In 2018, the NIMH convened the National Advisory Mental Health Council (NAMHC) Workgroup on Genomics. The report emphasizes that NIMH should support research into genes that have appropriate, genome-wide evidence for association with a trait, whether the variation is rare or common. The report and a summary of recommendations are available at the NIMH website.
The purpose of this Notice is to promote awareness of an NIMH curated list of human genes that include statistically significant variants associated with mental health traits or risk for psychiatric illnesses based on published studies. This list is intended to aid basic, translational, or clinical investigators who are interested in applying to NIMH for research studies involving particular genes based on their disease association.
Key points about the gene list include:
- The list includes examples of genes that have strong statistical support for association with mental illness, as well as documentation of the methods used to compile the list and further guidance regarding the use of the list.
- The list may be used as an aid to determine if particular genes have appropriate statistical support and align with NIMH priorities for genomics research.
- The emphasis of the list is on rare variation rather than common variation, as described below. NIMH continues to support studies of the biological consequences of common variation relevant to mental illness; however, comprehensive gene lists are not yet available for common variation, as noted below.
- Genes on this list are of interest to NIMH, and applications proposing to study the biological pathways downstream of these genes and/or their mechanistic relationship to mental illness may be prioritized for funding.
- The list is not meant to be restrictive. NIMH applicants are NOT restricted to studying only genes on this list to be considered for funding. NIMH will continue to support applications proposing to study genes that are not on this list, either because of basic science interest or with the inclusion of appropriate genome-wide evidence cited in the application.
- The list will be updated regularly based on the addition of published findings.
- NIMH encourages dialogue with the community about genes that investigators propose to study.
Rare and common variation
Genetic variants may be classified as common or rare based on their frequency in a population. Two broad classes of genetic variants are those defined as rare (e.g., having a minor allele frequency [MAF] <1%) and common (MAF >1%).
The NIMH gene list does not include genes implicated from studies of common variation, as there is not yet consensus in the field as to which specific genes from GWAS are relevant to disease. However, researchers may still choose to study genes implicated by GWAS. We encourage investigators to discuss with NIMH program staff the study of genes implicated by common variants linked to mental health traits or psychiatric illness. As with rare variants, common variants of basic science interest relevant to NIMH may also be supported with sufficient justification.
NIMH Program guidance for investigators
Documentation that accompanies the gene list provides further detailed guidance for investigators. Briefly:
- Genes on the list: NIMH encourages the study of genes that are present on this list (noting the caveats that the list is not comprehensive, and that it may contain false positive findings).
- Bonferroni versus 5% false discovery rate (FDR): All of the genes on the list are significant at the relatively lenient threshold of passing a 5% false discovery rate (FDR, with values obtained from publications). Some of the genes are also significant at the more stringent threshold of passing a Bonferroni correction.
- Genes not on the list: Many candidate genes that are not on the list lack appropriate genome-wide statistical support for association with mental illness.
- Genes not on the list that should be added: Investigators can nominate additional genes for inclusion on the list by emailing NIMHgenes@nih.gov. Please include appropriate documentation, including references.
- Genes identified by techniques other than RVAS: Many techniques other than GWAS and RVAS have been developed to identify genes that have a significant association with mental health illnesses and traits. Examples include transcriptome-wide association studies, epigenome-wide association studies, and methods for analyzing GWAS summary statistics. NIMH Program staff will evaluate arguments for inclusion on the list based on statistical significance on a case-by-case basis.
- Genes of medical relevance that lack genome-wide support: The medical genetics (or clinical genetics) field has convincingly implicated single genes in many diseases for which genome-wide significance has not necessarily been established. Contact NIMH Program staff to discuss studies involving such genes.
- Genes in copy number variant (CNV) or structural variation (SV) regions: Lists of CNVs and SVs are not currently included in the gene list but may be added in the future.
- Paralogs: For paralogs, each gene that is proposed to be studied should have genome-wide statistical evidence.
- Orthologs: For orthologs, please refer to the Notice of NIMHs Considerations Regarding the Use of Animal Neurobehavioral Approaches in Basic and Pre-clinical Studies on the use of animal models. This Notice discusses the study of human risk genes in animal models.
The gene list is publicly available on an NIMH website as a downloadable spreadsheet with accompanying explanatory documentation.
We anticipate updates to the list as new studies are published and as additional data sources are identified. Each gene list is assigned a version and date.