NDLI: Psychiatric manifestations of rare variation in medically actionable genes: a PheWAS approach

Content Provider	Springer Nature : BioMed Central
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.
Abstract	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.
Related Links	https://bmcgenomics.biomedcentral.com/counter/pdf/10.1186/s12864-022-08600-x.pdf
Ending Page	12
Page Count	12
Starting Page	1
File Format	HTM / HTML
ISSN	14712164
DOI	10.1186/s12864-022-08600-x
Journal	BMC Genomics
Issue Number	1
Volume Number	23
Language	English
Publisher	BioMed Central
Publisher Date	2022-05-19
Access Restriction	Open
Subject Keyword	Life Sciences Microarrays Proteomics Animal Genetics and Genomics Microbial Genetics and Genomics Plant Genetics and Genomics Genomic sequencing Incidental findings Rare variation Psychiatric disorders
Content Type	Text
Resource Type	Article
Subject	Biotechnology Genetics
Journal Impact Factor	3.5/2023
5-Year Journal Impact Factor	4.1/2023

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
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