Bipolar disorder runs in families, but researchers have struggled to identify specific genetic factors that put people at risk. Now, by scrutinizing the genes of thousands of people with and without the disorder, researchers have identified more than a dozen rare gene variants that may be involved. Their findings suggest that bipolar disorder may share some genetic roots with other serious psychiatric disorders, including schizophrenia and autism.

The research was led by Fernando S. Goes, M.D., at Johns Hopkins School of Medicine, a 2008 and 2015 Young Investigator and first author of the paper reporting the findings June 1 in the journal JAMA Psychiatry, and James B. Potash, M.D., M.P.H., at the University of Iowa Carver College of Medicine, a NARSAD 2000 Young Investigator, 2008 Independent Investigator, and BBRF Scientific Council Member. The other co-senior authors were 2004 Young Investigator Peter P. Zandi, Ph.D., at Johns Hopkins Bloomberg School of Public Health, and W. Richard McCombie, Ph.D., of Cold Spring Harbor Laboratory.

The researchers conducted their analysis in two stages. First they studied eight families in which multiple members had been diagnosed with bipolar disorder, since in these families there is more likely to be a powerful genetic causative factor at work. For each of 22 affected individuals, the researchers sequenced every protein-encoding section of the genome. This is a strategy known as exome sequencing, which comprehensively analyzes the portion of the genome in which irregularities that most directly impact protein function can be found. They then searched those sequences for rare variants that were shared by the bipolar-affected members within each family.

The search turned up 84 potentially harmful genetic variations that the scientists suspected might be involved in bipolar disorder. Several lay within genes that have been previously linked to autism and schizophrenia, while others affected a biological pathway involved in the developmental disability known as Fragile X syndrome.

The team then looked for those 84 variations in the genomes of a much larger group—3,541 people with bipolar disorder and 4,774 unaffected individuals. Nineteen of the variants, they found, were more common among people with bipolar disorder than they were in people without the illness.

Because these genetic factors are rare, further studies involving larger groups of people will be necessary to conclusively link any of them to bipolar disorder.

Four other NARSAD grantees also contributed to the research: 2001 and 2004 Young Investigator Virginia L. Willour, Ph.D., at the University of Iowa Carver College of Medicine; 2013 Young Investigator Eli Ayumi Stahl, Ph.D., at the Icahn School of Medicine at Mount Sinai; 2006 Young Investigator Shaun Matthew Purcell, Ph.D., at the Icahn School of Medicine at Mount Sinai; 1995 and 1998 Young Investigator, 2006 Independent Investigator, and BBRF Scientific Council Member Pamela B. Sklar, M.D., Ph.D., at the Icahn School of Medicine at Mount Sinai.