Debby W. Tsuang, M.D., M.Sc., with the support of a NARSAD Independent Investigator Grant, used innovative family-based methods to study genetic susceptibility to schizophrenia. The results of the research team’s work, published online today in JAMA Psychiatry, identifies new genes associated with the risk of developing schizophrenia. These genetic components may represent novel targets for schizophrenia medications.

Dr. Tsuang, Professor of Psychiatry and Behavioral Science at the University of Washington School of Medicine and Director of Geriatric Research Education and Clinical Center VAPSHCS, explains the approach: “Although commonly used genetic methods have successfully identified causative genes in many disorders, these approaches have been less successful in complex disorders like schizophrenia. For example, the genetic regions previously associated with schizophrenia only account for slightly increased risks of the disorder and miss rare variants that might cause the disorder. At the time I applied for the NARSAD Grant, one of the emerging approaches to gene identification was genomic sequencing, a method that could detect all of the genetic sequence changes or variants in a genome. Sequencing every one of the three billion nucleotides that is present in the human genome is not feasible, but it is possible to sequence the human exome, the areas that contains all of the exons or coding regions.”

 “Whole-exome sequencing posed two distinct advantages to other genetic methods: it avoided the bias of traditional candidate gene methods, which must select specific polymorphisms to genotype, and it offered the potential of identifying rare variants, unlike genome-wide association studies,” says Dr. Tsuang.

The research team decided to change the standard methodology [case-control] to a family-based study due to the discovery of rare mutations in multigenerational families in other complex disorders such as Alzheimer’s disease.

Dr. Tsuang continues, “We selected 5 large families from the National Institute of Mental Health Center for Collaborative Genomic Studies on Mental Disorders Initiative that each had multiple affected subjects for whom the genetic transmission appeared consistent with single-gene inheritance ... To identify rare disease-associated mutations, we retained variants that were shared between affected individuals within a family. We discriminated between variants that were protein-altering, present in all sequenced family members, not found among 23 in-house sequenced exomes of individuals without known psychiatric disorders, and not present or very rare in publicly available databases.”

The team found 22 unique variants in 21 different genes in all affected members of the family sample. Among the genes identified, only GRM5 had been previously implicated in schizophrenia.

Dr. Tsuang concludes that, “Our findings suggest that exome sequencing in multiplex pedigrees can be an effective strategy to gene discovery in complex disorders like schizophrenia. Because of the generous funding of the NARSAD Grant, we were able to uncover new genes associated with the risk of developing schizophrenia. These genetic components, particularly mGluR5 agonists, PPEF2, and LRP1B, may represent novel targets for schizophrenia medications.”