Schizophrenia, Bipolar Disorder Risk Traced to Common, Rare Variants in New Genetic Studies

Two new genetic studies on schizophrenia and bipolar disorder have uncovered complementary information on the common and rare contributors to schizophrenia. They center on shared pathways that provide insights into the underlying biology of the neuropsychiatric condition.

In the first of the studies, published in Nature on Wednesday, a team lead by researchers at the Broad Institute and Cardiff University presented findings from a two-stage schizophrenia genome-wide association study that involved 76,755 cases and 243,649 unaffected controls. That search highlighted common risk variants at 287 schizophrenia-associated loci, which were overrepresented in and around genes active in central nervous system neuronal cells.

"Enrichment of common variant associations was restricted to genes that are expressed in neurons of the central nervous system — both excitatory and inhibitory — and that have functions in fundamental biological processes related to neuronal function," the authors wrote. "This indicates that neurons are the most important site of pathology in schizophrenia."

With additional fine-mapping and functional analyses, the investigators flagged 106 protein-coding genes and more than a dozen noncoding genes that appeared to contribute to schizophrenia's biological changes. Again, neurological and synaptic processes came to the forefront, particularly neuronal development, differentiation, and synaptic transmission pathways.

In addition, the authors noted that fine-mapped candidate variants "were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders."

In a study appearing in Nature Genetics on Wednesday, meanwhile, researchers from Massachusetts General Hospital, the Broad Institute, and elsewhere outlined findings from an exome sequencing analysis of bipolar disorder, done through the Bipolar Exome (BipEx) collaboration, which also emphasized very rare coding variants linked to schizophrenia.

With protein-coding sequences from nearly 14,000 individuals with bipolar disorder and more than 14,400 unaffected controls, the team saw an overrepresentation of ultra-rare protein-truncating variants in CHD8 promoter-binding targets and in genes linked to schizophrenia through a published meta-analysis of exome sequence profiles from more than 24,200 schizophrenia cases and more than 97,300 control participants.

In particular, the researchers suggested that the new findings focused their attention on rare alterations affecting AKAP11, a gene coding for a protein that interacts with GSK3B and thought to be a target for lithium-based bipolar disorder treatment.

"[U]ltra-rare [protein truncating variants] in constrained genes are significantly enriched in [bipolar disorder] cases over controls, a result firmly established in schizophrenia and other early-onset neurodevelopment disorders," the authors wrote, noting that AKAP11 "shows shared evidence of risk for BD and schizophrenia, increasing our confidence that we are discovering true risk factors underlying psychiatric disease."

In contrast, members of that team noted that ultra-rare protein-truncating variants did not turn up in a prior bipolar disease GWAS that included 20,352 bipolar disorder cases and 31,358 controls, although there appeared to be tenuous ties to such variants in more than two dozen calcium channel genes.

"Overall, the current evidence suggests gene discovery in BD is on a similar trajectory to schizophrenia, where increased sample sizes and further collaborative efforts will inevitably lead to biologically meaningful risk genes and pathways underlying BD risk," the authors concluded.

In a related News and Views article in Nature, Icahn School of Medicine at Mount Sinai researchers Conrad Iyegbe and Paul O'Reilly noted that the new research "demonstrates how different study designs can support each other."

"Together, the current studies contribute to an emerging consensus that rare and common genetic risk factors for disease converge on many of the same biological mechanisms," they wrote, noting that "they each reaffirm the functional importance of synapses — connections between neurons — in schizophrenia."