component (PC) analysis, SNPs were LD pruned by removing 1 SNP in a 50 SNP window if r2 > 0. 3. One of a pair of related individuals (IBD > 0. 05) were removed. Pruned genotypes were merged with HapMap populations and EIGENSTRAT [47] was used to perform PC analysis both across (S1 Fig) and within populations. Final sample sizes for each population post quality control are AFA = 233, HIS = 352, and CAU = 578. We used 5-7 million non-LD pruned SNPs per population post quality control. PEER factor analysis within each population was performed on the expression data using the peer R package in order to correct for potential batch effects and experimental confounders [28]. We used Matrix eQTL [48] to perform a genome-wide cis-eQTL analysis in each population separately (AFA, HIS, CAU), in the AFA and HIS combined (AFHI), and in all three populations combined (ALL). We used SNPs with MAF > 0. 01 and defined cis-acting as SNPs within 1 Mb of the transcription start site (TSS). We tested a range of linear regression models with 0,3, 5, or 10 within population genotypic PC covariates and 0,10,20, or 30 within population PEER factors [28]. The false discovery rate (FDR) for each SNP was calculated using the Benjamini-Hochberg procedure. We estimate the pairwise population eQTL true positive rates with π1 statistics using the qvalue method [17,29]. π1 is the expected true positive rate and was estimated by selecting the SNP-gene pairs with FDR < 0. 05 in each discovery cohort (MESA) and examining their P value distribution in each replication cohort (FHS, GEU, MXL, YRI). π0 is the proportion of false positives estimated by assuming a uniform distribution of null P values and π1 = 1 − π0 [29]. We performed eQTL effect size comparisons between populations using Genome-wide Complex Trait Analysis (GCTA) software [30]. We performed a bivariate restricted maximum likelihood (REML) analysis to estimate the genetic correlation (rG) between each pair of MESA populations for each gene [31]. As in the eQTL analysis, we compared cis-region (within 1 Mb) SNPs for each gene. In our implementation, the models can be written as y 1 = X 1 b 1 + Z 1 g 1 + e 1 for population 1 and y 2 = X 2 b 2 + Z 2 g 2 + e 2 for population 2, where y1 and y2 are vectors of gene expression values, b1 and b2 are vectors of fixed effects, g1 and g2 are vectors of random polygenic effects, and e1 and e2 are residuals for populations 1 and 2, respectively. X and Z are incidence matrices for the effects b and g, respectively. The variance covariance matrix (V) is defined as V = [ Z 1 AZ 1 ′ σ g 1 2 + I σ e 1 2 Z 1 CZ 2 ′ σ g 1 g 2 2 Z 2 CZ 1 ′ σ g 1 g 2 2 Z 2 BZ 2 ′ σ g 2 2 + I σ e 2 2 ] where A, B, and C are the genetic relationship matrices based on SNP information for population 1, population 2, and both populations combined, respectively [30], I is an identity matrix, σ g 2 is the genetic variance, σ e 2 the is residual variance, and σ g 1 g 2 2 is the covariance between g1 and g2. In our models, the residual covariance component is ignored because no individual belongs to two populations. We used the average information-REML algorithm implemented in GCTA [31] to estimate rG, which is constrained between -1 and 1 for each gene by bending the variance-covariance matrix to be positive definite. The GCTA command per gene is: gcta64 --grm <pop1-pop2-combined> --reml-bivar --pheno <gene-exp> --out <out-file>. As in Brown et al. [32], the sample sizes for gene expression data are too small for obtaining accurate point estimates of rG for each gene. However, the large number of genes allow us to obtain accurate estimation of the global mean rG between populations. To verify that our rG analysis did not contain any small sample-size biases, we simulated gene expression phenotypes in each population with the same local heritability (h2) distributions as the real data. Effect sizes of cis-region SNPs for each gene were randomly generated from a standard normal distribution such that the individual population h2 estimate would be the same as the observed data. For ten sets of simulated gene expression phenotypes, we estimated rG between populations and compared the simulated results to the observed results (Fig 2). We used the glmnet R package [33] to fit an elastic net model to predict gene expression from cis-region SNP genotypes. The elastic net regularization penalty is controlled by the mixing parameter alpha, which can vary between ridge regression (α = 0) and lasso (α = 1, default). A gene with the optimal predictive performance when α = 0 has a polygenic architecture, whereas a gene with optimal performance when α = 1 has a sparse genetic architecture. In the MESA cohort we tested three values of the alpha mixing parameter (0. 05,0. 5, and 1) and a range of PEER factors (0,10,20,30) for optimal prediction of gene expression of 10,143 genes for each population alone (AFA, CAU, HIS), AFA and HIS combined (AFHI), and all three populations combined (ALL). We used the PredictDB pipeline developed by the Im lab to preprocess, train, and compile elastic net results into database files to use as weights for gene expression prediction [37]. We quantified the predictive performance of each model via nested cross-validation. We split the data into 5 disjoint folds, roughly equal in size, and for each fold, we calculated a 10-fold cross-validated elastic net model in 4/5 of the data where the lambda tuning parameter is cross-validated. Then, using predicted and observed gene expression, we calculate the coefficient of determination (R2) for how the model predicts on the held-out fold. We report the mean R2 over all 5 folds as our measure of model performance. R2 is defined as 1 - ∑ (y o - y p) 2 ∑ (y o - y ¯ o) 2 where yo is observed expression, yp is predicted expression, and y ¯ o is the mean of observed expression. See https: //github. com/WheelerLab/DivPop. We used the software GEMMA [49] to implement Bayesian Sparse Linear Mixed Modeling (BSLMM) [35] for each gene with 100K sampling steps per gene. BSLMM estimates the PVE (the proportion of variance in phenotype explained by the additive genetic model, analogous to the h2 estimated in GCTA) and PGE (the proportion of genetic variance explained by the sparse effects terms where 0 means that genetic effect is purely polygenic and 1 means that the effect is purely sparse). From the second half of the sampling iterations for each gene, we report the median and the 95% credible sets of the PVE and PGE. We also estimated heritability (h2) using a linear mixed model (LMM) implemented in GCTA [30] and Bayesian variable selection regression (BVSR) [36], which assume a polygenic and sparse architecture, respectively. We used the software piMASS for Bayesian variable selection regression (BVSR) [36]. For each gene, we used 10,000 burn-in steps and 100,000 sampling steps in the BVSR Markov chain Monte Carlo algorithm. From the output of every 10 sampling steps, we report the median re-estimated PVE based on sampling posterior effect sizes. We calculated the fixation index (FST) [50] for each SNP between each pair of populations using PLINK. Then, for each gene expression prediction model, we calculated both the mean FST and weighted average FST for SNPs in the model. In the weighted average calculation, FST values were multiplied by the elastic net model beta value to give SNPs with larger effect sizes more weight. We compared mean and weighted average FST values between genes with divergent predictive performance and genes with similar predictive performance between populations using Wilcoxon rank sum tests. To test for robustness across thresholds, we varied the absolute value R2 difference threshold to define the divergent and similar groups from 0. 05-0. 3. Using our elastic net models built in MESA AFA, HIS, CAU, AFHI, and ALL (α = 0. 5 with 10 PEER factors and 3 genotypic PCs), we predicted gene expression from genotypes in independent test populations: FHS, GEU, MXL, and YRI. As for eQTLs, we estimated the pairwise population prediction true positive rates with π1 statistics using the qvalue method [17,29]. The Pearson correlation between predicted and observed expression was calculated and the P value distribution of the correlation was evaluated using π1 statistics. We calculated π1 values in the test populations using several MESA model predictive performance R2 thresholds for gene inclusion (R2 = 0,0. 01,0. 05,0. 1, and 0. 2). We performed S-PrediXcan [37] with MESA models AFA, HIS, CAU, AFHI, and ALL using publicly available multiancestry GWAS summary statistics from a large asthma study by the Trans-National Asthma Genetic Consortium (TAGC) [38]. TAGC contained 23,948 cases and 118,538 controls with the following ancestry proportions: 127,669 European, 8,204 African, 5,215 Japanese, and 1,398 Latino [38]. The Bonferroni correction threshold used to define significant genes was calculated as P < (0. 05/gene count).
summary: Most genome-wide association studies (GWAS) have been conducted in populations of European ancestry leading to a disparity in understanding the genetics of complex traits between populations. For many complex traits, gene regulation is critical, given the consistent enrichment of regulatory variants among trait-associated variants. However, it is still unknown how the effects of these key variants differ across populations. We used data from MESA to study the underlying genetic architecture of gene expression by optimizing gene expression prediction within and across diverse populations. The populations with genotype and gene expression data available are from individuals with African American (AFA, n = 233), Hispanic (HIS, n = 352), and European (CAU, n = 578) ancestry. After calculating the prediction performance, we found that many genes that were well predicted in one population are poorly predicted in another. We further show that a training set with ancestry similar to the test set resulted in better gene expression predictions, demonstrating the need to incorporate diverse populations in genomic studies. Our gene expression prediction models and performance statistics are publicly available to facilitate future transcriptome mapping studies in diverse populations.
keywords: genome-wide association studies
  medicine and health sciences
  ecology and environmental sciences
  evolutionary biology
  population genetics
  geographical locations
  pulmonology
  mathematics
  forecasting
  statistics (mathematics)
  genome analysis
  population biology
  asthma
  research and analysis methods
  europe
  ecological metrics
  mathematical and statistical techniques
  gene expression
  statistical methods
  species diversity
  people and places
  ecology
  genetics
  biology and life sciences
  physical sciences
  genomics
  gene prediction
  computational biology
  human genetics
title: Genetic architecture of gene expression traits across diverse populations