An international collaboration will receive $12 million over four years from The National Institute of Mental Health of the National Institutes of Health to study the genetics of schizophrenia and other psychiatric disorders in chromosome 22q11.2 deletion syndrome. The multisystem disorder includes birth defects and developmental and behavioral differences across the life span.
More than half of the $12 million is awarded to Emory University, which will lead the genomics portion of the consortium.
The International Consortium on Brain and Behavior in 22q11.2 Deletion Syndrome is a large-scale effort among 22 institutions across North America, including Emory University School of Medicine, as well as institutions across Europe, Australia and South America.
Researchers will investigate the genetic causes for the high rates of schizophrenia and other neurocognitive disorders, including intellectual disabilities, in those who are affected with Chromosome 22q11.2 deletion syndrome.
Found in approximately 1 in 4,000 live births, 22q11.2 deletion syndrome has many possible signs and symptoms that can affect almost any part of the body, including heart abnormalities that often require surgery in the newborn period, an opening in the roof of the mouth, trouble fighting infection due to a poorly functioning immune system, seizures due to low calcium, and significant feeding and swallowing issues. Affected individuals may also have additional medical issues such as breathing problems, kidney abnormalities, scoliosis and hearing loss.
In contrast, some individuals with the 22q11.2 deletion have none of these medical issues. However, most children have developmental delays including delayed acquisition of motor milestones, learning disabilities, and significant delays in emergence of language. Moreover, some children have autism or autistic spectrum disorder, ADHD, OCD, and anxiety.
Later in life, persons with the 22q11.2 deletion are at an increased risk of developing mental illnesses such as schizophrenia, depression and anxiety. There is a substantial risk for developing psychotic illness in approximately 25 to 30 percent of adolescents and young adults with 22q11.2 deletion syndrome. The illness presentation and course are similar to those of schizophrenia, which occurs in the general population at a much lower rate (about 1 percent).
"22q11.2 deletion confers the highest known genetic risk factor for schizophrenia, yet little is understood as to the mechanism," says lead investigator Stephen T. Warren, PhD, chair of the Department of Human Genetics and the William P. Timmie Professor and Charles Howard Candler Chair of Human Genetics at Emory University School of Medicine.
"By sequencing the entire genomes of 1,000 patients with this syndrome, some with and some without psychosis, we hope to uncover variation elsewhere in the genome that contributes to psychosis risk, not only in 22q11.2 deletion syndrome but also in idiopathic psychosis."
Beyond the potential for yielding a better understanding of a severe manifestation of 22q11.2 deletion syndrome, the results will help identify pathways leading to schizophrenia in the general population in a way that will inform novel treatments.
The consortium sites have extensive experience in applying integrative genomic and brain-behavior strategies to study individuals with 22q11.2 deletion syndrome and schizophrenia across the lifespan, and together have provided data on 1,000 genetically and phenotypically characterized individuals with the syndrome, the largest such available sample to date.
The genomic efforts’ led by Emory investigators including David Cutler, PhD, Michael Zwick, PhD, Michael Epstein, PhD, Joseph Cubells, MD, PhD, and Jennifer Mulle, PhD, will include whole-genome sequencing in order to uncover genetic variation that may contribute to the heterogeneity of neuropsychiatric and neurobehavioral phenotypes of schizophrenia and psychosis.
"The project is an unprecedented international initiative to examine a common deletion associated with schizophrenia and elucidate its genomic and behavioral substrates," says Warren.
Not only does this successful application demonstrate the genuine commitment on the part of the National Institute of Mental Health to better understand the brain and psychiatric illness, but it highlights the need for such international collaborations, notes Warren. In this instance, 22 clinical and five basic science collaborating sites, all with extremely dedicated clinicians and researchers who have overcome the challenges of differing cultures, languages, time zones and healthcare systems, are working toward the common goal of improving patient care and long term outcome.
In addition to Emory, participating academic sites in the United States include New York’s Albert Einstein College of Medicine, Duke University, University of Pennsylvania, SUNY Syracuse, UCLA, and UC Davis. The consortium also includes sites in Canada (Toronto), Europe (Leuven, Belgium; Marseille, France; Dublin, Ireland; Rome, Italy; Utrecht and Maastricht, the Netherlands; Mallorca and Madrid, Spain; Geneva, Switzerland; Cardiff and London, United Kingdom); Tel Aviv, Israel; Australia (Newcastle); and Chile (Santiago).