A global overview of pleiotropy and genetic architecture in complex traits

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After a decade of genome-wide association studies (GWASs), fundamental questions in human genetics, such as the extent of pleiotropy across the genome and variation in genetic architecture across traits, are still unanswered. The current availability of hundreds of GWASs provides a unique opportunity to address these questions. We systematically analyzed 4,155 publicly available GWASs. For a subset of well-powered GWASs on 558 traits, we provide an extensive overview of pleiotropy and genetic architecture. We show that trait-associated loci cover more than half of the genome, and 90% of these overlap with loci from multiple traits. We find that potential causal variants are enriched in coding and flanking regions, as well as in regulatory elements, and show variation in polygenicity and discoverability of traits. Our results provide insights into how genetic variation contributes to trait variation. All GWAS results can be queried and visualized at the GWAS ATLAS resource (https://atlas.ctglab.nl).

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Fig. 1: Trait-associated locus, gene and SNP pleiotropy across the genome.
Fig. 2: Within- and between-domain genetic correlations.
Fig. 3: Distribution and characterization of lead SNPs and credible SNPs of 558 traits.
Fig. 4: SNP heritability and polygenicity of 558 traits.

Data availability

All publicly available GWAS summary statistics (original) files curated in this study are accessible from the original links provided at https://atlas.ctglab.nl. GWAS summary statistics for 600 traits from UK Biobank performed in this study are also provided at https://atlas.ctglab.nl and an archived file will be made available upon publication from https://ctg.cncr.nl/software/summary_statistics.


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We thank all consortiums and all other individual laboratories for making GWAS summary statistics publicly available. We also thank P. Visscher and N. Wray for their thoughtful suggestions and discussions. We additionally thank A. Dale for his suggestions. This work was funded by the Netherlands Organization for Scientific Research (grant nos. NWO VICI 453-14-005 and NWO VIDI 452-12-014).

Author information

D.P. designed the study. K.W. curated the database and performed analyses. T.J.C.P. assisted with harmonization of phenotype labels of the database. S.S. performed quality control on the UK Biobank data and wrote the analysis pipeline for UKB analyses. M.U.M. assisted with the fine-mapping analyses. C.d.L. assisted with the discussion of SNP heritability estimates with different models. O.F. and O.A.A. developed software the MiXeR and assisted with the analyses. S.v.d.S. and B.M.N. discussed and provided valuable suggestions for analyses. K.W. and D.P. wrote the paper. All authors critically reviewed the paper.

Correspondence to Danielle Posthuma.

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The authors declare no competing interests.

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Supplementary Information

Supplementary Note and Supplementary Figs. 1–12

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Supplementary Tables 1–26

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