Unraveling the Genetics Behind Psychotic Disorders

Research by Pamela Sklar, MD, PhD, is leading to a better understanding of the genetic risk factors that cause psychotic disorders to develop

Psychotic disorders such as schizophrenia and bipolar disorder, which are characterized by abnormal thinking, hallucinations and delusions, are estimated to affect more than three percent of the population. Over the last 50 years, medications including lithium for bipolar disorder and neuroleptics for psychosis, have dramatically improved the lives of patients suffering from psychosis. But devastating side effects, high recurrence rates and mounting safety concerns continually remind researchers how much more work remains to be done.

Pamela Sklar, MD, PhD, Professor of Psychiatry, Neuroscience, Genetics and Genomic Sciences at Mount Sinai, believes that the future of treating psychotic disorders lies mainly in understanding one thing: a patient’s genes. As Chief of Mount Sinai’s new Division of Psychiatric Genomics, she is building a world-class psychiatric genomics unit that will be a leader in translating human genetic insights into the clinical practice of psychiatry. Says Dr. Sklar: “By understanding genetic risk factors, physicians can target psychiatric diseases at their roots and intervene earlier with treatment.”

The landscape of human genetics has changed dramatically over the last ten years. Extensive fine-scale maps — including both single nucleotide and structural — have been made of human variation and provide the necessary genetic markers for genome-wide association studies. In addition, high-throughput methods for genotyping and next generation sequencing machines are now available at a reasonable cost. While human geneticists have had a long history of success in identifying genes for single-gene disorders, coupling genetic information and technology has led to extraordinary insights into complex multigenic disorders such as schizophrenia and bipolar disorder.

“We have learned that there are many more contributing genetic causes than previously thought, and while the effects of most of these causes are small, together they are quite meaningful,” explains Dr. Sklar. In addition, her team of researchers has also demonstrated that there is a very substantial overlap in the genetic underpinning of schizophrenia and bipolar disorder. “This has prompted us to rethink our traditional diagnostic categories,” she adds.

Research uncovering the genetics of schizophrenia is growing rapidly. According to Dr. Sklar, the next steps include completing the identification of potential disease associated human variation and connecting that variation with the pathobiology of schizophrenia. This will provide biological insight and lead to more appropriate targeting of proteins for therapeutic development.

Dr. Sklar also believes that over time it will be critical that individual-specific genetic information is incorporated into the care of psychiatric patients so that diagnoses, treatment options and prognoses can be personalized.