Identification of Genes Involved in Major Mood Disorders

National Institute Of Mental Health

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Abstract

NCT00001174 In collaboration with 10 academic centers across the US, we recruited 3,000 individuals with bipolar (BD) or other mood disorders. All participants did a diagnostic interview and a blood sample for DNA analysis. DNA and clinical data are available through the NIMH Center for Genetics. Genetic linkage studies of these data suggested several chromosomal regions containing genes that contribute to mood disorders. To identify individual causal genes, we conducted the first genome-wide association study (GWAS) of BD in 2007. The results implicated several genes 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 in over 40,000 individuals. Last year, the Psychiatric Genomics Consortium (PGC) 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. An additional collaborative study published in the last year showed that suicide attempts which commonly occur in people living with BD are associated with additional genetic risk factors shared by people with depression, smoking, risk-taking, and insomnia. The results suggest a shared underlying biology between suicide attempts, known suicide risk factors, and psychiatric disorders. Additional PGC collaborative studies were published this year. The results show that response to lithium therapy in BD is significantly associated with genetic variation in immune-modulating genes, genes previously associated with risk for schizophrenia, depression, or ADHD, as well as key clinical variables. This body of work aims to develop genetic tests that might identify patients most likely to benefit from lithium therapy. These large GWAS also provide a valuable set of reference data for calculating polygenic risk scores (PRS) that capture the combined influence of many genes 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 BD, a largely unexplained phenomenon. Results showed that among individuals with BD, genetic risk for anxiety is associated with comorbid anxiety disorders and recurrent suicide attempts in BD. In other samples, anxiety showed more genetic overlap with depression and neuroticism than with BD 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 BD with comorbid anxiety. 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 psychiatric diagnostic assessments, participants are asked to complete tests of cognition and dimensional measures of mood and anxiety. These data will allow us to better characterize the range of phenotypes present in carriers of risk genes, many of whom are not expected to have diagnosable mental illness. Skin or blood cells donated by selected participants are 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 many genetic variants that occur much more frequently in participants with a history of BD or a related illness. With this data set, we can look for recurrent rare mutations, as well as those 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. We have also found several large copy number variants (CNVs) that have been previously implicated in psychiatric disorders. In collaboration with Morgan Similuk and colleagues at NIAID, we are reaching out to participants diagnosed with a psychiatric illness who carry CNVs with a well-established role in psychiatric illness and offer these participants the opportunity to hear about their genetic findings and undergo formal genetic counseling. 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 high-risk genes. In the past year, we 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, and a modified version of the CoRonavIruS Health Impact Survey (CRISIS) were sent to hundreds of past participants at approximately 6-month intervals. Data from the first set of respondents has now been analyzed. The CRISIS survey was coded into dimensions measuring level of exposure to COVID-19, behavioral changes, and psychological distress. Results demonstrated that individuals with high levels of anxiety and psychological distress before the pandemic were significantly more likely to report increased depressive symptoms during the pandemic. This was especially true for those who reported more COVID-19 exposure and psychological distress during the pandemic. These preliminary results suggest that baseline mental health predicts depressive symptoms during the pandemic, esp. among those with more exposure and distress. Such individuals may benefit from targeted support and services. In the coming year, we will enroll additional participants, perform additional exome sequencing, expand exome-wide genetic association analyses in larger sets of samples, provide genetic information and counseling to additional study participants, and complete analyses of the second and third waves of the COVID-19 survey.