Article series: Genome-wide association studies

Pleiotropy in complex traits: challenges and strategies

Journal name:
Nature Reviews Genetics
Year published:
Published online


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.


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Author information


  1. Center for Human Genetics Research, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA.

    • Nadia Solovieff,
    • Phil H. Lee,
    • Shaun M. Purcell &
    • Jordan W. Smoller
  2. Department of Psychiatry, Harvard Medical School, 2 West, Room 305, 401 Park Drive, Boston, Massachusetts 02215, USA.

    • Nadia Solovieff,
    • Phil H. Lee,
    • Shaun M. Purcell &
    • Jordan W. Smoller
  3. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.

    • Nadia Solovieff,
    • Phil H. Lee,
    • Shaun M. Purcell &
    • Jordan W. Smoller
  4. Departments of Neurology and Genetics, Yale University School of Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA.

    • Chris Cotsapas
  5. Medical and Population Genetics, Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.

    • Chris Cotsapas
  6. Division of Psychiatric Genomics, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, New York, New York 10029–6574, USA.

    • Shaun M. Purcell

Competing interests statement

The authors declare no competing interests.

Corresponding author

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Author details

  • Nadia Solovieff

    Nadia Solovieff is a postdoctoral fellow in the Psychiatric and Neurodevelopmental Genetics Unit at Massachusetts General Hospital, Boston, Massachusetts, USA. Her research focuses on developing statistical approaches for the analysis of genome-wide association studies and next-generation sequencing and applying these approaches to studies of psychiatric disorders.

  • Chris Cotsapas

    Chris Cotsapas is an assistant professor of neurology and of genetics at Yale School of Medicine, New Haven, Connecticut, USA. His group focuses on cross-trait analyses of immune-mediated diseases, detecting pathways that are perturbed by genetic risk variants and developing new experimental paradigms to test common variant effects on immune function.

  • Phil H. Lee

    Phil H. Lee is an instructor at the Center for Human Genetics Research, Massachusetts General Hospital (MGH), Boston, Massachusetts, USA. As a computational geneticist, her research focuses on the analysis of high-throughput genomics and transcriptomics data and on the development of advanced analytical methods.

  • Shaun M. Purcell

    Shaun M. Purcell is an associate professor at Mount Sinai School of Medicine, New York, USA, and a faculty member at Massachusetts General Hospital and the Broad Institute of MIT and Harvard, both in Boston, Massachusetts, USA. His work focuses on developing computational and statistical tools for complex trait genetic studies with application to neuropsychiatric disease.

  • Jordan W. Smoller

    Jordan W. Smoller is the Director of the Psychiatric and Neurodevelopmental Genetics Unit at Massachusetts General Hospital, Professor of Psychiatry at Harvard Medical School and an associate member of the Broad Institute of MIT and Harvard, all in Boston, Massachusetts, USA. His research is focused on identifying and characterizing the genetic basis of neuropsychiatric disorders and related neuroimaging and neurophysiologic traits. Smoller is co-chair of the cross-disorder workgroup of the international Psychiatric Genomics Consortium.

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