A global overview of pleiotropy and genetic architecture in complex traits

Kyoko Watanabe, Sven Stringer, Oleksandr Frei, Maša Umićević Mirkov, Christiaan de Leeuw, Tinca J. C. Polderman, Sophie van der Sluis, Ole A. Andreassen, Benjamin M. Neale, Danielle Posthuma

Research output: Contribution to journalArticleAcademicpeer-review

514 Citations (Scopus)


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).
Original languageEnglish
Pages (from-to)1339-1348
Number of pages10
JournalNature Genetics
Issue number9
Early online date19 Aug 2019
Publication statusPublished - 1 Sept 2019


  • Genetic Pleiotropy
  • Genetics, Population
  • Genome-Wide Association Study/methods
  • Humans
  • Multifactorial Inheritance/genetics
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci

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