Polygene Risk Scores

A Philosophical Exploration

Authors

  • James Woodward Emeritus, Department of History and Philosophy of Science, University of Pittsburgh, Pittsburgh, PA https://orcid.org/0000-0003-1826-0735
  • Kenneth Kendler Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA https://orcid.org/0000-0001-8689-6570

DOI:

https://doi.org/10.5195/pom.2023.156

Keywords:

Polygene risk scores, genetic causation

Abstract

This paper explores the interpretation and use of polygenic risk scores (PRSs). We argue that PRSs generally do not directly embody causal information. Nonetheless, they can assist us in tracking other causal relationships concerning genetic effects. Although their purely  predictive/correlational use is important, it is this tracking feature that contributes to their potential usefulness in other applications, such as genetic dissection, and their use as controls, which allow us, indirectly, to "see" more clearly the role of environmental variables.

References

Belsky, Daniel W., Benjamin W. Domingue, Robbee Wedow, Louise Arseneault, Jason D. Boardman, Avshalom Caspi, Dalton Conley, et al. 2018. “Genetic Analysis of Social–Class Mobility in Five Longitudinal Studies.” Proceedings of the National Academy of Sciences 115, no. 31: e7275–7284. https://doi.org/10.1073/pnas.1801238115.

Bipolar Disorder and Schizophrenia Working Group of the Psychiatric Genomics Consortium. 2018. “Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes.” Cell 173, no. 7: 1705–1715. https://doi.org/10.1016/j.cell.2018.05.046.

Block, Ned and Gerald Dworkin. 1976. “IQ, Heritability and Inequality.” In The IQ Controversy, edited by Ned Block and Gerald Dworkin, 410–540. New York: Random House.

Bourrat, Pierrick. 2020. “Causation and Single Nucleotide Polymorphism Heritability.” Philosophy of Science 87, no. 5: 1073–1083. https://doi.org/10.1086/710517.

———. 2021. “Heritability, Causal Influence and Locality.” Synthese 198: 6689–6715. https://doi.org/10.1007/s11229-019-02484-3.

Burt, Callie H. 2022. “Challenging the Utility of Polygenic Scores for Social Science: Environmental Confounding, Downward Causation, and Unknown Biology,” Behavioral and Brain Sciences: 1–36. https://doi.org/10.1017/s0140525x22001145.

Cartwright, Nancy. 1979. “Causal Laws and Effective Strategies.” Noûs 13, no. 4: 419–437. https://doi.org/10.2307/2215337.

Coop, Graham and Molly Przeworski. 2022. “Lottery, Luck, or Legacy: A Review of The Genetic Lottery: Why DNA Matters for Social Equality.” Evolution 76, no. 4: 846–853. https://doi.org/10.1111/evo.14449.

Cross-Disorder Group of the Psychiatric Genomics Consortium. 2019. “Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders.” Cell 179, no. 7: 1469–1482. https://doi.org/10.1016/j.cell.2019.11.020.

Downes, Stephen M. and Lucas Matthews. 2019. “Heritability.” In Stanford Encyclopedia of Philosophy, edited by Edward N. Zalta. https://plato.stanford.edu/entries/heredity/.

Fisher, R.A. 1919. “The Correlation between Relatives on the Supposition of Mendelian Inheritance.” Earth and Environmental Science, Transactions of the Royal Society of Edinburgh 52, no. 2: 399–433. https://doi.org/10.1017/S0080456800012163.

———. 1930. The Genetical Theory of Natural Selection. Oxford: Oxford University Press.

Furukawa, T. and T. Shibayama. 1997. “Intra-individual versus Extra-individual Components of Social Support.” Psychological Medicine 27, no. 5: 1183–1191. https://doi.org/10.1017/S0033291797005424.

Grinfeld, Guy, David Lagnado, Tobias Gerstenberg, James F. Woodward, and Marius Usher. 2020. “Causal Responsibility and Robust Causation.” Frontiers in Psychology 11: 1–19. https://doi.org/10.3389/fpsyg.2020.01069.

Harden, Kathryn Paige. 2021. The Genetic Lottery: Why DNA Matters for Social Equality. Princeton: Princeton University Press.

Hill, William G., Michael E .Goddard, and Peter M. Visscher. 2008. “Data and Theory Point to Mainly Additive Genetic Variance for Complex Traits.” PLoS Genetics 4, no. 2: e1000008. https://doi.org/10.1371/journal.pgen.1000008.

Howe, Laurence J., Michel G. Nivard, Tim T. Morris, Ailin F. Hansen, Humaira Rasheed, Yoonsu Cho, Geetha Chittoor, et al. 2022. “Within-Sibship Genome-Wide Association Analyses Decrease Bias in Estimates of Direct Genetic Effects.” Nature Genetics 54, no. 5: 581–592. https://doi.org/10.1038/s41588-022-01062-7.

Jencks, Christopher, Marshall Smith, Henry Acland, Mary Jo Bane, David Cohen, Herbert Gintis, Barbara Heyns, and Stephanie Michelson. 1972. Inequality: A Reassessment of the Effect of Family and Schooling in America. New York: Basic Books.

Kendler, Kenneth S. 1997. “Social Support: A Genetic-Epidemiologic Analysis.” American Journal of Psychiatry 154: 1398–1404.

Koellinger, Philipp D. and K. Paige Harden. 2018. “Using Nature to Understand Nurture.” Science 359, no. 6374: 386–387. http://dx.doi.org/10.1126/science.aar6429.

Kong, Augustine, Gudmar Thorleifsson, Michael L. Frigge, Bjarni J. Vilhjalmsson, Alexander I. Young, Thorgeir E. Thorgeirsson, Stefania Benonisdottir, et al. 2018. “The Nature of Nurture: Effects of Parental Genotypes.” Science 359, no. 6374: 424–428. https://doi.org/10.1126/science.aan6877.

Lam, Max, Chia-Yen Chen, Zhiqiang Li, Alicia R. Martin, Julien Bryois, Xixian Ma, Helena Gasparet, et al. 2019. “Comparative Genetic Architectures of Schizophrenia in East Asian and European Populations.” Nature Genetics 51, no. 12: 1670–1678. https://doi.org/10.1038/s41588-019-0512-x.

Lee, James J. and Carson C. Chow. 2013. “The Causal Meaning of Fisher’s Average Effect.” Genetics Research 95: 89–109. https://doi.org/10.1017%2FS0016672313000074.

Lee, James J., Robbee Wedow, Aysu Okbay, Edward Kong, Omeed Maghzian, Meghan Zacher, Tuan Anh Nguyen-Viet, et al. 2018. “Gene Discovery and Polygenic Prediction from a Genome-Wide Association Study of Educational Attainment in 1.1 million Individuals.” Nature Genetics 50, no. 8: 1112–1121. https://doi.org/10.1038/s41588-018-0147-3.

Levey, Daniel F., Murray B. Stein, Frank R. Wendt, Gita A. Pathak, Hang Zhou, Mihaela Aslan, Rachel Quaden, et al. 2020. “GWAS of Depression Phenotypes in the Million Veteran Program and Meta-analysis in more than 1.2 Million Participants Yields 178 Independent Risk Loci.” MedRxiv. https://doi.org/10.1101/2020.05.18.20100685.

Lynch, Kate E. and Pierrick Bourrat. 2017. “Interpreting Heritability Causally.” Philosophy of Science 84, no. 1: 14–34. http://dx.doi.org/10.1086/688933.

Madole, James W. and K. Paige Harden. 2022. “Building Causal Knowledge in Behavior Genetics.” Behavioral and Brain Sciences: 1–76. https://doi.org/10.1017/S0140525X22000681.

Okbay, Aysu, Yeda Wu, Nancy Wang, Hariharan Jayashankar, Michael Bennett, Seyed Moeen Nehzati, Julia Sidorenko, et al. 2022. “Polygenic Prediction of Educational Attainment within and between Families from Genome-Wide Association Analyses in 3 Million Individuals.” Nature Genetics 54, no. 4: 437–449. https://doi.org/10.1038/s41588-022-01016-z.

Plomin, Robert and Sophie von Stumm. 2022. “Polygenic Scores: Prediction versus Explanation.” Molecular Psychiatry 27, no. 1: 1–4. http://dx.doi.org/10.1038/s41380-021-01348-y.

Purcell, Shaun M., Naomi R. Wray, Jennifer L. Stone, Peter M. Visscher, Michael C. O’Donovan, Patrick F. Sullivan, and Pamela Sklar. 2009. “Common Polygenic Variation Contributes to Risk of Schizophrenia and Bipolar Disorder.” Nature 460, no. 7256: 748–752. https://doi.org/10.1038/nature08185.

Raffington, Laurel, Travis Mallard, and K. Paige Harden. 2020. “Polygenic Scores in Developmental Psychology: Invite Genetics in, Leave Biodeterminism behind.” Annual Review of Developmental Psychology 2: 389–411. https://dx.doi.org/10.1146/annurev-devpsych-051820-123945.

Ripke, Stephan, James T.R. Walters, and Michael C. O’Donovan. 2020. “Mapping Genomic Loci Prioritises Genes and Implicates Synaptic Biology in Schizophrenia.” MedRxiv. https://doi.org/10.1101/2020.09.12.20192922.

Ruderfer, Douglas M., Ayman H. Fanous, Stephan Ripke, Andrew McQuillin, Richard L. Amdur, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, et al. 2014. “Polygenic Dissection of Diagnosis and Clinical Dimensions of Bipolar Disorder and Schizophrenia.” Molecular Psychiatry 19, no. 9: 1017–1024. https://doi.org/10.1038/mp.2013.138.

Schaid, Daniel J., Wenan Chen, and Nicholas B. Larson. 2018. “From Genome-wide Associations to Candidate Causal Variants by Statistical Fine-mapping.” Nature Reviews Genetics 19: 491–504. https://doi.org/10.1038/s41576-018-0016-z.

Spirtes, Peter, Clark Glymour, and Richard Scheines. 2001. Causation, Prediction and Search. Cambridge, MA: MIT Press.

Woodward, James. 2003. Making Things Happen: A Theory of Causal Explanation. New York: Oxford University Press.

———. 2006. “Sensitive and Insensitive Causation.” Philosophical Review 115, no. 1: 1–50. http://dx.doi.org/10.1215/00318108-2005-001.

———. 2010. “Causation in Biology.” Biology and Philosophy 25, no. 3: 287–318. http://dx.doi.org/10.1007/s10539-010-9200-z.

Young, Alexander I., Stefania Benonisdottir, Molly Przeworski, and Augustine Kong. 2019. “Deconstructing the Sources of Genotype-Phenotype Associations in Humans.” Science 365, no. 6460: 1396–1400. https://doi.org/10.1126/science.aax3710.

Downloads

Published

2023-07-05

How to Cite

Woodward, J., & Kendler, K. (2023). Polygene Risk Scores: A Philosophical Exploration. Philosophy of Medicine, 4(1). https://doi.org/10.5195/pom.2023.156

Issue

Vol. 4 No. 1 (2023)

Section

Original Research Articles (biomedical science)

License

Copyright (c) 2023 James Woodward, Kenneth Kendler

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Authors who publish with this journal agree to the following terms:

  1. The Author retains copyright in the Work, where the term “Work” shall include all digital objects that may result in subsequent electronic publication or distribution.
  2. Upon acceptance of the Work, the author shall grant to the Publisher the right of first publication of the Work.
  3. The Author shall grant to the Publisher and its agents the nonexclusive perpetual right and license to publish, archive, and make accessible the Work in whole or in part in all forms of media now or hereafter known under a Creative Commons Attribution 4.0 International License or its equivalent, which, for the avoidance of doubt, allows others to copy, distribute, and transmit the Work under the following conditions:
    1. Attribution—other users must attribute the Work in the manner specified by the author as indicated on the journal Web site;
    with the understanding that the above condition can be waived with permission from the Author and that where the Work or any of its elements is in the public domain under applicable law, that status is in no way affected by the license.
  4. The Author is able to enter into separate, additional contractual arrangements for the nonexclusive distribution of the journal's published version of the Work (e.g., post it to an institutional repository or publish it in a book), as long as there is provided in the document an acknowledgement of its initial publication in this journal.
  5. Authors are permitted and encouraged to post online a prepublication manuscript (but not the Publisher’s final formatted PDF version of the Work) in institutional repositories or on their Websites prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work. Any such posting made before acceptance and publication of the Work shall be updated upon publication to include a reference to the Publisher-assigned DOI (Digital Object Identifier) and a link to the online abstract for the final published Work in the Journal.
  6. Upon Publisher’s request, the Author agrees to furnish promptly to Publisher, at the Author’s own expense, written evidence of the permissions, licenses, and consents for use of third-party material included within the Work, except as determined by Publisher to be covered by the principles of Fair Use.
  7. The Author represents and warrants that:
    1. the Work is the Author’s original work;
    2. the Author has not transferred, and will not transfer, exclusive rights in the Work to any third party;
    3. the Work is not pending review or under consideration by another publisher;
    4. the Work has not previously been published;
    5. the Work contains no misrepresentation or infringement of the Work or property of other authors or third parties; and
    6. the Work contains no libel, invasion of privacy, or other unlawful matter.
  8. The Author agrees to indemnify and hold Publisher harmless from Author’s breach of the representations and warranties contained in Paragraph 6 above, as well as any claim or proceeding relating to Publisher’s use and publication of any content contained in the Work, including third-party content.
  9. The Author agrees to digitally sign the Publisher’s final formatted PDF version of the Work.