Scientists have identified thousands of tiny genetic variations which together could account for more than a third of the inherited risk of schizophrenia.
They also showed the condition is genetically similar to bipolar disorder also known as manic depression.
The findings came from work by three separate teams, who analysed DNA from thousands of people.
The studies - the biggest ever into the genetics of schizophrenia - appear in the journal Nature.
The findings suggest that schizophrenia is much more complex than previously thought, and can arise not only from rare genetic variants, but common ones as well.
It is hoped the work could lead to new diagnostic tests and treatments for the condition.
Schizophrenia is a common form of mental illness, affecting up to 1% of adults worldwide.
Symptoms tend to appear in late adolescence or early adulthood, and can include delusions, hallucinations, paranoia, and depression.
The cause of schizophrenia remains unclear, but it is thought that up to 90% of cases may be inherited.
Research linking the condition to specific genes was published last year, but it is thought they accounted for only a few cases.
Potentially, the findings of the latest studies could be much more significant.
The researchers say that individually many of the genetic variations they have identified play only a tiny role in raising the risk of passing schizophrenia down the generations.
Cumulative effect
However, Dr Shaun Purcell, from Harvard University, who co-led one of the three teams, said: "Cumulatively, they play a major role, accounting for at least one-third - and probably much more - of disease risk."
The researchers stress that more work is needed to establish exactly how the genetic variants translate into schizophrenia.
But researcher Dr Pamela Sklar, of Massachusetts General Hospital, said: "We fully expect that future work will assemble them into meaningful pathways that will teach us about the biology of schizophrenia."
All three studies highlight genes found on Chromosome 6 in area known as the Major Histocompatibility Complex, which plays a role in the immune system, and in controlling when other genes are switched on and off.
The researchers believe this might help explain why environmental factors also seem to affect risk for schizophrenia.
For example, there is evidence that children whose mothers contract flu while pregnant have a higher risk.
Bipolar disorder
In total the researchers identified 30,000 tiny genetic variants more common in people with schizophrenia.
A similar pattern was found in people with bipolar disorder - indicating a previously unrecognised overlap between the two conditions.
Dr Thomas Insel, of the US National Institute of Mental Health, said: "These new results recommend a fresh look at our diagnostic categories.
"If some of the same genetic risks underlie schizophrenia and bipolar disorder, perhaps these disorders originate from some common vulnerability in brain development."
The three research teams, who shared their data, were the International Schizophrenia Consortium, the Molecular Genetics of Schizophrenia consortium and SGENE.
In total, they analysed genetic data from 8,014 people with schizophrenia, comparing them to samples from 19,090 people who did not have the condition.
Paul Corry, of the mental health charity Rethink, said: "This exciting research brings us one step closer to understanding the causes of schizophrenia, but we are still a long way from a full explanation.
"Most of the genetic contribution to this illness is still unknown and it is crucial to realise that genes are only part of the picture - environmental and social factors, such as drug use or trauma, can exacerbate or even trigger schizophrenia."
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