VA Probes Genes to Improve Care of Veterans With Severe Mental Illness

The heritability of schizophrenia is estimated to be 64% to 81%. At 79% to 91%, the heritability of bipolar disorder is among the highest known, exceeding even BRCA1/2 breast cancer. That’s why genomic research on serious mental illness, is so important. The VA is both significantly affected by the burden of caring for a large number of individuals with SMI and is one of the leading research organizations in the country.

NEW YORK — As the understanding of the genetic underpinnings of an ever-growing number of diseases increases, researchers have developed a similarly expanding panoply of targeted therapies and risk assessment tools. These developments offer hope to families affected by many hereditary conditions and to individuals found to have genes that put them at risk, who can sometimes take actions to prevent manifestation of the disease or minimization of its effects.

Severe mental illness—schizophrenia, bipolar disorder and major depressive disorder—have lagged, complicated by challenges in identifying a large enough cohort for analysis or enrolling a sufficient number of participants in large-scale studies. Yet, the need for new therapies and more effective interventions remains urgent. The cost of care for schizophrenia and bipolar disorder alone exceeded $200 billion in 2015.

Genetic research is crucial to advancing understanding of schizophrenia and bipolar disorder, which have been shown to share some genetic bases. The heritability of schizophrenia is estimated to be 64% to 81%. At 79% to 91%, the heritability of bipolar disorder is among the highest known, exceeding even BRCA1/2 breast cancer.

The VA stands at a unique intersection as a healthcare system significantly impacted by the burden of caring for many individuals with severe mental illness and as one of the leading research organizations in the country.

The VA’s electronic health system and related databases combined with the research power unleashed by the Million Veteran Project put it in a position to uncover new understandings of the genetic basis and implications of diseases from the most common, such as diabetes, to conditions seldom seen by physicians in most healthcare systems, such as rare blood cancers.

Research at the VA extends into severe mental illness, as well. With more than 200,000 veterans in VHA care diagnosed with schizophrenia or bipolar disorder, the VA has a compelling interest in gaining greater understanding of these diseases and facilitating the development of new, more-effective therapies, which are desperately needed. Ultimately, the ability to target the critical biological processes in the progression of these challenging conditions could produce significant improvements in quality of life for many veterans and reduced costs for the healthcare system.

VA researchers across the country, led by Tim Bigdeli, PhD, of the VA New York Harbor Health System, recently undertook one of the largest genome wide association studies (GWAS) of schizophrenia and bipolar disorder to date. They recruited and genotyped 3,690 veterans diagnosed with schizophrenia and 5,095 veterans with bipolar I disorder. As part of the study, recently published in Schizophrenia Bulletin, they also conducted in-person assessments and clinical interviews to determine neurocognitive function and disabilities.

Prior genome wide association studies have produced significant breakthroughs in schizophrenia, identifying more than 176 susceptibility loci through increasingly larger studies.

The large population of African Americans treated by the VA healthcare system and in the Million Veteran Program—from which the 350,000 screened controls were drawn —enabled the VA to conduct the largest study of those illnesses in that cohort. African Americans accounted for 54.3% of the participants with schizophrenia and 24.5% of those with bipolar I, while European Americans accounted for 39.8% of those included with schizophrenia and 70.2% of individuals with bipolar I. The majority of participants with both illnesses were male, 92.7% of those with schizophrenia and 81.4% of participants with bipolar I. As an indication of the personal burden of the conditions, more than half of all participants had attempted suicide or exhibited suicidal behavior.

The research team used a custom array with probes for 723,305 single-nucleotide polymorphisms (SNPs).

New Insights

The genomic analysis offered “new insights into the etiologies of these disorders and [demonstrated] that published findings are largely transferable to this diverse cohort of U.S. veterans.” By combining the results with summaries from other recent GWAS, the team created “the largest and most inclusive GWAS of these disorders to date and explore[d] the biological relevance of 52 newly identified susceptibility loci,” the team wrote.

The schizophrenia analysis found a new association in chromodomain helices DNA-binding protein 7 (CHD7), which plays a role in epigenetic regulation of neuronal differentiation. Disruption of this function appears to be associated with both schizophrenia and autism and CHD7 mutations have been associated with some developmental disorders and a variety of traits.

Variants upstream of CRHR1 also emerged as associated with schizophrenia. They have also recently been found by VA researchers to be associated with post-traumatic stress disorder in a study of participants in the Million Veteran Program.

The team also discovered an association between SORC3, which encodes sortilin-related VPS10 domain-containing receptor 3. SORC3 mediates glutamate homeostasis and is associated with long-term depression of the hippocampal neurons. Variants have been associated with schizophrenia, major depression, anorexia nervosa, attention deficit hyperactivity disorder, Tourette’s syndrome and cognition, the team noted.

Combining the study’s results with those of other published studies, the researchers identified an additional 39 susceptibility loci for schizophrenia and 10 for bipolar I disorder. The combination also permitted fine-mapping of 84 associations and indicated a significant role for glutamatergic dysregulation in schizophrenia and possibly bipolar I.

“Our findings are demonstrative of a shared genetic basis of schizophrenia and bipolar disorder between this highly selected and severely affected veteran cohort and previous case-control studies of both disorders. We expect that the comprehensive assessment and validity of the clinical assessments in [the study] represent a ‘gold standard’ for the curation of serious mental illness phenotypes in the U.S. veteran population,” the researchers concluded.

Future analyses of this study population and the Million Veteran Program “hold considerable promise to advance our understanding of how genetic and environmental/experiential factors influence disease susceptibility, neurocognitive function, treatment response, and patient outcomes,” they added. Future analyses could illuminate the genomic bases of suicidal ideation and behavior, PTSD risk and other symptoms and mental illnesses.

1. Bigdeli TB, Fanous AH, Li Y, Rajeevan N, Sayward F, et. Al. Genome-Wide Association Studies of Schizophrenia and Bipolar Disorder in a Diverse Cohort of US Veterans. Schizophr Bull. 2021 Mar 16;47(2):517-529. doi: 10.1093/schbul/sbaa133. PMID: 33169155; PMCID: PMC7965063.