Sharing of Genes and Pathways Across Complex Phenotypes: A Multilevel Genome-Wide Analysis

Genetics. 2017 Jul;206(3):1601-1609. doi: 10.1534/genetics.116.198150. Epub 2017 May 11.


Evidence from genome-wide association studies (GWAS) suggest that pleiotropic effects on human complex phenotypes are very common. Recently, an atlas of genetic correlations among complex phenotypes has broadened our understanding of human diseases and traits. Here, we examine genetic overlap, from a gene-centric perspective, among the same 24 phenotypes previously investigated for genetic correlations. After adopting the multilevel pipeline (freely available at, which includes intragenic single nucleotide polymorphisms (SNPs), genes, and gene-sets, to estimate genetic similarities across phenotypes, a large amount of sharing of several biologically related phenotypes was confirmed. In addition, significant genetic overlaps were also found among phenotype pairs that were previously unidentified by SNP-level approaches. All these pairs with new genetic links are supported by earlier epidemiological evidence, although only a few of them have pleiotropic genes in the GWAS Catalog. Hence, our gene and gene-set analyses are able to provide new insights into cross-phenotype connections. The investigation on genetic sharing at three different levels presents a complementary picture of how common DNA sequence variations contribute to disease comorbidities and trait manifestations.

Keywords: GWAS; complex diseases; gene-based; genetic sharing; pleiotropy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Datasets as Topic
  • Genetic Linkage
  • Genetic Pleiotropy*
  • Genetic Predisposition to Disease
  • Genome, Human*
  • Genome-Wide Association Study / methods
  • Genome-Wide Association Study / standards*
  • Humans
  • Polymorphism, Single Nucleotide