- The American College of Medical Genetics and Genomics (ACMG) maintains a list of genes for which it recommends reporting results that are unrelated to the indication for ordering sequencing but may have implications for patient care
- Using the same approach as in a phenome-wide association study, this study evaluated in 11,181 individuals whether 37 psychiatric disorders were associated with rare variations in 56 genes from the ACMG list and two genes linked to psychiatric traits
- No genes were identified in which rare deleterious variants were enriched in patients with psychiatric disorders
- The return of incidental findings from clinical sequencing is expected to become an increasingly important issue as genomic data generation and technology advance
In clinical exome and genome sequencing, there is potential for detecting incidental findings that are unrelated to the indication for ordering the test but may have implications for genetic counseling and patient care.
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The American College of Medical Genetics and Genomics (ACMG) regularly updates a list of genes for which it recommends reporting these incidental findings—genes in which pathogenic coding variants are highly penetrant and medically actionable. Here these are called "ACMG genes."
The problem is that pleiotropy—in which a variant or gene controls more than one trait—is ubiquitous in the human genome. Extensive pleiotropy of both common and rare gene variants across psychiatric illnesses and other diseases could complicate genetic counseling when incidental findings are returned.
Yen-Chen A. Feng, ScD, a postdoctoral researcher at The Center for Genomic Medicine at Massachusetts General Hospital, Jordan W. Smoller, MD, ScD, director of the Psychiatric and Neurodevelopmental Genetics Unit in the Department of Psychiatry, and colleagues recently conducted the first systematic evaluation of psychiatric manifestations associated with rare variation in ACMG genes. In BMC Genomics, they report no association between psychiatric disorders and incidental findings in medically actionable genes.
The researchers used data from the Electronic Medical Records and Genomics consortium, a national network that links electronic health records and DNA sequence data at 11 healthcare systems.
This analysis included 15,181 individuals of European descent with complete phenotypic information. The researchers looked for relationships between 37 common psychiatric disorders and rare coding variations in 58 genes: 56 ACMG genes, listed in Genetics in Medicine in 2013, plus two genes previously implicated in major psychiatric traits, CACNA1C and TCF4.
No Associations With Psychiatric Disease
As a positive control, the team replicated the known association between rare mutations in LDLR and hypercholesterolemia. However, no genes were identified that were significantly enriched with rare variants conferring risk for psychiatric disorders.
This might be attributable to limited power, as some of the psychiatric disorders were present in very small numbers of people.
The team did find that some of the ACMG genes harbored a nominal excess of rare deleterious coding variants in people with psychiatric conditions compared with controls:
- Depression was linked to rare variants in PTEN, LDLR, and CACNA1S
- Substance use disorders (collectively) were linked to rare variants in KCNQ1
- Tobacco use disorder was linked to rare variants in APOB
These associations should be interpreted with caution, but it's worth noting that KCNQ1 and CACNA1S are involved in the formation and function of potassium and calcium channels broadly implicated in brain-related disorders.
Studies of much larger sequencing datasets are warranted because the return of incidental findings is expected to become an increasingly important issue as genomic data generation and technology advance.
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