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Polygenic scores, and the genome-wide association studies they derive from, will have difficulty identifying genes that predispose one to develop a social behavioral trait

Published online by Cambridge University Press:  11 September 2023

Edward Fox*
Affiliation:
Department of Psychological Science, Purdue University, West Lafayette, IN, USA au_gc@psych.purdue.edu https://www.purdue.edu/hhs/psy/directory/faculty/Fox_Edward.html

Abstract

Polygenic scores (PGSs) have several limitations. They are confounded with environmental effects on behavior and cannot be used to study how mutations affect brain function and behavior. For this, mutations with large effects, which often arise in only one geographical population are needed. Genome-wide association studies (GWASs), commonly used for identifying mutations, have difficulty detecting these mutations. A strategy that overcomes this challenge is discussed.

Type
Open Peer Commentary
Copyright
Copyright © The Author(s), 2023. Published by Cambridge University Press

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References

Astle, W. J., Elding, H., Jiang, T., Allen, D., Ruklisa, D., Mann, A. L., … Soranzo, N. (2016). The allelic landscape of human blood cell trait variation and links to common complex disease. Cell, 167(5), 14151429, e1419. doi: 10.1016/j.cell.2016.10.042CrossRefGoogle ScholarPubMed
Bloom, J. S., Boocock, J., Treusch, S., Sadhu, M. J., Day, L., Oates-Barker, H., & Kruglyak, L. (2019). Rare variants contribute disproportionately to quantitative trait variation in yeast. eLife, 8. https://doi.org/10.7554/eLife.49212CrossRefGoogle ScholarPubMed
Bomba, L., Walter, K., & Soranzo, N. (2017). The impact of rare and low-frequency genetic variants in common disease. Genome Biology, 18(1), 77. doi: 10.1186/s13059-017-1212-4CrossRefGoogle ScholarPubMed
Brzustowicz, L. M., Hodgkinson, K. A., Chow, E. W., Honer, W. G., & Bassett, A. S. (2000). Location of a major susceptibility locus for familial schizophrenia on chromosome 1q21–q22. Science (New York, N.Y.), 288(5466), 678682. doi: 10.1126/science.288.5466.678CrossRefGoogle Scholar
Brzustowicz, L. M., Simone, J., Mohseni, P., Hayter, J. E., Hodgkinson, K. A., Chow, E. W., & Bassett, A. S. (2004). Linkage disequilibrium mapping of schizophrenia susceptibility to the CAPON region of chromosome 1q22. American Journal of Human Genetics, 74(5), 10571063. doi: 10.1086/420774CrossRefGoogle Scholar
Carrel, D., Hernandez, K., Kwon, M., Mau, C., Trivedi, M. P., Brzustowicz, L. M., & Firestein, B. L. (2015). Nitric oxide synthase 1 adaptor protein, a protein implicated in schizophrenia, controls radial migration of cortical neurons. Biological Psychiatry, 77(11), 969978. doi: 10.1016/j.biopsych.2014.10.016CrossRefGoogle ScholarPubMed
Chorley, B. N., Wang, X., Campbell, M. R., Pittman, G. S., Noureddine, M. A., & Bell, D. A. (2008). Discovery and verification of functional single nucleotide polymorphisms in regulatory genomic regions: Current and developing technologies. Mutation Research, 659(1–2), 147157. doi: 10.1016/j.mrrev.2008.05.001CrossRefGoogle ScholarPubMed
Colonna, V., Pistis, G., Bomba, L., Mona, S., Matullo, G., Boano, R., … Toniolo, D. (2013). Small effective population size and genetic homogeneity in the Val Borbera isolate. European Journal of Human Genetics, 21(1), 8994. doi: 10.1038/ejhg.2012.113CrossRefGoogle ScholarPubMed
Gibson, G. (2012). Rare and common variants: Twenty arguments. Nature Review Genetics, 13(2), 135145. doi: 10.1038/nrg3118CrossRefGoogle ScholarPubMed
Hernandez, K., Swiatkowski, P., Patel, M. V., Liang, C., Dudzinski, N. R., Brzustowicz, L. M., & Firestein, B. L. (2016). Overexpression of isoforms of nitric oxide synthase 1 adaptor protein, encoded by a risk gene for schizophrenia, alters actin dynamics and synaptic function. Frontiers in Cellular Neuroscience, 10, 6. doi: 10.3389/fncel.2016.00006CrossRefGoogle ScholarPubMed
Lalonde, E., Ha, K. C., Wang, Z., Bemmo, A., Kleinman, C. L., Kwan, T., … Majewski, J. (2011). RNA sequencing reveals the role of splicing polymorphisms in regulating human gene expression. Genome Research, 21(4), 545554. doi: 10.1101/gr.111211.110CrossRefGoogle ScholarPubMed
Laviolette, S. R. (2007). Dopamine modulation of emotional processing in cortical and subcortical neural circuits: Evidence for a final common pathway in schizophrenia? Schizophrenia Bulletin, 33(4), 971981. doi: 10.1093/schbul/sbm048CrossRefGoogle ScholarPubMed
Moltke, I., Grarup, N., Jørgensen, M. E., Bjerregaard, P., Treebak, J. T., Fumagalli, M., … Hansen, T. (2014). A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes. Nature, 512(7513), 190193. doi: 10.1038/nature13425CrossRefGoogle ScholarPubMed
Padilla-Coreano, N., Tye, K. M., & Zelikowsky, M. (2022). Dynamic influences on the neural encoding of social valence. Nature Reviews Neuroscience, 23(9), 535550. doi: 10.1038/s41583-022-00609-1CrossRefGoogle ScholarPubMed
Pain, O., Glanville, K. P., Hagenaars, S. P., Selzam, S., Fürtjes, A. E., Gaspar, H. A., … Lewis, C. M. (2021). Evaluation of polygenic prediction methodology within a reference-standardized framework. PLoS Genetics, 17(5), e1009021. doi: 10.1371/journal.pgen.1009021CrossRefGoogle ScholarPubMed
Zuk, O., Schaffner, S. F., Samocha, K., Do, R., Hechter, E., Kathiresan, S., … Lander, E. S. (2014). Searching for missing heritability: Designing rare variant association studies. Proceedings of the National Academy of Sciences USA, 111(4), E455E464. doi: 10.1073/pnas.1322563111CrossRefGoogle ScholarPubMed