Distinguishing genetic correlation from causation across 52 diseases and complex traits

Nat Genet. 2018 Dec;50(12):1728-1734. doi: 10.1038/s41588-018-0255-0. Epub 2018 Oct 29.

Abstract

Mendelian randomization, a method to infer causal relationships, is confounded by genetic correlations reflecting shared etiology. We developed a model in which a latent causal variable mediates the genetic correlation; trait 1 is partially genetically causal for trait 2 if it is strongly genetically correlated with the latent causal variable, quantified using the genetic causality proportion. We fit this model using mixed fourth moments [Formula: see text] and [Formula: see text] of marginal effect sizes for each trait; if trait 1 is causal for trait 2, then SNPs affecting trait 1 (large [Formula: see text]) will have correlated effects on trait 2 (large α1α2), but not vice versa. In simulations, our method avoided false positives due to genetic correlations, unlike Mendelian randomization. Across 52 traits (average n = 331,000), we identified 30 causal relationships with high genetic causality proportion estimates. Novel findings included a causal effect of low-density lipoprotein on bone mineral density, consistent with clinical trials of statins in osteoporosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autistic Disorder / epidemiology
  • Autistic Disorder / genetics
  • Bone Density / genetics
  • Causality*
  • Computer Simulation
  • Disease / etiology*
  • Disease / genetics
  • Genetic Predisposition to Disease*
  • Genotype
  • Humans
  • Hypothyroidism / epidemiology
  • Hypothyroidism / genetics
  • Linkage Disequilibrium
  • Models, Theoretical
  • Multifactorial Inheritance* / genetics
  • Myocardial Infarction / epidemiology
  • Myocardial Infarction / genetics
  • Osteoporosis / epidemiology
  • Osteoporosis / genetics
  • Phenotype
  • Polymorphism, Single Nucleotide