The number of mutations, discovered in 108 regions of the genome, is large enough that scientists are starting to see patterns, according to research published in the journal Nature.
"We can group them into identifiable pathways -- which genes are known to work together to perform specific functions in the brain," said study co-author Stephan Ripke of the Massachusetts General Hospital's Broad Institute.
"This is helping us to understand the biology of schizophrenia."
The disorder affects about 24 million people in the world, and is characterised by hallucinations, delusions, paranoia and a breakdown of thought processes.
Symptoms typically start between the ages of 15 and 35.
Treatment is available but for many has limited effect -- as it addresses only the psychotic symptoms of the disorder and not its debilitating cognitive effects, according to a Broad Institute statement.
There has been little innovation in drug development in more than 60 years, in part "because the biological mechanisms underlying schizophrenia have not been understood," it said.
Now, the biggest-ever molecular genetic study of any neuropsychiatric disorder has implicated genes involved in the functioning of the neurons and synapses of the brain, including in the learning and memory regions.
Most of the mutations uncovered are common, and all are inherited from one's parents.
The team found that a smaller number of genes linked to higher schizophrenia risk were also active in the immune system -- backing theories that immune dysfunction may be involved in the disease.
"The wealth of new findings have the potential to kick-start the development of new treatments in schizophrenia, a process which has stalled for the last 60 years," said senior author Michael O'Donovan of Cardiff University MRC Centre for Neuropsychiatric Genetics and Genomics.
But he cautioned that "reaping the full benefits of this research for treatment will be a medium to long game."
- Debate settled -
Gerome Breen of Kings College London's Institute of Psychiatry, said the study had pinpointed several well-studied pathways, which can turn genes on and off, for which drugs already existed in other disorders.
"This is perhaps the most important study in psychiatric genetics to date," he said in comments provided by the Science Media Centre.
For experts Jonathan Flint and Marcus Munafo, the study settles a long-standing debate.
"Dispute over schizophrenia's genetic basis has been ferocious," they wrote in a comment carried by Nature.
"Its biological roots have often been denied and, in the anti-psychiatry movement of the 1970s, there was even outright rejection of its existence."
The latest work, they said, will "(lay) to rest forever the idea that genetics is not an important cause of the illness."
The study involved more than 300 scientists from 35 countries.