A multi-institutional team of researchers studying schizophrenia and bipolar disorder has been awarded a $16 million grant from the National Institute of Mental Health (NIMH) to create the most extensive genetic resource to date for these two devastating psychiatric disorders, using DNA samples assembled by the University of Southern California (USC).

The four-year award, shared by USC, the University of Michigan and the Broad Institute Inc., will help fund a project titled: “Whole Genome Sequencing of Schizophrenia and Bipolar Disorder in the Genomic Psychiatry Cohort (GPC).”

Keck School of Medicine of USC researchers Carlos N. Pato, MD, PhD, Franz Alexander Professor and chair of the Department of Psychiatry and Behavioral Sciences and Michele Pato, MD, professor and Della Martin Chair of Psychiatry, created the GPC, which includes more than 37,000 participants who have agreed to provide DNA samples for genomic, epidemiological and clinical studies.

“The GPC is a cohort of patients and controls who have agreed to partner with us in extensive genomic studies of human heredity, ranging from normal function to a variety of illnesses,” said Carlos N. Pato, principal investigator of the new award. “This study will greatly increase the data available on the human genomic sequence. By design, it will help us study schizophrenia and bipolar disorder, but this resource should prove extremely important for understanding the role of the human genome in a broad set of disorders and in normal human functions.”

Schizophrenia and bipolar disorder are chronic, disabling and often life-threatening. Despite estimated lifetime prevalence of just more than 1 percent worldwide and their burden on individuals, families and public health, little is known about the molecular basis of the disorders. The high heritability of these disorders – which involve five- to 10-fold increased risk to first-degree relatives – indicates that potential insights about their molecular basis may be found in the ways in which genome sequences vary from person to person. Better understanding of the genetic basis of schizophrenia and bipolar disorder could identify molecular mechanisms for novel drugs, therapies and preventive strategies.

“The failures and successes of genetic analyses over the past 15 years have shown that schizophrenia and bipolar disorder are highly polygenic illnesses, which means that making meaningful observations about the genetic basis of schizophrenia and bipolar disorder will require analyzing the largest possible number of genomes,” said Michele Pato. “The important challenge is not only to find variants that affect the function or expression of a gene, but to find the subset of variants that truly matters to psychiatric illness.”

The study will sequence total genomic DNA from 10,000 or more ethnically diverse individuals from the GPC, split evenly among schizophrenia cases, bipolar disorder cases and psychiatrically normal controls. The resulting genome sequence data will be processed to obtain the most informative view of the genomes for these individuals. The team will also conduct association analyses within these and other available sequence data, and through genotype imputation with the Psychiatric GWAS Consortium comprising approximately 100,000 additional genomes, to identify genetic variants associated with schizophrenia and bipolar disorder.

Since 2008, the GPC has enrolled a multi-ethnic cohort of 25,000 participants in addition to an existing set of 12,000. These new GPC participants provide consent for sharing de-identified demographic, clinical, diagnostic, and genetic data, and for deposition and sharing of biological samples. They are given a re-contact option to enable prospective follow-up and 88 percent of participants have agreed.

The NIMH, part of the National Institutes of Health (NIH), aims to transform the understanding and treatment of mental illness through basic and clinical research. Associated grant numbers for this award include U01MH105573 (USC), U01MH105653 (Michigan) and U01MH105641 (Broad).

by John Cleary