A saturated map of common genetic variants associated with human height

<jats:title>Abstract</jats:title><jats:p>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 sizes<jats:sup>1</jats:sup>. 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 panel<jats:sup>2</jats:sup>) 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.</jats:p>

section_content: 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 sizes 1. 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 panel 2 ) 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. 

Since 2007, genome-wide association studies (GWASs) have identified thousands of associations between common SNPs and height, mainly using studies with participants of European ancestry. The largest GWAS published so far for adult height focused on common variation and reported up to 3,290 independent associations in 712 loci using a sample size of up to 700,000 individuals 3. Adult height, which is highly heritable and easily measured, has provided a larger number of common genetic associations than any other human phenotype. In addition, a large collection of genes has been implicated in disorders of skeletal growth, and these are enriched in loci mapped by GWASs of height in the normal range. These features make height an attractive model trait for assessing the role of common genetic variation in defining the genetic and biological architecture of polygenic human phenotypes. 

As available sample sizes continue to increase for GWASs of common variants, it becomes important to consider whether these larger samples can 'saturate' or nearly completely catalogue the information that can be derived from GWASs. This question of completeness can take several forms, including prediction accuracy compared with heritability attributable to common variation, the mapping of associated genomic regions that account for this heritability, and whether increasing sample sizes continue to provide additional information about the identity of prioritized genes and gene sets. Furthermore, because most GWASs continue to be performed largely in populations of European ancestry, it is necessary to address these questions of completeness in the context of multiple ancestries. Finally, some have proposed that, when sample sizes become sufficiently large, effectively every gene and genomic region will be implicated by GWASs, rather than certain subsets of genes and biological pathways being specified 4. 

Here, using data from 5. 4 million individuals, we set out to map common genetic associations with adult height, using variants catalogued in the HapMap 3 project (HM3), and to assess the saturation of this map with respect to variants, genomic regions and likely causal genes and gene sets. We identify significant variants, examine signal density across the genome, perform out-of-sample estimation and prediction analyses within studies of individuals of European ancestry and other ancestries and prioritize genes and gene sets as likely mediators of the effects on height. We show that this set of common variants reaches predicted limits for prediction accuracy within populations of European ancestry and largely saturates both the genomic regions associated with height and broad categories of gene sets that are likely to be relevant; future work will be required to extend prediction accuracy to populations of other ancestries, to account for rarer genetic variation and to more definitively connect associated regions with individual probable causal genes and variants. 

An overview of our study design and analysis strategy is provided in Extended Data Fig. 1. marginal genome-wide significance (P GWAS < 5 × 10 -8 ) in EUR (Supplementary Tables 5 6 7 8 ). Furthermore, more than 91% of associations detected in non-EUR meta-analyses fall within 100 kb of a GWS SNP identified in EUR (Extended Data Fig. 2 ). By contrast, a randomly sampled HM3 SNP (matched with GWS SNPs identified in non-EUR metaanalyses on 24 functional annotations; Methods) falls within 100 kb of a EUR GWS SNP 55% of the time on average (s. d. = 1% over 1,000 draws). Next, we quantified the cross-ancestry correlation of marginal allele substitution effects (ρ b ) at GWS SNPs for all pairs of ancestry groups. We estimated ρ b using five subsets of GWS SNPs identified in each of the ancestry groups, which also reached marginal genome-wide significance in at least one group. After correction for winner's curse 11, 12, we found that ρ b ranged between 0. 64 and 0. 99 across all pairs of ancestry groups and all sets of GWS SNPs (Supplementary Figs. 8-12). We also extended the estimation of ρ b for SNPs that did not reach genome-wide significance and found that ρ b > 0. 5 across all comparisons (Supplementary Fig. 13 ). Thus, the observed GWS height associations are substantially shared across major ancestral groups, consistent with previous studies based on smaller sample sizes 13, 14. 

To find signals that are specific to certain groups, we tested whether any individual SNPs detected in non-EUR GWASs are conditionally independent of signals detected in EUR GWASs. We fitted an approximate joint model that includes GWS SNPs identified in EUR and non-EUR, using LD reference panels specific to each ancestry group. Given that our results show a strong genetic overlap of GWAS signals across ancestries, we performed a fixed-effect meta-analysis of all five ancestry groups to maximize statistical power for discovering associa-Article Q-statistic is around 34% across SNPs, which indicates moderate heterogeneity of SNP effects between ancestries. The mean chi-square association statistic in our fixed-effect meta-analysis (hereafter referred to as META FE ) is around 36, and around 18% of all HM3 SNPs are marginally GWS. Moreover, we found that allele frequencies in our META FE were very similar to that of EUR (mean fixation index of genetic differentiation (F ST ) across SNPs between EUR and META FE is around 0. 001), as expected because our META FE consists of more than 75% EUR participants and around 14% participants with admixed European and non-European ancestries that is, HIS and AFR). To further assess whether LD in our META FE could be reasonably approximated by the LD from EUR, we performed an LD score regression 16 analysis of our META FE using LD scores estimated in EUR. In this analysis, we focused on the attenuation ratio statistic (R LDSC-EUR ), for which large values can also indicate strong LD inconsistencies between a given reference and GWAS summary statistics. A threshold of R LDSC > 20% was recommended by the authors of the LDSC software as a rule-of-thumb to detect such inconsistencies. Using EUR LD scores in the GWAS of HIS, which is the non-EUR group that is genetically closest to EUR (F ST ≈ 0. 02), yields an estimated R LDSC-EUR of around 25% (standard error (s. e. ) 1. 8%), consistent with strong LD differences between HIS and EUR. By contrast, in our META FE, we found an estimated R LDSC-EUR of around 4. 5% (s. e. 0. 8%), which is significantly lower than 20% and not statistically different from 3. 8% (s. e. 0. 8%) in our EUR meta-analysis. Furthermore, we show in Supplementary Note 1 that using a composite LD reference containing samples from various ancestries (with proportions matching that in our META FE ) does not improve signal detection over using an EUR LD reference. Altogether, these analyses suggest that LD in our META FE can be reasonably approximated by LD from EUR. 

We therefore proceeded to identify quasi-independent GWS SNPs from the multi-ancestry meta-analysis by performing a COJO analysis of our META FE, using genotypes from around 350,000 unrelated EUR participants in the UK Biobank (UKB) as an LD reference. We identified 12,111 quasi-independent GWS SNPs, including 9,920 (82%) primary signals with a GWS marginal effect and 2,191 secondary signals that only reached GWS in a joint regression model (Supplementary Table 10 ). Figure 1 represents the relationship between frequency and joint effect sizes of minor alleles at these 12,111 associations. Of the GWS SNPs obtained from the non-EUR meta-analyses above that were conditionally independent of the EUR GWS SNPs, 0/2 in SAS, 5/17 in AFR, 27/49 in EAS and 27/63 in HIS were marginally significant in our META FE (Supplementary Table 9 ), and 24 of those (highlighted in Fig. 2 ) overlapped with our list of 12,111 quasi-independent GWS SNPs. 

We next sought to replicate the 12,111 META FE signals using GWAS data from 49,160 participants in the Estonian Biobank (EBB). We first re-assessed the consistency of allele frequencies between our META FE and the EBB set. We found a correlation of allele frequencies of around 0. 98 between the two datasets and a mean F ST across SNPs of around 0. 005, similar to estimates that were obtained between populations from the same continent. Of the 12,111 GWS SNPs identified through our COJO analysis, 11,847 were available in the EBB dataset, 97% of which (11,529) have a MAF greater than 1% (Supplementary Table 10 ). Given the large difference in sample size between our discovery and replication samples, direct statistical replication of individual associations at GWS is not achievable for most SNPs identified (Extended Data Fig. 3a ). Instead, we assessed the correlation of SNP effects between our discovery and replication GWASs as an overall metric of replicability 3, 17. Among the 11,529 out of 11,847 SNPs that had a MAF greater than 1% in the EBB, we found a correlation of marginal SNP effects of ρ b = 0. 93 ( jackknife standard error; s. e. 0. 01) and a correlation of conditional SNP effects using the same LD reference panel of ρ b = 0. 80 (s. e. 0. 03; Supplementary Fig. 14 ). Although we had limited power to replicate associations with 238 GWS variants that are rare in the EBB (MAF < 1%), we found, consistent with expectations (Methods and Extended Data Fig. 3b ), that 60% of them had a marginal SNP effect that was sign-consistent with that from our discovery GWAS (Fisher's exact test; P = 0. 001). The proportion of sign-consistent SNP effects was greater than 75% (Fisher's exact test; P < 10 -50 ) for variants with a MAF greater than 1%also consistent with expectations (Extended Data Fig. 3b ). Altogether, our analyses demonstrate the robustness of our findings and show their replicability in an independent sample.
section_name: A saturated map of common genetic variants associated with human height

section_content: To examine signal density among the 12,111 GWS SNPs detected in our META FE, we defined a measure of local density of association signals for each GWS SNP on the basis of the number of additional independent associations within 100 kb (Supplementary Fig. 15 ). Supplementary Fig. 16 shows the distributions of signal density for GWS SNPs identified in each ancestry group and in our META FE. We observed that 69% of GWS SNPs shared their location with another associated, conditionally independent, GWS SNP (Fig. 2 ). The mean signal density across the entire genome is 2. 0 (s. e. 0. 14), consistent with a non-random genomic distribution of GWS SNPs. Next, we evaluated signal density around 462 autosomal genes curated from the Online Mendelian Inheritance in Man (OMIM) database 18 as containing pathogenic mutations that cause syndromes of abnormal skeletal growth ('OMIM genes'; Methods and Supplementary Table 11 ). We found that a high density of heightassociated SNPs is significantly correlated with the presence of an OMIM gene nearby 19, 20 (enrichment fold of OMIM gene when density is greater than 1: 2. 5×; P < 0. 001; Methods and Extended Data Fig. 4a ). Notably, the enrichment of OMIM genes almost linearly increases with the density of height-associated SNPs (Extended Data Fig. 4b ). Thus, these 12,111 GWS SNPs nonrandomly cluster near each other and near known skeletal growth genes. 

The largest density of conditionally independent associations was observed on chromosome 15 near ACAN, a gene mutated in short stature and skeletal dysplasia syndromes, where 25 GWS SNPs co-localize within 100 kb of one another (Fig. 2 and Supplementary Fig. 17 ). We show in Supplementary Note 3 and Extended Data Fig. 5a-d, using haplotypeand simulation-based analyses, that a multiplicity of independent causal variants is the most likely explanation of this observation. We also found that signal density is partially explained by the presence of a recently identified 21, 22 height-associated variable-number tandem repeat (VNTR) polymorphism at this locus (Supplementary Note 3). In fact, the 25 independent GWS SNPs clustered within 100 kb of rs4932198 explain more than 40% of the VNTR length variation in multiple ancestries (Extended Data Fig. 5e ), and an additional approximately 0. 24% (P = 8. 7 × 10 -55 ) of phenotypic variance in EUR above what is explained by the VNTR alone (Extended Data Fig. 5f ). Altogether, our conclusion is consistent with previous evidence of multiple types of common variation influencing height through ACAN gene function, involving multiple enhancers 23, missense variants 24 and tandem repeat polymorphisms 21, 22.
section_name: Genomic distribution of height-associated SNPs

section_content: To quantify the proportion of height variance that is explained by GWS SNPs identified in our META FE, we stratified all HM3 SNPs into two groups: SNPs in the close vicinity of GWS SNPs, hereafter denoted GWS loci; and all remaining SNPs. We defined GWS loci as non-overlapping genomic segments that contain at least one GWS SNP, such that GWS SNPs in adjacent loci are more than 2 × 35 kb away from each other (that is, a 35-kb window on each side). We chose this size window because it was predicted that causal variants are located within 35 kb of GWS SNPs with a probability greater than 80% (ref. 25 ). Accordingly, we grouped the 12,111 GWS SNPs identified in our META FE into 7,209 non-overlapping loci (Supplementary 26. 

To estimate the fraction of heritability that is explained by common variants within the 21% of the genome overlapping GWS loci, we calculated two genomic relationship matrices (GRMs)-one for SNPs within these loci and one for SNPs outside these loci-and then used both matrices to estimate a stratified SNP-based heritability (h SNP 2 ) of height in eight independent samples of all five population groups represented in our META FE (Fig. 3 and Methods). Altogether, our stratified estimation of SNP-based heritability shows that SNPs within these 7,209 GWS loci explain around 100% of h SNP 2 in EUR and more than 90% of h SNP 2 across all non-EUR groups, despite being drawn from less than 21% of the genome (Fig. 3 ). We also varied the window size used to define GWS loci and found that 35 kb was the smallest window size for which this level of saturation of SNP-based heritability could be achieved (Supplementary Fig. 18 ). 

To further assess the robustness of this key result, we tested whether the 7,209 height-associated GWS loci are systematically enriched for trait heritability. We chose body-mass index (BMI) as a control trait, given its small genetic correlation with height (r g = -0. 1, ref. 27 ) and found no significant enrichment of SNP-based heritability for BMI within height-associated GWS loci (Supplementary Fig. 19 ). Furthermore, we repeated our analysis using a random set of SNPs matched with the 12,111 height-associated GWS SNPs on EUR MAF and LD scores. We found that this control set of SNPs explained only around 27% of h SNP 2 for height, consistent with the proportion of SNPs within the loci defined by this random set of SNPs (Supplementary Figs. 18 and 19 ). Finally, we extended our stratified estimation of SNP-based heritability to all well-imputed common SNPs (that is, beyond the HM3 panel) and found, consistently across population groups, that although more genetic variance can be explained by common SNPs that are not included in the HM3 panel, all information remains concentrated within these 7,209 GWS loci (Extended Data Fig. 6 ). Thus, with this large GWAS, nearly all of the variability in height that is attributable to common genetic variants can be mapped to regions comprising around 21% of the genome. Further work is required in cohorts of non-European ancestries to map the remaining 5-10% of the SNP-based heritability that is not captured within those regions.
section_name: Variance explained by SNPs within identified loci

section_content: We quantified the accuracy of multiple polygenic scores (PGSs) for height on the basis of GWS SNPs (hereafter referred to as PGS GWS ) and on the basis of all HM3 SNPs (hereafter referred to as PGS HM3 ). PGS GWS were calculated using joint SNP effects from COJO, and PGS HM3 using joint effects calculated using the SBayesC method 28 (Methods). We denote R GWS 2 and R HM3 2 as the prediction accuracy of PGS GWS and PGS HM3, respectively. For conciseness, we also use the abbreviations PGS GWS-X and PGS HM3-X (and R GWS-X 2 and R HM3-X 2 ) to specify which GWAS 9. Signal density was calculated for each associated SNP as the number of other independent associations within 100 kb. A density of 1 means that a GWS COJO SNP shares its location with another independent GWS COJO SNP within less than 100 kb. The mean signal density across the genome is 2 and the median signal density is 1 (s. e. 0. 14 and 0. 0, respectively). The s. e. values were calculated using a leave-one-chromosome-out jackknife approach (LOCO-S. E. ). SNPs that did not reach genome-wide significance are not represented on the figure. 

meta-analysis each PGS (and corresponding prediction accuracy) was trained from. For example, PGS GWS-METAFE refers to PGSs based on 12,111 GWS SNPs identified from our META FE. We first present results from PGS GWS across different ancestry groups. PGS GWS-METAFE yielded prediction accuracies greater than or equal to that of all other PGS GWS (Fig. 4a ), partly reflecting sample size differences between ancestry-specific GWASs and also consistent with previous studies 29. PGS GWS-EUR (based on 9,863 SNPs) was the second best of all PGS GWS across ancestry groups except in AFR. Indeed, PGS GWS-AFR (based on 453 SNPs) yielded an accuracy of 8. 5% (s. e. 0. 6%) in AFR individuals from UKB and PAGE; that is, significantly larger than the 5. 9% (s. e. 0. 6%) and 7. 0% (s. e. 0. 6%) achieved by PGS GWS-EUR in these two samples, respectively (Fig. 4a ). PGS GWS-METAFE was the best of all PGS GWS in AFR participants with an accuracy R GWS-METAFE 2 = (12. 3% + 9. 9%)/2 = 10. 8% (s. e. 0. 5%) on average between UKB and PAGE (Fig. 4a ). Across ancestry groups, the highest accuracy of PGS GWS-METAFE was observed in EUR participants (R GWS-METAFE 2 ~40%; s. e. 0. 6%) and the lowest in AFR participants from the UKB (R GWS-METAFE 2 ≈ 9. 4%; s. e. 0. 7%). Note that the difference in R GWS-METAFE 2 between the EUR and AFR ancestry cohorts is expected because of the over-representation of EUR in our META FE, and consistent with a relative accuracy (R GWS-METAFE 2 in AFR)/(R GWS-METAFE 2 in EUR) of around 25% that was previously reported 30. We extended analyses of PGS GWS to PGS based on SNPs identified with COJO at lower significance thresholds (Extended Data Fig. 7 ). As in previous studies 3, 20, the inclusion of sub-significant SNPs increased the accuracy of ancestry-specific PGSs. However, lowering the significance thresholds in our META FE mostly improved accuracy in EUR (from 40% to 42%), whereas it slightly decreased the accuracy in AFR. 

Overall, ancestry-specific PGS HM3 consistently outperform their corresponding PGS GWS in most ancestry-groups. However, PGS HM3 was sometimes less transferable across ancestry groups than PGS GWS, in particular in AFR and HIS individuals from PAGE. In EUR, PGS HM3 reaches an accuracy of 44. 7% (s. e. 0. 6%), which is higher than previously published SNP-based predictors of height derived from individual-level data [31] [32] [33] and from GWAS summary statistics 28, 34, 35 across various experimental designs (different SNP sets, different sample sizes and so on). Finally, the largest improvement of PGS HM3 over PGS GWS was observed in AFR individuals from the PAGE study (R GWS-AFR 2 = 8. 5% versus R HM3 2 = 15. 4%; Fig. 4a ) and the UKB (R GWS-AFR 2 = 8. 5% versus R HM3 2 = 14. 4%; Fig. 4a ). Furthermore, we sought to evaluate the prediction accuracy of PGSs relative to that of familial information as well as the potential improvement in accuracy gained from combining both sources of information. We analysed 981 unrelated EUR trios (that is, two parents and one child) and 17,492 independent EUR sibling pairs from the UKB, who were excluded from our META FE. We found that height of any first-degree relative yields a prediction accuracy between 25% and 30% (Fig. 4b ). Moreover, the accuracy of the parental average is around 43. 8% (s. e. 3. 2%), which is lower than yet not significantly different from the accuracy of PGS HM3-EUR in EUR. In addition, we found that a linear combination of the average height of parents and of the child's PGS yields an accuracy of 54. 2% (s. e. 3. 2%) with PGS GWS-EUR and 55. 2% (s. e. 3. 2%) with PGS HM3-EUR. This observation reflects the fact that PGSs can explain within-family differences between siblings, whereas average parental height cannot. To show this empirically, we estimate that our PGSs based on GWS SNPs explain around 33% (s. e. 0. 7%) of height variance between siblings (Methods). Finally, we show that the optimal weighting between parental average and PGS can be predicted theoretically as a function of the prediction accuracy of the PGS, the full narrow sense heritability and the phenotypic correlation between spouses (Supplementary Note 4 and Supplementary Fig. 20 ). 

In summary, the estimation of variance explained and prediction analyses in samples with European ancestry show that the set of 12 in all ancestries is explained by SNPs within GWS loci identified in this study. The cumulative length of non-overlapping GWS loci is around 647 Mb; that is, around 21% of the genome, assuming a genome length of around 3,039 Mb (ref. 26 ). The proportion of HM3 SNPs in GWS loci is around 27%.
section_name: Out-of-sample prediction accuracy

section_content: Our large study offers the opportunity to quantify empirically how much increasing GWAS sample sizes and ancestry diversity affects the discovery of variants, genes and biological pathways. To address this question, we re-analysed three previously published GWASs of height 3, 19, 20 and also down-sampled our meta-analysis into four subsets (including our EUR and META FE GWASs). Altogether, we analysed seven GWASs with a sample size increasing from around 0. 13 million up to around 5. 3 million individuals (Table 2 ). 

For each GWAS, we quantified eight metrics grouped into four variant-and locus-based metrics (number of GWS SNPs; number of GWS loci; prediction accuracy (R GWS 2 ) of PGS based on GWS SNPs; and proportion of the genome covered by GWS loci), a functional-annotationbased metric (enrichment statistics from stratified LDSC 39, 40 ), two genebased metrics (number of genes prioritized by summary-data-based Mendelian randomization 41 (SMR; Methods) and proximity of variants with OMIM genes) and a gene-set-based metric (enrichment within clusters of gene sets or pathways). Overall, we found different patterns for the relationship between those metrics and GWAS sample size and ancestry composition, consistent with varying degrees of saturation achieved at different sample sizes. 

We observed the strongest saturation for the gene-set and functionalannotation metrics, which capture how well general biological functions can be inferred from GWAS results using currently available computational methods. Using two popular gene-set prioritization methods (DEPICT 42 and MAGMA 43 ), we found that the same broad clusters of related gene sets (including most of the clusters enriched for OMIM genes) are prioritized at all GWAS sample sizes (Supplementary Fig. 21, Extended Data Fig. 8, Supplementary Tables 13-15 and Supplementary Note 5). Similarly, stratified LDSC estimates of heritability enrichment within 97 functional annotations also remain stable across the range of sample sizes (Extended Data Fig. 9 ). Overall, we found no significant improvement for all these higher-level metrics from adding non-EUR samples to our analyses. The latter observation is consistent with other analyses showing that GWASs expectedly implicate similar biology across major ancestral groups (Supplementary Note 5 and Supplementary Fig. 22 ). 

For the gene-level metric, the excess in the number of OMIM genes that are proximate to a GWS SNP (compared with matched sets of random genes) plateaus at sample sizes of larger than 1. 5 million, whereas the relative enrichment of GWS SNPs near OMIM genes first decreases with sample size, then plateaus when n is greater than 1. 5 million (Supplementary Fig. 23a-c ). Notably, the decrease observed for n values of less than 1. 5 million reflects the preferential localization of larger effect variants (those identified with smaller sample sizes) closer to OMIM genes (Supplementary Fig. 23d ) and, conversely, that more recently identified variants with smaller effects tend to localize further away from OMIM genes (Supplementary Fig. 23e ). We also investigated the number of genes prioritized using SMR (hereafter referred to as SMR genes; Methods) using expression quantitative trait loci (eQTLs) as genetic instruments (Supplementary Table 16 ) as an alternative gene-level metric and found it to saturate for n values greater than 4 million (Supplementary Fig. 23f ). Note that saturation of SMR genes is partly affected by the statistical power of current eQTL studies, which do not always survey biologically relevant tissues and cell types for height. Therefore, we can expect more genes to be prioritized when integrating GWAS summary statistics from this study with those from larger eQTL studies that may be available in the future and may involve more tissue types. Gene-level metrics were also not substantially affected by adding non-EUR samples, again consistent with broadly similar sets of genes affecting height across ancestries. 

At the level of variants and genomic regions, we saw a steady and almost linear increase in the number of GWS SNPs as a function of sample size, as previously reported 44. However, given that newly identified variants tend to cluster near ones identified at smaller sample sizes, we also saw a saturation in the number of loci identified for n values greater than 2. 5 million, where the upward trend starts to weaken (Supplementary Fig. 24a ). We found a similar pattern for the percentage of the genome covered by GWS loci, with the degree of saturation varying as a function of the window size used to define loci (Supplementary Fig. 24b ). The observed saturation in PGS prediction accuracy (both within ancestry-that is, in EUR-and multi-ancestry) was more noticeable than that of the number and genomic coverage of GWS loci. In fact, increasing the sample size from 2. 5 million to 4 million by adding another 1. 5 million EUR samples increased the number of GWS SNPs from 7,020 to 9,863-that is, an increase of around 1. 4-fold ((9,863 - 7,020)/7,020)but the absolute increase in prediction accuracy is less than 2. 7%. This improvement is mainly observed in EUR but remains lower than 1. 3% in individuals of the EAS and AFR ancestry groups. However, adding another approximately 1 million participants of non-EUR improves the multi-ancestry prediction accuracy by more than 3. 4% (Supplementary Fig. 24c ), highlighting the value of including non-EUR populations. 

Altogether, these analyses show that increasing the GWAS sample size not only increases the prediction accuracy, but also sheds more light on the genomic distribution of causal variants and, at all but the largest sample sizes, the genes proximal to these variants. By contrast, enrichment of higher-level, broadly defined biological categories such as gene sets and pathways and functional annotations can be identified using relatively small sample sizes (n ≈ 0. 25 million for height). Of note, we confirm that increased genetic diversity in GWAS discovery samples significantly improves the prediction accuracy of PGSs in under-represented ancestries.
section_name: GWAS discoveries, sample size and ancestry diversity

section_content: By conducting one of the largest GWASs so far in 5. 4 million individuals, with a primary focus on common genetic variation, we have provided insights into the genetic architecture of height-including a saturated genomic map of 12,111 genetic associations for height. Consistent with previous studies 19, 20, we have shown that signal density of associations (known and novel) is not randomly distributed across the genome; rather, associated variants are more likely to be detected around genes that have been previously associated with Mendelian disorders of growth. Furthermore, we observed a strong genetic overlap of association across cohorts with various ancestries. Effect estimates of associated SNPs are moderately to highly correlated (minimum = 0. 64; maximum = 0. 99), suggesting even larger correlations of effect sizes of underlying causal variants 13. Moreover, although there are significant differences in power to detect an association between cohorts with European and non-European ancestries, most genetic associations for height observed in populations with non-European ancestry lie in close proximity and in linkage disequilibrium to associations identified within populations of European ancestry. 

By increasing our experimental sample size to more than seven times that of previous studies, we have explained up to 40% of the interindividual variation in height in independent European-ancestry samples using GWS SNPs alone, and more than 90% of h SNP 2 across diverse populations when incorporating all common SNPs within 35 kb of GWS SNPs. This result highlights that future investigations of common (MAF > 1%) genetic variation associated with height in many ancestries will be most likely to detect signals within the 7,209 GWS loci that we have identified in the present study. A question for the future is whether rare genetic variants associated with height are also concentrated within the same loci. We provide suggestive evidence supporting this hypothesis from analysing imputed SNPs with 0. 1% < MAF < 1% (Supplementary Note 6, Extended Data Fig. 10 and Supplementary Fig. 25 ). 

Our results are consistent with findings from a previous study 45, which showed across 492 traits a strong colocalization between common and rare coding variants associated with the same trait. Nevertheless, our conclusions remain limited by the relatively low performances of imputation in this MAF regime 46, 47. Therefore, large samples with wholegenome sequences will be required to robustly address this question. Such datasets are increasingly becoming available [48] [49] [50]. Separately, previous studies have reported a significant enrichment of height heritability near genes as compared to inter-genic regions (that is, >50 kb away from the start or stop genomic position of genes) 51. Our findings are consistent with but not reducible to that observation, given that up to 31% of GWS SNPs identified in this study lie more than 50 kb away from any gene. 

Our study provides a powerful genetic predictor of height based on 12,111 GWS SNPs, for which accuracy reaches around 40% (that is, 80% of h SNP 2 ) in individuals of European ancestries and up to around 10% in individuals of predominantly African ancestries. Notably, we show using a previously developed method 38 that LD and MAF differences between European and African ancestries can explain up to around 84% (s. e. 1. 5%) of the loss of prediction accuracy between these populations (Methods), with the remaining loss being presumably explained by differences in heritability between populations and/or differences in effect sizes across populations (for example, owing to gene-by-gene or gene-by-environment interactions). This observation is consistent with common causal variants for height being largely shared across ancestries. Therefore, we anticipate that fine-mapping of GWS loci identified in this study, ideally using methods that can accommodate dense sets of signals and large populations with African ancestries, would substantially improve the accuracy of a derived height PGS for populations of non-European ancestry. Our study has a large number of participants with African ancestries as compared with previous efforts. However, we emphasize that further increasing the size of GWASs in populations of non-European ancestry, including those with diverse African ancestries, is essential to bridge the gap in prediction accuracy-particularly as most studies only partially capture the wide range of ancestral diversity both within Africa and globally. Such increased sample sizes would help to identify potential ancestry-specific causal variants, to facilitate ancestry-specific fine-mapping and to inform gene-environment and gene-ancestry interactions. Another important finding of our study is to show how individual PGS can be optimally combined with familial information and thereby improve the overall accuracy of height prediction to above 54% in populations of European ancestry. 

Although large sample sizes are needed to pinpoint the variants responsible for the heritability of height (and larger samples in multiple ancestries will probably be required to map these at finer scale), the prioritization of relevant genes and gene sets is feasible at smaller Summary statistics from the three published GWASs were imputed using the ImpG-Summary software to maximize the coverage of HM3 SNPs (Methods). GWS loci are defined as in the legend of Table 1. 

a Summary statistics from the Lango Allen et al. study 19, initially over-corrected for population stratification using a double genomic control correction, were re-inflated such that the LD score regression intercept estimated from re-inflated test statistics equals 1. 

sample sizes than that required to account for the common variant heritability. Thus, the sample sizes required for saturation of GWAS are smaller for identifying enriched gene sets, with the identification of genes implicated as potentially causal and mapping of genomic regions containing associated variants requiring successively larger sample sizes. Furthermore, unlike prediction accuracy, prioritization of genes that are likely to be causal and even mapping of associated regions is consistent across ancestries, reflecting the expected similarity in the biological architecture of human height across populations. 

Recent studies using UKB data predicted that GWAS sample sizes of just over 3 million individuals are required to identify 6,000-7,000 GWS SNPs explaining more than 90% of the SNP-based heritability of height 52. We showed empirically that these predictions are downwardly biased given that around 10,000 independent associations are, in fact, required to explain 80-90% of the SNP-based heritability of height in EUR individuals. Discrepancies between observed and predicted levels of saturation could be explained by several factors, such as (i) heterogeneity of SNP effects between cohorts and background ancestries, which may have reduced the statistical power of our study as compared to a homogenous sample like UKB; (ii) inconsistent definitions of GWS SNPs (using COJO in this study versus standard clumping in ref. 52 ); and, most importantly, (iii) misspecification of the SNP-effects distribution assumed to make these predictions. Nevertheless, if these predictions reflect proportional levels of saturation between traits, then we could expect that two-to tenfold larger samples would be required for GWASs of inflammatory bowel disease (×2, that is, n = 10 million), schizophrenia (×7; n = 35 million) or BMI (×10; n = 50 million) to reach a similar saturation of 80-90% of SNP-based heritability. 

Our study has a number of limitations. First, we focused on SNPs from the HM3 panel, which only partially capture common genetic variation. However, although a significant fraction of height variance can be explained by common SNPs outside the HM3 SNPs panel, we showed that the extra information (also referred to as 'hidden heritability') remains concentrated within GWS loci identified in our HM3-SNP-based analyses (Extended Data Fig. 6 ). This result underlines the widespread allelic heterogeneity at height-associated loci. Another limitation of our study is that we determined conditional associations using a EUR LD reference (n ≈ 350,000), which is sub-optimal given that around 24% of our discovery sample is of non-European ancestry. We emphasize that no analytical tool with an adequately large multi-ancestry reference panel is at present available to properly address how to identify conditionally independent associations in a multi-ancestry study. Fine-mapping of variants remains a particular challenge when attempted across ancestries in loci containing multiple signals (as is often the case for height). A third limitation of our study is our inability to perform well-powered replication analyses of genetic associations specific to populations with non-European ancestries, owing to the current limited availability of such data. Finally, as with all GWASs, definitive identification of effector genes and the mechanisms by which genes and variants influence phenotype remains a key bottleneck. Therefore, progress towards identifying causal genes from GWAS of height may be achieved by a combination of increasingly large whole-exome sequencing studies, allowing straightforward SNP-to-gene mapping 45, the use of relevant complementary data (for example, context-specific eQTLs in relevant tissues and cell types) and the development of computational methods that can integrate these data. 

In summary, our study has been able to show empirically that the combined additive effects of tens of thousands of individual variants, detectable with a large enough experimental sample size, can explain substantial variation in a human phenotype. For human height, we show that studies of the order of around 5 million participants of various ancestries provide enough power to map more than 90% (around 100% in populations of European ancestry) of genetic variance explained by common SNPs down to around 21% of the genome. Mapping the missing 5-10% of SNP-based heritability not accounted for in the four non-European ancestries studied here will require additional and directed efforts in the future. 

Height has been used as a model trait for the study of human polygenic traits, including common diseases, because of its high heritability and relative ease of measurement, which enable large sample sizes and increased power. Conclusions about the genetic architecture, sample size requirements for additional GWAS discovery and scope for polygenic prediction that were initially made for height have by-and-large agreed with those for common disease. If the results from this study can also be extrapolated to disease, this would suggest that substantially increased sample sizes could largely resolve the heritability attributed to common variation to a finite set of SNPs (and small genomic regions). These variants and regions would implicate a particular subset of genes, regulatory elements and pathways that would be most relevant to address questions of function, mechanism and therapeutic intervention.
section_name: Discussion

section_content: Any methods, additional references, Nature Research reporting summaries, source data, extended data, supplementary information, acknowledgements, peer review information; details of author contributions and competing interests; and statements of data and code availability are available at https://doi. org/10. 1038/s41586-022-05275-y. GWS) is lower than 0. 8 in both EUR and corresponding non-EUR data. Single-step COJO analyses were performed using the --cojo-joint option of GCTA, which does not involve model selection and simply approximates a multivariate regression model in which all selected SNPs on a chromosome are fitted jointly. LD correlations used in these filters were estimated in ancestry-matched samples of the 1000 Genomes Project (1KGP; release 3). More specifically, LD was estimated in 661 AFR, 347 HIS (referred to with the AMR label in 1KGP), 504 EAS, 503 EUR and 489 SAS 1KGP participants. We used the same LD reference samples in these analyses as for our main discovery analysis described at the beginning of the section.
section_name: Online content

section_content: We used two statistics to evaluate whether an EUR LD reference could approximate well enough the LD structure in our trans-ancestry GWAS meta-analysis. The first statistic that we used is the Wright fixation index 57, which measures allele frequency divergence between two populations. We used the Hudson's estimator of F ST 58 as previously recommended 59 to compare allele frequencies from our META FE with that from our EUR GWAS meta-analysis and an independent replication sample from the EBB. The other statistic that we used is the attenuation ratio statistic from the LD score regression methodology. These LD score regression analyses were performed using version 1. 0 of the LDSC software and using LD scores calculated from EUR participants in the 1KGP (see 'URLs' section). Moreover, we performed a stratified LD score regression analysis to quantify the enrichment of height heritability in 97 genomic annotations curated and described previously 40. as the baseline-LD model. Annotation-weighted LD scores used for those analyses were also calculated using data from 1KGP (see 'URLs' section).
section_name: F ST calculation and (stratified) LD score regression

section_content: We defined the density of independent signals around each GWS SNP as the number of other independent associations identified with COJO within a 100-kb window on both sides. Therefore, a SNP with no other associations within 100 kb has a density of 0, whereas a SNP colocalizing with 20 other GWS associations within 100 kb will have a density of 20. 

We quantified the standard error of the mean signal density across the genome using a leave-one-chromosome-out jackknife procedure. We then quantified the enrichment of 462 curated OMIM 18 genes near GWS SNPs with a large signal density, by counting the number of OMIM genes within 100 kb of a GWS SNP, then comparing that number for SNPs with a density of 0 and those with a density of at least 1. The strength of the enrichment was measured using an odds ratio calculated from a 2×2 contingency table: 'presence/absence of an OMIM gene' versus 'density of 0 or larger than 0'. To assess the significance of the enrichment, we simulated the distribution of enrichment statistics for a random set of 462 length-matched genes. We used 22 length classes (<10 kb; between i × 10 kb and (i + 1) × 10 kb, with i = 1,…,9; between i × 100 kb and (i + 1) × 100 kb, with i = 1,…,10; between 1 Mb and 1. 5 Mb; between 1. 5 Mb and 2 Mb; and >2 Mb) to match OMIM genes with random genes. OMIM genes within a given length class were matched with the same number of non-OMIM genes present in the class. We sampled 1,000 random sets of genes and calculated for each them an enrichment statistic. Enrichment P value was calculated as the number of times enrichment statistics of random genes exceeded that of OMIM genes. The list of OMIM genes is provided in Supplementary Table 11.
section_name: Density of GWS signal and enrichment near OMIM genes

section_content: We assessed the genomic colocalization between 2,747 GWS SNPs identified in non-EUR (Supplementary Tables 5 6 7 8 ) and 9,863 GWS SNPs identified in EUR (Supplementary Table 4 ) by quantifying the proportion of EUR GWS SNPs identified within 100 kb of any non-EUR GWS SNP. We tested the statistical significance of this proportion by comparing it with the proportion of EUR GWS SNPs identified within 100 kb of random HM3 SNPs matched with non-EUR GWS SNPs on 24 binary functional annotations 39. 

These 24 annotations (for example, coding or conserved) are thoroughly described in a previous study 39 and were downloaded from https:// alkesgroup. broadinstitute. org/LDSCORE/baselineLD_v2. 1_annots/. 

Our matching strategy consists of three steps. First, we calibrated a statistical model to predict the probability for a given HM3 SNP to be GWS in any of our non-EUR GWAS meta-analyses as a function of their annotation. For that, we used a logistic regression of the non-EUR GWS status (1 = if the SNP is GWS in any of the non-EUR GWAS; 0 = otherwise) onto the 24 annotations as regressors. Second, we used that model to predict the probability to be GWS in non-EUR. Thirdly, we used the predicted probability to sample (with replacement) 1,000 random sets of 2,747 SNPs. Finally, we estimated the proportion of EUR GWS SNPs within 100 kb of SNPs in each sampled SNP set. We report in the main text the mean and s. d. over these 1,000 proportions. 

To validate our matching strategy, we compared the mean value of each of these 24 annotations (for example, proportion of coding SNPs) between non-EUR GWS SNPs and each of the 1,000 random sets of SNPs, using a Fisher's exact test. For each of the 24 annotations, both the mean and median P value were greater than 0. 6 and the proportion of P values < 5% was less than 1%, suggesting no significant differences in the distribution of these 24 annotations between non-EUR GWS SNPs and matched SNPs.
section_name: Genomic colocalization of GWS SNPs identified across ancestries

section_content: To assess the replicability of our results, we tested whether the correlation ρ b of estimated SNP effects between our discovery GWAS and our replication sample of 49,160 participants of the EBB was statistically different from 1. We used the estimator of ρ b from a previous study 60, which accounts for sampling errors in both discovery and replication samples. Standard errors were calculated using a leave-one-SNPout jackknife procedure. We quantified the correlation of marginal and also that of joint SNP effects. Joint SNP effects in our replication sample were obtained by performing a single-step COJO analysis of GWAS summary statistics from our EBB sample, using the same LD reference as in the discovery GWAS. Correlation of SNP effects were calculated after correcting SNP effects for winner's curse using a previously described method 12. We provide the R scripts used to apply these corrections and estimate the correlation of SNP effects (see 'URLs' section). The expected proportion, E[P], of sign-consistent SNP effects between discovery and replication was calculated using the quadrant probability of a standard bivariate Gaussian distribution with correlation E[ρ b ], denoting the expected correlation between estimated SNP effects in the discovery and replication sample: where N d and N r denote the sizes of the discovery and replication samples, respectively; h d and h r the average heterozygosity under Hardy-Weinberg equilibrium (that is, 2 × MAF × (1 - MAF)) across GWS SNPs in the discovery and replication samples, respectively; and σ b 2 the mean per-SNP variance explained by GWS SNPs, which we calculated (as per ref. 60. ) as the sample variance of estimated SNP effects in the discovery sample minus the median squared standard error.
section_name: Replication analyses

section_content: We estimated the variance explained by GWS SNPs using the genetic relationship-based restricted maximum likelihood (GREML) approach implemented in GCTA 1, 7. This approach involves two main steps: (i) calcu lation of genetic relationships matrices (GRM); and (ii) estimation of variance components corresponding to each of these matrices using a REML algorithm. We partitioned the genome in two sets containing GWS loci on the one hand and all other HM3 SNPs on the other hand. GWS loci were defined as non-overlapping genomic segments containing at least one GWS SNP and such that GWS SNPs in adjacent loci are more than 2 × 35 kb away from each other (that is, a 35-kb window on each side). We then calculated a GRM based on each set of SNPs and estimated jointly a variance explained by GWS alone and that explained by the rest of the genome. We performed these analyses in multiple samples independent of our discovery GWAS, which include participants of diverse ancestry. Details about the samples used for these analyses are provided below. We extended our analyses to also quantify the variance explained by GWS loci using alternative definitions based on a window size of 0 kb and 10 kb around GWS SNPs (Supplementary Figs. 18 and 19 ). We also repeated our analyses using a random set of 12,111 SNPs matched with GWS SNPs on MAF and LD. Loci for these 12,111 random SNPs were defined similarly as for GWS loci. To match random SNPs with GWS SNPs on MAF and LD, we first created 28 MAF-LD classes of HM3 SNPs (7 MAF classes × 4 LD score classes). MAF classes were defined as <1%; between 1% and 5%; between 5% and 10%; between 10% and 20%; between 20% and 30%; between 30% and 40%; and between 40% and 50%. LD score classes were defined using quartiles of the HM3 LD score distribution. We next matched GWS SNPs in each of the 28 MAF-LD classes, with the same number of SNPs randomly sampled from that MAF-LD class.
section_name: Variance explained by GWS SNPs and loci

section_content: Height was first mean-centred and scaled to variance 1 within each sex. We quantified the prediction accuracy of height predictors as the difference between the variance explained by a linear regression model of sex-standardized height regressed on the height predictor, age, 20 genotypic principal components and study-specific covariates (full model) minus that explained by a reduced linear regression not including the height predictor. Genetic principal components were calculated from LD pruned HM3 SNPs (r LD 2 < 0. 1). We used height of siblings or parents as a predictor of height as well as various polygenic scores (PGSs) calculated as a weighted sum of height-increasing alleles. The direction and magnitude of these weights was determined by estimated SNP effects from our discovery GWAS meta-analyses. No calibration of tuning parameters in a validation was performed. 

Between-family prediction. We analysed two classes of PGS. The first class is based on SNPs ascertained using GCTA-COJO. We applied GCTA-COJO to ancestry-specific and cross-ancestry GWAS metaanalyses using an ancestry-matched and an EUR LD reference, respectively. We compared PGSs based on SNPs ascertained at different significance thresholds: P < 5 × 10 -8 (GWS: reported in the main text) and P < 5 × 10 -7, P < 5 × 10 -6 and P < 5 × 10 -5. For all COJO-based PGS, we used estimated joint effects to calculate the PGS. The second class of PGS uses weights for all HM3 SNPs obtained from applying the SBayesC method 28 to ancestry-specific and cross-ancestry GWAS meta-analyses with ancestry-matched and EUR-specific LD matrices, respectively. The SBayesC method is a Bayesian PGS-method implemented in the GCTB software (v. 2. 0), which uses the same prior as the LDpred method 61, 62. 

In brief, SBayesC models the distribution of joint effects of all SNPs using a two-component mixture distribution. The first component is a point-mass Dirac distribution on zero and the other component a Gaussian distribution (for each SNP) with mean 0 and a variance parameter to estimate. Full LD matrices (that is, not sparse) were calculated using GCTB across around 250 overlapping (50% overlap) blocks of around 8,000 SNPs (average size is around 20 Mb). These LD matrices were calculated using the same sets of genotypes used for COJO analyses (described above). We ran SBayesC in each block separately with 100,000 Monte Carlo Markov Chain iterations. In each run, we initialized the proportion of causal SNPs in a block at 0. 0001 and the heritability explained by SNPs in the block at 0. 001. Posterior SNP effects of SNPs present in two blocks were meta-analysed using inverse-variance meta-analysis. Prediction accuracy was quantified in 61,095 unrelated individuals from three studies, including 33,001 participants of the UKB who were not included in our discovery GWAS (that is, 14,587 EUR; 9,257 SAS; 6,911 AFR and 2,246 EAS; Methods section 'Samples used for prediction and estimation of variance explained'); 14,058 EUR participants from the Lifelines cohort study; and 8,238 HIS and 5,798 AFR participants from the PAGE study. 

Within-family prediction. The prediction accuracy of sibling's height was assessed in 17,942 unrelated sibling pairs from the UKB. Those pairs were determined by intersecting the list of UKB sibling pairs determined by Bycroft et al. 63 with a list of genetically determined European ancestry participants from the UKB also described previously 3. We then filtered the resulting list for SNP-based genetic relationship between members of different families to be smaller than 0. 05. The prediction accuracy of parental height (each parent and their average) was assessed in 981 unrelated trios obtained as described above by crossing information from Bycroft et al. 63 (calling of relatives) with that from Yengo et al. 3 (calling of European ancestry participants). We quantified the within-family variance explained by PGS as the squared correlation of height difference between siblings with PGS difference between siblings. We describe in Supplementary Note 4 how familial information and PGS were combined to generate a single predictor.
section_name: Prediction analyses

section_content: We quantified the accuracy of a PGS based on GWS SNPs as well as the variance explained by SNPs within GWS loci, in eight different datasets independent of our discovery GWAS meta-analyses. These datasets include two samples of EUR from the UKB (n = 14,587) and the Lifelines study (n = 14,058), two samples of AFR from the UKB (n = 6,911) and the PAGE study (n = 8,238), two samples of EAS (n = 2,246) from the UKB and the China Kadoorie Biobank (CKB; n = 47,693), one sample of SAS from the UKB (n = 9,257) and one sample of HIS from the PAGE study (n = 4,939). Analyses were adjusted for age, sex, 20 genotypic principal components and study-specific covariates (for example, recruitment centres). Genotypes of EUR UKB participants were imputed to the Haplotype Reference Consortium (HRC) and to a combined reference panel including haplotypes from the 1KG Project and the UK10K Project. To improve variant coverage in non-EUR participants of UKB, we re-imputed their genotypes to the 1KG reference panel, as described previously 38. Lifelines samples were imputed to the HRC panel. PAGE and CKB were imputed to the 1KG reference panel. Standard quality control (r INFO 2 > 0. 3, P HWE > 10 -6 and MAC > 5) were applied to imputed genotypes in each dataset.
section_name: Samples used for prediction and estimation of variance explained

section_content: We defined the EUR-to-AFR relative accuracy as the ratio of prediction accuracies from an AFR sample over that from a EUR sample. We used a previously published method 38 to quantify the expectation of that relative accuracy under the assumption that causal variants and their effects are shared between EUR and AFR, whereas MAF and LD structures can differ. In brief, this method contrasts LD and MAF patterns within 100-kb windows around each GWS SNPs and uses them to predict the expected loss of accuracy. As previously described 38, we used genotypes from 503 EUR and 661 AFR participants of the 1KGP as a reference sample to estimate ancestry-specific MAF and LD correlations between GWS SNPs and SNPs in their close vicinity, and defined candidate causal variants as any sequenced SNP with an r LD 2 > 0. 45 with a GWS SNP within that 100-kb window. Standard errors were calculated using a delta-method approximation as previously described 38.
section_name: Contribution of LD and MAF to the loss of prediction accuracy

section_content: In addition to our EUR GWAS meta-analysis and our trans-ancestry metaanalysis (META FE ), we re-analysed five down-sampled GWASs as shown in Table 2. These down-sampled GWASs include various iterations of previous efforts of the GIANT consortium and have a sample size varying between around 130,000 and 2. 5 million (EUR participants from 23andMe). To ensure sufficient genomic coverage of HM3 SNPs we imputed GWAS summary statistics from Lango Allen et al. 19, Wood et al. 20 and Yengo et al. 3. with ImpG-Summary (v. 1. 0. 1) 64 using haplotypes from 1KGP as a LD reference. GWAS summary statistics from Lango Allen et al. only contain P values (P), height-increasing alleles and per-SNP sample sizes (N). Therefore, we first calculated Z-scores (Z) from P values assuming that Z-scores are normally distributed, then derived SNP effects (β) and corresponding standard errors (s. e. ) using linear regression theory as β Z N Z = / 2MAF × (1 -MAF) × ( + ) 2 and SE = β/Z. Imputed GWAS summary statistics from these three studies are made publicly available on the GIANT consortium website (see 'URLs' section). We next performed a COJO analysis of all down-sampled GWAS using genotypes of 348,501 unrelated EUR participants in the UKB as a LD reference panel, as for our META FE and EUR GWAS meta-analysis.
section_name: Down-sampled GWAS analyses

section_content: We used SMR to identify genes whose expression could mediate the effects of SNPs on height. SMR analyses were performed using the SMR software v. 1. 03. We used publicly available gene eQTLs identified from two large eQTL studies; namely, the GTEx 65 v. 8 and the eQTLgen studies (see 'URLs' section). To ensure that our SMR results robustly reflect causality or pleiotropic effects of height-associated SNPs on gene expression, we only report here significant SMR results (that is, P < 5 × 10 -8 ), which do not pass the heterogeneity in dependent instrument (HEIDI) test (that is, P > 0. 01; Methods). The significance threshold for the HEIDI test was chosen on the basis of recommendations from another study 66.
section_name: Gene prioritization using SMR

section_content: To generate a list of genes that are known to underlie syndromes of abnormal skeletal growth, we queried the Online Mendelian Inheritance in Man database (OMIM; https://www. omim. org/). From July 2019 to August 2020, we performed queries using search terms of "short stature", "tall stature", "overgrowth", "skeletal dysplasia" and "brachydactyly. " We then used the free text descriptions in OMIM to manually curate the resulting combined list of genes, as well as genes in our earlier list from Wood et al. 20 and all genes listed as causing skeletal disease in an online endocrine textbook (https://www. endotext. org/, accessed September 2020). For short stature, we only included genes that underlie syndromes in which short stature was either consistent (less than -2 s. d. in the vast majority of patients with data recorded), or present in multiple families or sibships and accompanied by (a) more severe short stature (-3 s. d. ), (b) presence of skeletal dysplasia (beyond poor bone quality/fractures); or (c) presence of brachydactyly, shortened digits, disproportionate short stature or limb shortening (not simply absence of specific bones). We removed genes underlying syndromes in which short stature was likely to be attributable to failure to thrive, specific metabolic disturbances, intestinal failure or enteropathy and/or very severe disease (for example, early lethality or severe neurological disease). For tall stature or overgrowth, we only included genes underlying syndromes in which tall stature was consistent (more than +2 s. d. in the vast majority of patients with data recorded) or present in multiple families or sibships and accompanied by either (a) more severe tall stature (>+3 s. d. ) or (b) arachnodactyly. For brachydactyly, we required more than only fifth finger involvement, and that brachydactyly be either consistent (present in the vast majority of patients) or accompanied by consistent short stature or other skeletal dysplasias. For skeletal dysplasias, we only considered genes that underlie syndromes in which the skeletal dysplasia involved long bones or the spine and was accompanied by short stature, brachydactyly or limb or digit shortening. We also included all genes in a list we generated in Lango Allen et al. 19, which was curated using similar criteria. The resulting list contained 536 genes, of which 462 (Supplementary Table 11 ) are autosomal on the basis of annotation from PLINK (https:// www. cog-genomics. org/static/bin/plink/glist-hg19).
section_name: Selection of OMIM genes

section_content: GIANT consortium data files: https://portals. broadinstitute. org/ collaboration/giant/index. php/GIANT_consortium_data_files. Analysis script for within-and across-ancestry meta-analysis: https:// github. com/loic-yengo/ScriptsForYengo2022_HeightGWAS/blob/main/ run-meta-analyses-within-ancestries. R and https://github. com/ loic-yengo/ScriptsForYengo2022_HeightGWAS/blob/main/run-metaanalyses-across-ancestries. R. Analysis script for correction of winner's curse: https://github. com/loic-yengo/ScriptsForYengo2022_Height-GWAS/blob/main/WC_correction. R. Genotypes from 1KG: https:// ftp. 1000genomes. ebi. ac. uk/vol1/ftp/release/20130502/. eQTL data for SMR: GTEx v. 8: https://yanglab. westlake. edu. cn/data/SMR/GTEx_ V8_cis_eqtl_summary. html; eQTLgen: https://www. eqtlgen. org/ cis-eqtls. html. Annotation-weighted LD scores for stratified LD score regression analyses: https://alkesgroup. broadinstitute. org/LDSCORE/ LDSCORE/. LDSC software: https://github. com/bulik/ldsc.
section_name: URLs

section_content: Further information on research design is available in the Nature Research Reporting Summary linked to this article.
section_name: Reporting summary

section_content: Program, the Global University Project from the Ministry of Education, Culture, Sports, Science and Technology of Japan ; the Practical Research Project for Rare/Intractable Diseases ( ek0109070, ek0109283, ek0109196, ek0109348 ), and the Program for an Integrated Database of Clinical and Genomic Information (kk0205008), from the Japan Agency for Medical Research and Development; Takeda Medical Research Foundation ; Astellas Pharma, Inc. ; Daiichi Sankyo Co., Ltd. ; Mitsubishi Tanabe Pharma Corporation ; Otsuka Pharmaceutical Co., Ltd. ; Taisho Pharmaceutical Co., Ltd. ; Takeda Pharmaceutical Co., Ltd. ; JSPS KAKENHI ( 22H00476 ), AMED ( JP21gm4010006, JP22km0405211, JP22ek0410075, JP22km0405217, JP22ek0109594 ), JST Moonshot R&D ( JPMJMS2021, JPMJMS2024 ) (Y. O. ); Type 1 Diabetes Genetics Consortium ; the French Ministry of Research ; the Chief Scientist Office of the Scottish Government CZB/4/276 and CZB/4/710 ; Arthritis Research UK ; Royal Society URF (J. F. W. ); the Atlantic Philanthropies ; the UK Economic and Social Research Council awards ES/L008459/1 and ES/L008459/1 ; the UKCRC Centre of Excellence for Public Health Northern Ireland ; the Centre for Ageing Research and Development in Ireland ; the Office of the First Minister and Deputy First Minister ; the Health and Social Care Research and Development Division of the Public Health Agency ; the Wellcome Trust/Wolfson Foundation ; Queen's University Belfast ; the Science Foundation Ireland-Department for the Economy Award 15/IA/3152 (NICOLA); NI HSC R&D division STL/5569/19 ( L. J. Smyth ); the Italian Ministry of Education, University and Research (MIUR) number 5571/DSPAR/2002 (OGP study); GlaxoSmithKline; the Faculty of Biology and Medicine of Lausanne ; the Swiss National Science Foundation grants 33CSCO-122661, 33CS30-139468, 33CS30-148401 and 33CS30_177535/1 ; the Montreal Heart Institute Biobank ; the Canadian Institutes of Health Research PJT 156248 ; the Canada Research Chair Program, Genome Quebec and Genome Canada, and the Montreal Heart Institute Foundation (G. L. ); the Strategic Priority CAS Project grant number XDB38000000, Shanghai Municipal Science and Technology Major Project grant number 2017SHZDZX01 and the National Natural Science Foundation of China grant number 81970684 ; the National Medical Research Council (grants 0796/2003, 1176/2008, 1149/2008, STaR/0003/ 2008, 1249/2010, CG/SERI/2010, CIRG/1371/2013 and CIRG/1417/2015 ) and the Biomedical Research Council (grants 08/1/35/19/550 and 09/1/35/19/616 ) of Singapore; the Ministry of Health, Singapore ; the National University of Singapore and the National University Health System, Singapore; the Agency for Science, Technology and Research, Singapore ; Merck Sharp & Dohme Corp. ; Kuwait Foundation for Advancements of Sciences (The KODGP); the Oogfonds, MaculaFonds, Landelijke Stichting voor Blinden en Slechtzienden, Stichting Blindenhulp, Stichting A. F. Deutman Oogheelkunde Researchfonds ; in Mexico, the Fondo Sectorial de Investigación en Salud y Seguridad Social SSA/IMSS / ISSSTECONACYT project 150352 ; Temas Prioritarios de Salud Instituto Mexicano del Seguro Social 2014-FIS/IMSS/ PROT/PRIO/14/34 ; the Fundación IMSS ; Compute Ontario (https://www. computeontario. ca/)and the Digital Research Alliance of Canada (https://alliancecan. ca/); CIHR Operating grants and a CIHR New Investigator Award (E. J. P. ); the Westlake Education Foundation (Jian Yang) ; AstraZeneca ; a Miguel Servet contract from the ISCIII Spanish Health Institute number CP17/00142 and co-financed by the European Social Fund (M. S. -L. ); the Dutch Ministry of Justice ; the European Science Foundation EuroSTRESS project FP-006 ; Biobanking and Biomolecular Resources Research Infrastructure BBMRI-NL award CP 32 ; Accare Centre for Child and Adolescent Psychiatry ; the Dutch Brain Foundation ; the Federal Ministry of Science, Germany award 01 EA 9401 ; German Cancer Aid award 70-2488-Ha I; the participating Departments, the Division and the Board of Directors of the Leiden University Medical Centre and the Leiden University, Research Profile Area 'Vascular and Regenerative Medicine' ; Research Project For Excellence ΙΚΥ/SIEMENS ; the Wake Forest School of Medicine grant M01 RR07122 and Venture Fund; the Greek General Secretary of Research and Technology award PENED 2003; the MRC-PHE Centre for Environment and Health ; the Singapore Ministry of Health's National Medical Research Council under its Singapore Translational Research Investigator (STaR) Award NMRC/STaR/0028/2017 (J. C. C); the German Research Foundation Project-ID 431984000 -SFB 1453 ( M. Wuttke, A. Köttgen ); the KfH Foundation for Preventive Medicine, and Bayer Pharma AG ; the German Research Foundation grant KO 3598/5-1 ( A. Köttgen ); the Leipzig Research Center for Civilization Diseases ; the Medical Faculty of the University of Leipzig ; the Free State of Saxony ; the Medical Research Funds from Kangbuk Samsung Hospital (H. -N. K. ); the Division of Adult and Community Health, Centers for Disease Control and Prevention ; AstraZeneca (P. M. R., D. I. C. ); Amgen (P. M. R., D. I. C. ); a gift from the Smilow family; the Perelman School of Medicine at the University of Pennsylvania ; the University of Bristol ; a comprehensive list of grants funding is available on the ALSPAC website; the US Centers for Disease Control and Prevention/Association of Schools of Public Health awards S043, S1734 and S3486, and US Centers for Disease Control and Prevention awards U01 DP003206 and U01 DP006266 ; the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania; Hjartavernd (the Icelandic Heart Association ), and the Althingi (the Icelandic Parliament) ; Bristol Myers Squibb ; the Netherlands Genomics Initiative's Netherlands Consortium for Healthy Aging grant 050-060-810 ; the Netherlands Heart Foundation grant 2001 D 032 (J. W. J. ); the Chief Scientist Office of the Scottish Government Health Directorates award CZD/16/6, the Scottish Funding Council award HR03006 ; the Stiftelsen Kristian Gerhard Jebsen; Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology; Central Norway Regional Health Authority ; the Medical Research Council of Canada and the Canadian Institutes of Health Research grant FRN-CCT-83028 (The Quebec Family Study) ; Pfizer ; the Servier Research Group ; Leo Laboratories; Estonian Research Council grants PUT 1371, EMBO Installation grant 3573, and The European Regional Development Fund project no. 2014-2020. 4. 01. 15-0012 ( K. Lüll, A. Metspalu ); the Estonian Research Council grants PUT PRG687, PRG1291 (EBB, T. 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section_name: Article

section_content: Medicine, Stanford, CA, USA. 236 Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany. 237DZHK ( German Centre for Cardiovascular Research ), partner site Greifswald, Greifswald, Germany. 238 Cardiology Division, Department of Pediatrics, University of California, San Francisco, Oakland, CA, USA. 239 Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK. 240Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. 241Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands. 242Central Diagnostics Laboratory, Division Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands. 243Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands. 244Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. 245Core Facility Metabolomics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. 246Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands. 247Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 248Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. 249NIHR Barts Cardiovascular Biomedical Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. 250 Department of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing, China. 251Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK. 252 Department of Dermatology, Medical University of Vienna, Vienna, Austria. 253Department of Research and Innovation, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway. 254Department of Neurology, Oslo University Hospital, Oslo, Norway. 255MRC Unit for Lifelong Health and Ageing at UCL, Institute of Cardiovascular Science, University College London, London, UK. 256 Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany. 257Department of Medicine IV -Nephrology and Primary Care, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany. 258Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA. 259Department of Medical Biochemistry, Kurume University School of Medicine, Kurume, Japan. 260Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA. 261Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA. 262Department of Genetic Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar. 263Department of Computer and Systems Engineering, Alexandria University, Alexandria, Egypt. 264Department of Cardiology, German Heart Centre Munich, Technical University Munich, Munich, Germany. 265Department of Cardiology, Ealing Hospital, London North West University Healthcare NHS Trust, London, UK. 266 Department of Epidemiology and Biostatistics, Imperial College London, London, UK. 

267 Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK. 268Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA. 269Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. 270Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. 271 Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. 272Carolina Population Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. 273Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands. 274Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands. 275Latin American Brain Health (BrainLat), Universidad Adolfo Ibáñez, Santiago, Chile. 276Unidad de Investigacion de Enfermedades Metabolicas and Direction of Nutrition, Instituto Nacional de Ciencias Medicas y Nutricion, Mexico City, Mexico. 277Escuela de Medicina y Ciencias de la Salud, Tecnologico de Monterrey, Monterrey, Mexico. 278Department of Epidemiology and Dean's Office, College of Public Health, University of Kentucky, Lexington, KY, USA. 279Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, UK. 280 Health Data Research UK and Institute of Health Informatics, University College London, London, UK. 281 KG Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, NTNU, Trondheim, Norway. 282HUNT Research Centre, Department of Public Health and Nursing, Norwegian University of Science and Technology, Levanger, Norway.
section_name: Article

section_name: Data availability

section_content: Summary statistics for ancestry-specific and multi-ancestry GWASs (excluding data from 23andMe) as well as SNP weights for polygenic scores derived in this study are made publicly available on the GIANT consortium website (see 'URLs' for GIANT consortium data files). GWAS summary statistics derived involving 23andMe participants will be made available to qualified researchers under an agreement with 23andMe that protects the privacy of participants. Application for data access can be submitted at https://research. 23andme. com/ dataset-access/. We used genotypes from various publicly available databases to estimate linkage disequilibrium correlations required for conditional analyses and genome-wide prediction analyses. These databases include the UK Biobank under project 12505 and the database of Genotypes and Phenotypes (dbGaP) under project 15096. Accession numbers for dbGaP datasets are phs000788. v2. p3. c1, phs000386, phs000557. v4. p1, phs000286. v5. p1, phs000613. v1. p2, phs000284. v2. p1, phs000283. v7. p3 and phs001395. v2. p1 cohorts. Details for each dbGaP dataset are given in the Methods. Source data are provided with this paper.
section_name: Data availability

section_content: We used publicly available software tools for all analyses. These software tools are listed in the main text and in the Methods. Source data are provided with this paper.
section_name: Code availability

section_content: Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

section_content: Transdisciplinary Research Initiatives, Osaka University, Osaka, Japan. 494 Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. 495 Departments of Pediatrics and Genetics, Harvard Medical School, Boston, MA, USA. 496 Present address: Department of Mathematics and Statistics, St Cloud State University, St Cloud, MN, USA. 497 Genentech, South San Francisco, CA, USA. 498 Present address: Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan. 499 Department of Genome Informatics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. 500 These authors contributed equally: Loïc Yengo, Sailaja Vedantam, Eirini Marouli. 501 These authors jointly supervised this work: Yukinori Okada, Andrew R. Wood, Peter M. 

Visscher, Joel N. Hirschhorn. *A list of authors and their affiliations appears online. Understanding Society Scientific Group Meena Kumari 386 Full lists of members and their affiliations appear in the Supplementary Information. 

Full lists of members and their affiliations appear in the Supplementary Information. 

Full lists of members and their affiliations appear in the Supplementary Information. 

Full lists of members and their affiliations appear in the Supplementary Information. 

Full lists of members and their affiliations appear in the Supplementary Information. 

Full lists of members and their affiliations appear in the Supplementary Information. 

Full lists of members and their affiliations appear in the Supplementary Information.
section_name: Article

section_content: A summary of the methods, together with a full description of genomewide association analyses and follow-up analyses is described below. Written informed consent was obtained from every participant in each study, and the study was approved by relevant ethics committees (Supplementary Table 1 ).
section_name: Methods

section_content: All study files were checked for quality using the software EasyQC 53 that was adapted to the format from RVTESTS (versions listed in Supplementary Table 2 ) 54. The checks performed included allele frequency differences with ancestry-specific reference panels, total number of markers, total number of markers not present in the reference panels, imputation quality, genomic inflation factor and trait transformation. We excluded two studies that did not pass our quality checks in the data.
section_name: Quality control checks of individual studies

section_content: We first performed ancestry-group-specific GWAS meta-analyses of 173 studies of EUR, 56 studies of EAS, 29 studies of AFR, 11 studies of HIS and 12 studies of SAS. Meta-analyses within ancestry groups were performed as described before 19, 20 using a modified version of RAREM-ETAL 55 (v. 4. 15. 1), which accounts for multi-allelic variants in the data. Study-specific GWASs are described in Supplementary Tables 1 2 3. Details about imputation procedures implemented by each study are also given in Supplementary Table 2. We kept in our analyses SNPs with an imputation accuracy (r INFO 2 ) > 0. 3, Hardy-Weinberg Equilibrium (HWE) P value (P HWE ) > 10 -8 and a minor allele count (MAC) > 5 in each study. Next, we performed a fixed-effect inverse variance weighted meta-analysis of summary statistics from all five ancestry groups GWAS meta-analysis using a custom R script using the R package meta (see 'URLs' section).
section_name: GWAS meta-analysis

section_content: We excluded 56,477 UK Biobank (UKB) participants from our discovery GWAS for following analyses including quantification of population stratification. More precisely, our hold-out EUR sample consists of 17,942 sibling pairs and 981 trios (two parents and one child) plus all UKB participants with an estimated genetic relationship larger than 0. 05 with our set of sibling pairs and trios. We identified 14,587 individuals among these 56,477 UKB participants who were unrelated (unrelatedness was determined as when the genetic relationship coefficient estimated from HM3 SNPs was lower than 0. 05) to each other and used their data to quantify the variance explained by SNPs within GWS loci (described below) and the prediction accuracy of PGSs.
section_name: Hold-out sample from the UK Biobank

section_content: We performed COJO analyses of each of the five ancestry group-specific GWAS meta-analyses using the software GCTA (version v. 1. 93) 6, 7. We used default parameters for all ancestry groups except in AFR and HIS, for which we found that default parameters could yield biased estimates of joint SNP effects because of long-range LD. This choice is discussed in Supplementary Note 1. The GCTA-COJO method implements a stepwise model selection that aims at retaining a set of SNPs the joint effects of which reach genome-wide significance, defined in this study as P < 5 × 10 -8. In addition to GWAS summary statistics, COJO analyses also require genotypes from an ancestry-matched sample that is used as a LD reference. For all sets of genotypes used as LD reference panels, we selected HM3 SNPs with r INFO 2 > 0. 3 and P HWE > 10 -6. For EUR, we used genotypes at 1,318,293 HM3 SNPs (MAC > 5) from 348,501 unrelated EUR participants in the UKB as our LD reference. For EAS, we used genotypes at 1,034,263 quality-controlled (MAF > 1%, SNP missingness < 5%) HM3 SNPs from a merged panel of n = 5,875 unrelated participants from the UKB (n = 2,257) and Genetic Epidemiology Research on Aging (GERA; n = 3,618). Data from the GERA study were obtained from the database of Genotypes and Phenotypes (dbGaP; accession number: phs000788. v2. p3. c1) under project 15096. For SAS, we used genotypes at 1,222,935 HM3 SNPs (MAC > 5; SNP missingness < 5%) from 9,448 unrelated individuals. For AFR, we used genotypes at 1,007,949 quality-controlled (MAF > 1%, SNP missingness < 5%) HM3 SNPs from a merged panel of 15,847 participants from the Women's Health Initiative (WHI; n = 7,480), and the National Heart, Lung, and Blood Institute's Candidate Gene Association Resource (CARe 56, n = 8,367). Both WHI and CARe datasets were obtained from dbGaP (accession numbers: phs000386 for WHI; CARe including phs000557. v4. p1, phs000286. v5. p1, phs000613. v1. p2, phs000284. v2. p1, phs000283. v7. p3 for ARIC, JHS, CARDIA, CFS and MESA cohorts) and processed following the protocol provided by the dbGaP data submitters. After excluding samples with more than 10% missing values and retaining only unrelated individuals, our final LD reference included data from n = 10,636 unrelated AFR individuals. For HIS, we used genotypes at 1,246,763 sequenced HM3 SNPs (MAF > 1%) from n = 4,883 unrelated samples from the Hispanic Community Health Study/Study of Latinos (HCHS/ SOL; dbGaP accession number: phs001395. v2. p1) cohorts. Finally, we performed a COJO analysis of the combined meta-analysis of all ancestries (referred to as META FE in the main text) using 348,501 unrelated EUR participants in the UKB as the reference panel. 

To assess whether SNPs detected in non-EUR were independent of signals detected in EUR, we performed another COJO analysis of ancestry groups GWAS by fitting jointly SNPs detected in EUR with those detected in each of the non-EUR GWAS meta-analyses. For each non-EUR GWAS, we performed a single-step COJO analysis only including SNPs identified in that non-EUR GWAS and for which the LD squared correlation (r LD 2 ) with any of the EUR signals (marginally or conditionally Horizontal dotted line represents replication at P<0. 001 and the vertical dotted line indicates 80% of statistical power. SNPs highlighted in green have an expected statistical power for replication >80%. One outlier (rs11100870), highlighted in red, does not replicate in the EBB sample. b, Proportion (P) of SNPs with a sign-consistent estimated effect between discovery GWAS (N~5. 3M) and EBB. Expected proportions (E[P]) are calculated using
section_name: COJO analyses

section_content: (2) the Methods. Error are defined as 1. 96× P P m (1 -)/, where m is the number of SNPs in the corresponding MAF interval.
section_name: GWAS meta-analysis of height in 281 studies

section_content: Extended Data Fig. 4 | Enrichment of genes containing pathogenic mutations that cause extreme height or abnormal skeletal growth syndromes near hotspots of GWS SNPs. Four hundred and sixty-two (462) autosomal genes were curated from the Online Mendelian Inheritance in Man (OMIM) database. a, Red arrow indicates the observed enrichment statistic (OR = 2. 5-fold) measuring the odds ratio of the presence of an OMIM gene within 100 kb of a GWS SNPs with a density > 1. The blue histogram represents the distribution of enrichment statistics from 1,000 random genes matched, which length distribution matches that of the OMIM genes. b, Enrichment of OMIM genes near high density GWS SNPs. High density is defined by on the x-axis by the minimum number of other independent GWS SNPs detected within 100 kb. 

Extended Data Fig. 5 | Haplotypic analysis at the ACAN locus. a, Distribution of estimated haplotype effects from 14,117 haplotypes covering a 100 kb long genomic region near the ACAN gene (hg19 genomic coordinates: chr15:89,307,521-89,407,521). b, Quantile-quantile plot of associations between these 14,117 haplotypes and height. c, Distribution of the variance explained by each of the 14,117 haplotypes. d, Mean signals density (y-axis) across simulated data where 1 causal SNP within the locus explains between 0. 5% and 5% (x-axis) of trait variance. Causal variants were sampled from a pool of 13 SNPs with a 1. 4×10 -5 < MAF < 1% genotyped in 291,683 unrelated EUR participants of the UKB, with no missing values at these 13 SNPs. Standard errors were calculated as the standard deviation (s. d. ) of signal density across 100 simulation replicates. GCTA-COJO analyses to identify independent signals were performed using a subset of 10,000 unrelated EUR participants of the UKB to mimic the large discrepancy between the size of the discovery GWAS and that of the LD reference used in our real data analyses. e, Proportion of VNTR length explained by 25 GWS SNPs identified near ACAN in 4 ancestries (European: EUR; South Asian: SAS; East Asian: EAS; African: AFR). f, Proportion of height variance explained in a sample of EUR UK Biobank participants by various sets of polymorphisms at the ACAN locus. rs3817428 and rs34949187 are two missense variants and rs7176941 is an intronic variant with high posterior causal probability identified in ref. 28. In e and f, error bars represent standard error (s. e. )., and that contributed by SNPs outside these loci is denoted h other 2. These results are further discussed in Supplementary Note 6.
section_name: Article