The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease

Cell. 2016 Nov 17;167(5):1415-1429.e19. doi: 10.1016/j.cell.2016.10.042.

Abstract

Many common variants have been associated with hematological traits, but identification of causal genes and pathways has proven challenging. We performed a genome-wide association analysis in the UK Biobank and INTERVAL studies, testing 29.5 million genetic variants for association with 36 red cell, white cell, and platelet properties in 173,480 European-ancestry participants. This effort yielded hundreds of low frequency (<5%) and rare (<1%) variants with a strong impact on blood cell phenotypes. Our data highlight general properties of the allelic architecture of complex traits, including the proportion of the heritable component of each blood trait explained by the polygenic signal across different genome regulatory domains. Finally, through Mendelian randomization, we provide evidence of shared genetic pathways linking blood cell indices with complex pathologies, including autoimmune diseases, schizophrenia, and coronary heart disease and evidence suggesting previously reported population associations between blood cell indices and cardiovascular disease may be non-causal.

Keywords: Mendelian randomization; autoimmune diseases; blood; cardiovascular diseases; complex disease; epigenetics; genetics; hematology; hematopoiesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Cell Differentiation
  • European Continental Ancestry Group / genetics
  • Genetic Predisposition to Disease
  • Genetic Variation*
  • Genome-Wide Association Study*
  • Hematopoietic Stem Cells / metabolism*
  • Hematopoietic Stem Cells / pathology
  • Humans
  • Immune System Diseases / genetics*
  • Immune System Diseases / pathology
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci