Groundbreaking Genetic Research Helps Identify How and When the Brain May Produce Mental Illness

Joel E. Kleinman, M.D., Ph.D. of National Institute of Mental Health (NIMH)
Joel E. Kleinman, M.D., Ph.D.

From The Quarterly, Winter 2012

Joel E. Kleinman, M.D., Ph.D., winner of the Brain & Behavior Research Foundation Lieber Prize for Outstanding Achievement in Schizophrenia Research in 2011, is working to unravel the mystery of what goes awry in the brain—and how—to cause mental illness. Chief of the Section on Neuropathology and deputy chief of the Clinical Brain Disorders Branch in the Genes, Cognition and Psychosis Program at the National Institute of Mental Health (NIMH), he has for over three decades studied the molecular biology of brain development and disorders, particularly schizophrenia, for which he has amassed one of the most important collections of postmortem human brains. 

Dr. Kleinman’s latest research is helping to resolve a primary question in neuroscience: when and where different genes are expressed—turned on—in the brain over the course of a lifetime. He and his team studied 269 postmortem healthy brains ranging from 14 days prenatal to 80 years of age, developing a database of one trillion pieces of information. The findings, reported in the Oct. 26 issue of the journal Nature, along with the results of a second landmark study on the subject, have important implications for understanding the timeline and genetic variation involved in mental illness.  

In the process of gene expression, genes, made of DNA, are transcribed by another molecule called messenger RNA, or mRNA. The messages mRNA transcripts carry are a direct production of the proteins that perform life’s functions. Each gene can make several mRNA transcripts expressed in patterns influenced by some 1.5 million DNA variations unique to each person. This set of transcripts, the transcriptome, is each individual’s molecular signature.

The databases Dr. Kleinman and colleagues have created now allow neuroscientists to examine how genetic variation is associated with the expression of mRNA in the brain across the lifespan. Dr. Kleinman’s laboratory has focused on the prefrontal cortex, the region responsible for higher brain functions, such as planning and judgment. He says: “Our study shows how 650,000 common genetic variations that make each of us a unique person may influence the ebb and flow of 24,000 genes in the most distinctly human part of our brain as we grow and age.”

The research revealed, among other things, rapid gene expression during fetal development that slows abruptly after birth, levels off in middle age, and then surges anew in old age. In previous studies, Dr. Kleinman had found that all genetic variations implicated to date in schizophrenia are associated with transcripts expressed in the fetal brain. Current research seems to point to a contrasting situation for affective disorders, such as depression, which may be associated with transcripts later in life. Dr. Kleinman and his colleagues are continuing and expanding their research to include all transcripts of all human genes, examining 1,000 postmortem brains, including brains of people who had schizophrenia and other brain disorders.

NIMH Director Thomas R. Insel, M.D., states: “Having at our fingertips detailed information about when and where specific gene products are expressed in the brain brings new hope for understanding how this process can go awry in schizophrenia, autism and other brain disorders.”