Biomedical Frontiers: Winter/Spring 1996, Vol.3, No.2
Schizophrenia: Searching for answers

Schizophrenia affects approximately one out of every 100 Americans and costs society an estimated $65 billion a year in terms of direct and indirect costs. Yet treatments for this disease are still often less than effective, failing to completely eliminate symptoms or producing undesirable side effects. Columbia-Presbyterian researchers are making headway against schizophrenia on a variety of fronts.

Along with Harvard University and Washington University, Columbia is part of an intensive, large-scale effort initiated by the National Institute of Mental Health in 1989 to search for the gene or genes involved in schizophrenia. Although a few studies in the past have tentatively linked schizophrenia to gene locations on various chromosomes, those studies have been unsubstantiated. Now, the NIMH Genetics Initiative, as the project is known, aims to correct that. "In schizophrenia, the earlier in the course of the disease that treatment is instituted, the better the prognosis," says Dr. Charles A. Kaufmann, principal investigator of the schizophrenia genetics initiative at Columbia, associate professor of clinical psychiatry, and head of the molecular neurobiology lab at the New York State Psychiatric Institute (NYSPI). "If we had a gene marker, we could start treatment early. There's a lot of potential for drug development that gets at the primary pathology."

Men line up for food rations during the Dutch "Hunger Winter" of 1944-45. Babies conceived in the last three months of the famine had twice the risk of schizophrenia.

The search for a schizophrenia gene has been complicated by several factors. First, it's not clear exactly which components of the disease are heritable. For instance, it may be only the negative symptoms, such as social isolation, flat expression, and poverty of ideas that are genetically passed on. Likewise, the positive symptoms-hallucinations or delusions-may be genetically transmitted in families.

Furthermore, it may not be the disease per se that is inherited but a genetic risk factor that is brought into play by environmental insult. "The disease itself probably doesn't travel through the generations. The inherited component may be only genes that increase the risk of psychopathology," says Dr. Kaufmann. However, Dr. Kaufmann and colleagues also have found that schizophrenia appears to be characterized by anticipation, a clinical phenomenon in which age of disease onset decreases and disease severity increases in successive generations. This phenomenon has also been seen in about a dozen other neuropsychiatric disorders, including Huntington's disease and Friederich's ataxia, and has been associated with a particular gene mutation: trinucleotide repeat expansion. Dr. Kaufmann and collaborators in Sweden are currently searching for such mutations in schizophrenia pedigrees.

Finally, researchers speculate that schizophrenia involves several genes with different genes operating in different cases. "Schizophrenia is a complex disorder with reduced penetrance, variable expressivity, and genetic and non-genetic causes," says Dr. Dolores Malaspina, co-principal investigator of the genetics initiative, assistant professor of clinical psychiatry at Columbia, and head of the clinical neurobiology lab at NYSPI.

In their work for the genetics initiative, Columbia researchers have studied 124 pedigrees; by September 1997 they expect that number to increase to 162. Related work by other investigators, in turn, has led them to a number of possible locations for schizophrenia genes, including the short arm of chromosome 6, and chromosomes 8, 5, 18, and 22. The next step in the process will be to narrow down the possible regions even more by looking at larger groups of families. "We will take 300 of our most informative individuals, identify regions of interest, and then look at the genome intensively," says Dr. Kaufmann. In April, NIMH genetics initiative researchers made the diagnostic information and blood lines studied so far publically available to all qualified investigators. "The NIMH project is meant not only to be a resource for us collaborating investigators and institutions, but also a national resource," says Dr. Kaufmann.

In the process of their search, Columbia researchers, along with researchers from the two other schizophrenia sites and four sites dedicated to the search for a gene for bipolar disorder, developed the Diagnostic Interview for Genetic Studies, an assessment tool that has become an industry standard. The computerized assessment provides some 2,000 data points on each individual in a study, including age of onset, comorbid conditions, and psychosis-inducing drug exposures, helping scientists determine which diagnostic conventions an individual meets and allowing for the use of a full range of statistical approaches. These approaches include segregation analysis and linkage analysis.

One site being studied as a possible location of a gene involved in determining the predisposition to schizophrenia is the major histocompatibility complex (MHC) locus, located on the short arm of chromosome 6. In addition to linkage studies that point to this region, researchers at Johns Hopkins University found that rheumatoid arthritis and schizophrenia occur together much less frequently than would be expected on the basis of chance. Rheumatoid arthritis is an autoimmune disease that affects the joints and other organs in about 1 percent of the population. The inheritance of rheumatoid arthritis is also genetically complex, but one genetic locus has been mapped to the MHC.

Dr. Robert Winchester, professor of pediatrics and of pathology and director of the division of autoimmune and molecular diseases, and colleagues have unravelled the curious genetics of rheumatoid arthritis operating at that locus. They found that a predisposition to rheumatoid arthritis is conferred by about 10 structurally different alleles of the more than 100 alleles of the DRB1 locus of MHC. By sequencing these alleles, they further mapped susceptibility into a motif of 24 nucleotides present only in each of the alleles associated with susceptibility to rheumatoid arthritis. The nucleotides of this susceptibility motif encode a sequence of amino acids that are found at the margin of the class II MHC molecule and appear to be important in binding certain peptides to these molecules for presentation to CD4 T-cells. "Because so many different alleles are involved, this suggests the hypothesis that either the alleles bearing this motif somehow prevent the development of schizophrenia, or that another allele with a motif that does not predispose to rheumatoid arthritis is linked to a gene that predisposes to schizophrenia," says Dr. Winchester.

An MHC molecule that presents peptides to T-cells. Red portion confers susceptibility to RA.

Dr. Winchester's lab is directly sequencing the DRB1 alleles of a cohort of schizophrenia patients in association with Dr. Kaufmann and other collaborators, with the prediction that alleles with the susceptibility motif will be underrepresented in individuals with schizophrenia.

Another important aspect of Columbia's schizophrenia research is the newly established Developing Clinical Research Center for the Study of Schizophrenia. In July 1995, Columbia received a five-year NIMH grant toward the establishment of the center, located at NYSPI and Creedmoor Psychiatric Center. "The center is unique because it offers researchers well-characterized research patients, a resource that is rarely available elsewhere," says Dr. Jack Gorman, principal investigator of the center, professor of clinical psychiatry at Columbia, and deputy director of NYSPI. The center has 36 research beds dedicated to schizophrenia research, which have no length-of-stay requirements. Core areas of study are diagnosis and assessment, genetics, neuroimmunology, neuropathology, brain imaging, pharmacology, and epidemiology.