Pleiotropy in complex traits: challenges and strategies

Abstract

Genome-wide association studies have identified many variants that each affects multiple traits, particularly across autoimmune diseases, cancers and neuropsychiatric disorders, suggesting that pleiotropic effects on human complex traits may be widespread. However, systematic detection of such effects is challenging and requires new methodologies and frameworks for interpreting cross-phenotype results. In this Review, we discuss the evidence for pleiotropy in contemporary genetic mapping studies, new and established analytical approaches to identifying pleiotropic effects, sources of spurious cross-phenotype effects and study design considerations. We also outline the molecular and clinical implications of such findings and discuss future directions of research.

Figure 1. Types of pleiotropy

In each scenario, the observed genetic variant (S) is associated with phenotypes 1 and 2 (P₁ and P₂). We assume that the observed genetic variant is in linkage disequilibrium (LD) with a causal variant (red star) that affects one or more phenotypes. In some cases, the causal variant may be identified directly and the figures can be simplified accordingly. The various figures correspond to the unobserved underlying pleiotropic structure. a | Biological pleiotropy at the allelic level: the causal variant affects both phenotypes. b | Colocalizing association (biological pleiotropy): the observed genetic variant is in strong LD with two causal variants in the same gene that affect different phenotypes. c | Biological pleiotropy at the genic level: two independent causal variants in the same gene affect different phenotypes. d | Mediated pleiotropy: the causal variant affects P₁, which lies on the causal path to P₂, and thus an association occurs between the observed variant and both phenotypes. e | Spurious pleiotropy: the causal variant affects only P₁, but P₂ is enriched for P₁ owing to misclassification or ascertainment bias, and a spurious association occurs between the observed variant and the phenotype 2. f | Spurious pleiotropy: the observed variant is in LD with two causal variants in different genes that affect different phenotypes. GWAS, genome-wide association study.