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Psychiatric manifestations of rare variation in medically actionable genes: a PheWAS approach
BACKGROUND: As genomic sequencing moves closer to clinical implementation, there has been an increasing acceptance of returning incidental findings to research participants and patients for mutations in highly penetrant, medically actionable genes. A curated list of genes has been recommended by the...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9121574/ https://www.ncbi.nlm.nih.gov/pubmed/35590255 http://dx.doi.org/10.1186/s12864-022-08600-x |
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author | Feng, Yen-Chen A. Stanaway, Ian B. Connolly, John J. Denny, Joshua C. Luo, Yuan Weng, Chunhua Wei, Wei-Qi Weiss, Scott T. Karlson, Elizabeth W. Smoller, Jordan W. |
author_facet | Feng, Yen-Chen A. Stanaway, Ian B. Connolly, John J. Denny, Joshua C. Luo, Yuan Weng, Chunhua Wei, Wei-Qi Weiss, Scott T. Karlson, Elizabeth W. Smoller, Jordan W. |
author_sort | Feng, Yen-Chen A. |
collection | PubMed |
description | BACKGROUND: As genomic sequencing moves closer to clinical implementation, there has been an increasing acceptance of returning incidental findings to research participants and patients for mutations in highly penetrant, medically actionable genes. A curated list of genes has been recommended by the American College of Medical Genetics and Genomics (ACMG) for return of incidental findings. However, the pleiotropic effects of these genes are not fully known. Such effects could complicate genetic counseling when returning incidental findings. In particular, there has been no systematic evaluation of psychiatric manifestations associated with rare variation in these genes. RESULTS: Here, we leveraged a targeted sequence panel and real-world electronic health records from the eMERGE network to assess the burden of rare variation in the ACMG-56 genes and two psychiatric-associated genes (CACNA1C and TCF4) across common mental health conditions in 15,181 individuals of European descent. As a positive control, we showed that this approach replicated the established association between rare mutations in LDLR and hypercholesterolemia with no visible inflation from population stratification. However, we did not identify any genes significantly enriched with rare deleterious variants that confer risk for common psychiatric disorders after correction for multiple testing. Suggestive associations were observed between depression and rare coding variation in PTEN (P = 1.5 × 10(–4)), LDLR (P = 3.6 × 10(–4)), and CACNA1S (P = 5.8 × 10(–4)). We also observed nominal associations between rare variants in KCNQ1 and substance use disorders (P = 2.4 × 10(–4)), and APOB and tobacco use disorder (P = 1.1 × 10(–3)). CONCLUSIONS: Our results do not support an association between psychiatric disorders and incidental findings in medically actionable gene mutations, but power was limited with the available sample sizes. Given the phenotypic and genetic complexity of psychiatric phenotypes, future work will require a much larger sequencing dataset to determine whether incidental findings in these genes have implications for risk of psychopathology. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12864-022-08600-x. |
format | Online Article Text |
id | pubmed-9121574 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-91215742022-05-21 Psychiatric manifestations of rare variation in medically actionable genes: a PheWAS approach Feng, Yen-Chen A. Stanaway, Ian B. Connolly, John J. Denny, Joshua C. Luo, Yuan Weng, Chunhua Wei, Wei-Qi Weiss, Scott T. Karlson, Elizabeth W. Smoller, Jordan W. BMC Genomics Research BACKGROUND: As genomic sequencing moves closer to clinical implementation, there has been an increasing acceptance of returning incidental findings to research participants and patients for mutations in highly penetrant, medically actionable genes. A curated list of genes has been recommended by the American College of Medical Genetics and Genomics (ACMG) for return of incidental findings. However, the pleiotropic effects of these genes are not fully known. Such effects could complicate genetic counseling when returning incidental findings. In particular, there has been no systematic evaluation of psychiatric manifestations associated with rare variation in these genes. RESULTS: Here, we leveraged a targeted sequence panel and real-world electronic health records from the eMERGE network to assess the burden of rare variation in the ACMG-56 genes and two psychiatric-associated genes (CACNA1C and TCF4) across common mental health conditions in 15,181 individuals of European descent. As a positive control, we showed that this approach replicated the established association between rare mutations in LDLR and hypercholesterolemia with no visible inflation from population stratification. However, we did not identify any genes significantly enriched with rare deleterious variants that confer risk for common psychiatric disorders after correction for multiple testing. Suggestive associations were observed between depression and rare coding variation in PTEN (P = 1.5 × 10(–4)), LDLR (P = 3.6 × 10(–4)), and CACNA1S (P = 5.8 × 10(–4)). We also observed nominal associations between rare variants in KCNQ1 and substance use disorders (P = 2.4 × 10(–4)), and APOB and tobacco use disorder (P = 1.1 × 10(–3)). CONCLUSIONS: Our results do not support an association between psychiatric disorders and incidental findings in medically actionable gene mutations, but power was limited with the available sample sizes. Given the phenotypic and genetic complexity of psychiatric phenotypes, future work will require a much larger sequencing dataset to determine whether incidental findings in these genes have implications for risk of psychopathology. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12864-022-08600-x. BioMed Central 2022-05-19 /pmc/articles/PMC9121574/ /pubmed/35590255 http://dx.doi.org/10.1186/s12864-022-08600-x Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Feng, Yen-Chen A. Stanaway, Ian B. Connolly, John J. Denny, Joshua C. Luo, Yuan Weng, Chunhua Wei, Wei-Qi Weiss, Scott T. Karlson, Elizabeth W. Smoller, Jordan W. Psychiatric manifestations of rare variation in medically actionable genes: a PheWAS approach |
title | Psychiatric manifestations of rare variation in medically actionable genes: a PheWAS approach |
title_full | Psychiatric manifestations of rare variation in medically actionable genes: a PheWAS approach |
title_fullStr | Psychiatric manifestations of rare variation in medically actionable genes: a PheWAS approach |
title_full_unstemmed | Psychiatric manifestations of rare variation in medically actionable genes: a PheWAS approach |
title_short | Psychiatric manifestations of rare variation in medically actionable genes: a PheWAS approach |
title_sort | psychiatric manifestations of rare variation in medically actionable genes: a phewas approach |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9121574/ https://www.ncbi.nlm.nih.gov/pubmed/35590255 http://dx.doi.org/10.1186/s12864-022-08600-x |
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