Schizophrenia and bipolar disorder share genetic roots

A trio of genome-wide studies – collectively the largest to date – has pinpointed a vast array of genetic variation that cumulatively may account for at least one third of the genetic risk for schizophrenia. One of the studies traced schizophrenia and bipolar disorder, in part, to the same chromosomal neighborhoods.

"These new results recommend a fresh look at our diagnostic categories," said Thomas R. Insel, M.D., director of the National Institute of Mental Health (NIMH), part of the National Institutes of Health. "If some of the same genetic risks underlie schizophrenia and bipolar disorder, perhaps these disorders originate from some common vulnerability in brain development."

Three schizophrenia genetics research consortia, each funded in part by NIMH, report separately on their genome-wide association studies online July 1, 2009, in the journal Nature. However, the SGENE, International Schizophrenia (ISC) and Molecular Genetics of Schizophrenia (MGS) consortia shared their results – making possible meta-analyses of a combined sample totaling 8,014 cases and 19,090 controls.

All three studies implicate an area of Chromosome 6 (6p22.1), which is known to harbor genes involved in immunity and controlling how and when genes turn on and off. This hotspot of association might help to explain how environmental factors affect risk for schizophrenia. For example, there are hints of autoimmune involvement in schizophrenia, such as evidence that offspring of mothers with influenza while pregnant have a higher risk of developing the illness.

"Our study was unique in employing a new way of detecting the molecular signatures of genetic variations with very small effects on potential schizophrenia risk," explained Pamela Sklar, M.D., Ph.D., of Harvard University and the Stanley Center for Psychiatric Research, who co-led the ISC team with Harvard's Shaun Purcell, Ph.D.

"Individually, these common variants' effects do not all rise to statistical significance, but cumulatively they play a major role, accounting for at least one third – and probably much more – of disease risk," said Purcell.

Among sites showing the strongest associations with schizophrenia was a suspect area on Chromosome 22 and more than 450 variations in the suspect area on Chromosome 6. Statistical simulations confirmed that the findings could not have been accounted for by a handful of common gene variants with large effect or just rare variants. This involvement of many common gene variants suggests that schizophrenia in different people might ultimately be traceable to distinct disease processes, say the researchers.

"There was substantial overlap in the genetic risk for schizophrenia and bipolar disorder that was specific to mental disorders," added Sklar. "We saw no association between the suspect gene variants and half a dozen common non-psychiatric disorders."

Still, most of the genetic contribution to schizophrenia, which is estimated to be at least 70 percent heritable, remains unknown.