CRF Blog

Runs in the Family

by Bill Hayes

In Runs in the Family for the New Yorker, Siddhartha Mukherjee reports on new findings about schizophrenia.

That schizophrenia runs in families was evident even to the person who first defined the illness. In 1911, Eugen Bleuler, a Swiss-German psychiatrist, published a book describing a series of cases of men and women, typically in their teens and early twenties, whose thoughts had begun to tangle and degenerate. “In this malady, the associations lose their continuity,” Bleuler wrote. “The threads between thoughts are torn.” Psychotic visions and paranoid thoughts flashed out of nowhere. Some patients “feel themselves weak, their spirit escapes, they will never survive the day. There is a growth in their heads. Their bones have turned liquid; their hearts have turned into stone…. The patient’s wife must not use eggs in cooking, otherwise he will grow feathers.” His patients were often trapped between flickering emotional states, unable to choose between two radically opposed visions, Bleuler noted. “You devil, you angel, you devil, you angel,” one woman said to her lover.

Bleuler tried to find an explanation for the mysterious symptoms, but there was only one seemingly common element: schizophrenic patients tended to have first-degree relatives who were also schizophrenic. He had no tools to understand the mechanism behind the heredity. The word “gene” had been coined just two years before Bleuler published his book. The notion that a mental illness could be carried across generations by unitary, indivisible factors — corpuscles of information threading through families — would have struck most of Bleuler’s contemporaries as mad in its own right. Still, Bleuler was astonishingly prescient about the complex nature of inheritance. “If one is looking for ‘the heredity,’ one can nearly always find it,” he wrote. “We will not be able to do anything about it even later on, unless the single factor of heredity can be broken down into many hereditary factors along specific lines.”

In the nineteen-sixties, Bleuler’s hunch was confirmed by twin studies. Psychiatrists determined that if an identical twin was schizophrenic the other twin had a forty-to-fifty-per-cent chance of developing the disease — fiftyfold higher than the risk in the general population. By the early two-thousands, large population studies had revealed a strong genetic link between schizophrenia and bipolar disorder. Some of the families described in these studies had a crisscrossing history that was achingly similar to my own: one sibling affected with schizophrenia, another with bipolar disorder, and a nephew or niece also schizophrenic.

“The twin studies clarified two important features of schizophrenia and bipolar disorder,” Jeffrey Lieberman, a Columbia University psychiatrist who has studied schizophrenia for thirty years, told me. “First, it was clear that there wasn’t a single gene, but dozens of genes involved in causing schizophrenia — each perhaps exerting a small effect. And, second, even if you inherited the entire set of risk genes, as identical twins do, you still might not develop the disease. Obviously, there were other triggers or instigators involved in releasing the illness.” But while these studies established that schizophrenia had a genetic basis, they revealed nothing about the nature of the genes involved. “For doctors, patients, and families in the schizophrenia community, genetics became the ultimate mystery,” Lieberman said. “If we knew the identity of the genes, we would find the causes, and if we found the causes we could find medicines.”

In 2006, an international consortium of psychiatric geneticists launched a genomic survey of schizophrenia, hoping to advance the search for the implicated genes. With 3,322 patients and 3,587 controls, this was one of the largest and most rigorous such studies in the history of the disease. Researchers scanned through the nearly seven thousand genomes to find variations in gene segments that were correlated with schizophrenia. This strategy, termed an “association study,” does not pinpoint a gene, but it provides a general location where a disease-linked gene may be found, like a treasure map with a large “X” scratched in a corner of the genome.

The results, reported in 2009 (and updated in 2014) in the journal Nature, were a dispiriting validation of Bleuler’s hunch about multiple hereditary factors: more than a hundred independent segments of the genome were associated with schizophrenia. “There are lots of small, common genetic effects, scattered across the genome,” one researcher said. “There are many different biological processes involved.” Some of the putative culprits made biological sense — if dimly. There were genes linked to transmitters that relay messages between neurons, and genes for molecular channels that move electrical signals up and down nerve cells. But by far the most surprising association involved a gene segment on chromosome 6. This region of the genome — termed the MHC region — carries hundreds of genes typically associated with the immune system. [more]