Identification of Genes Involved in Major Mood Disorders

National Institute Of Mental Health

Investigators

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Abstract

NCT00001174 Starting in 1993, in collaboration with 10 academic centers across the US, we recruited a large sample of over 3,000 individuals with bipolar or other mood disorders. All participants did a diagnostic interview and provided a blood sample for DNA analysis. DNA and clinical data are available through the NIMH Center for Genetics. Genetic linkage studies suggested several chromosomal regions may contain genes that contribute to mood disorders in this sample. To identify individual causal genes, we conducted the first genome-wide association study (GWAS) of bipolar disorder (BD) in 2007. The results implicated several genes, each of small effect, suggesting that BD is a polygenic disease. A second, larger study published in 2010 implicated a cluster of genes on chromosome 3p21 and suggested genetic overlap with major depression. An even larger study published in 2013 that included patients of Asian ancestry supported many of the previous findings and found 3 additional genetic markers of BD. Most of these findings have now been replicated in independent samples. To identify additional risk loci, in 2018 we performed a meta-analysis of >9 million genetic variants in over 40,000 individuals. In the past year, the Psychiatric Genomics Consortium Bipolar Disorder Workgroup, in which we are active collaborators, completed an additional GWAS with over 50,000 cases, the largest to date. The results identified 64 genome-wide significant loci, over half of which are novel. Taken together, the common risk variants account for almost one-third of the inherited risk of bipolar disorder. Implicated genes are enriched for targets of antipsychotics, calcium channel blockers, antiepileptics, and other novel drugs. These large GWAS also provide a valuable set of reference data for calculating polygenic risk scores (PRS) that capture the combined influence of many alleles of small effect. We are exploring ways in which the PRS can be used to better understand individual differences in the onset, course, and presentation of BD. In the past year, we completed a study of PRS to address the high rates of comorbid anxiety in bipolar disorder, a largely unexplained phenomenon. Does this comorbidity reflect shared genetic risk? Results showed that among individuals with BD, genetic risk for anxiety is associated with comorbid anxiety disorders and recurrent suicide attempts in BD. Surprisingly, genetic risk for bipolar disorder itself was not related to any of these variables. In other samples, anxiety showed more genetic overlap with depression and neuroticism than with bipolar disorder itself. These findings suggest that comorbid anxiety in BD reflects partly non-overlapping contributions of bipolar and anxiety-related genes. Treatments that address this dual genetic burden may improve outcomes in people with this common comorbidity. To identify rarer genetic variants that may have a larger impact on risk for major mood disorders, we have undertaken genome sequencing studies in families and special populations. So far, we have collected more than 1000 individuals from Amish and Mennonite communities whose unique genetic history makes them especially good candidates for this kind of study. All blood samples are processed by the Rutgers Cell and DNA Repository which distributes DNA as a resource for the general scientific community. In addition to standard psychiatric diagnostic assessments, participants are asked to complete measures of memory, concentration, and other cognitive domains, along with dimensional measures of mood and anxiety. These data will allow us to better characterize the range of phenotypes present in carriers of risk alleles, many of whom are not expected to have diagnosable mental illness. Through a collaboration with investigators at the Univ Maryland, we will also investigate brain connectivity in selected cases, using multi-modal neuroimaging. Skin biopsies are obtained on sequenced individuals and converted to fibroblasts. Several fibroblast lines have been reprogrammed into induced pluripotent stem cells for functional genomic studies (see ZIA-MH002810). In collaboration with investigators at Regeneron, Inc., we have now performed exome sequencing on over 1000 participants. Preliminary analyses have identified hundreds of otherwise rare genetic variants that occur much more frequently in participants with a history of BD or a related mental illness. With this data set, we are able to look for recurrent rare mutations, as well as mutations that have accumulated within individual genes and gene-sets. The current sample size is well powered to detect variants that confer substantial risk for BD. If such variants are not detected, larger samples will be needed to detect variants that confer more modest risk of illness. The exome data have been submitted to the Bipolar Sequencing Consortium, where they will become part of a large meta-analysis that brings together samples from many groups around the world in order to improve statistical power to detect variants of modest effect. We have also found several large copy number variants (CNVs) that have been previously implicated in psychiatric disorders. Tissue samples from carriers of these CNVs have been reprogrammed into induced pluripotent stem cells for use in ongoing and planned functional genomics studies (see ZIA MH002810). This year, in collaboration with Morgan Similuk and colleagues at the NIAID Genetic Counseling Group, we have reached out to participants diagnosed with a psychiatric illness who carry certain CNVs whose role in psychiatric illness is well established to offer them the opportunity to be informed of our genetic findings and undergo formal genetic counseling. In the course of these interactions we will measure mood, anxiety, perceived stigma, and understanding of the genetic information we present. This will provide valuable data concerning the impact of genetic diagnosis on psychiatric patients who carry pathogenic CNVs. In the past year, we also reached out to recent study participants to investigate the impact of the COVID-19 pandemic on their mental health. Surveys of stress, anxiety, mood, and general well-being were sent to hundreds of past participants. Data from the first wave of respondents is currently being prepared for analysis. In the coming year, we will enroll additional participants, perform additional exome sequencing, expand exome-wide genetic association analyses in larger sets of sequenced samples, provide genetic information and counseling to selected study participants, and complete our study of the mental health impact of the COVID-19 pandemic on study participants.