Bipolar disorder-associated variants in RAB5A disrupt its function in endolysosomal trafficking in fruit fly and mammalian systems.
Bipolar disorder is a severe neuropsychiatric disorder associated with significant morbidity and mortality. Although the heritability of bipolar disorder is among the highest of all neuropsychiatric disorders, the specific genetic etiologies for most affected individuals have remained elusive. This is due, in part, to difficulty confirming pathogenicity of genomic variants identified in bipolar disorder populations. From the Bipolar Exomes Browser (BipEX) project, we identified three missense variants in RAB5A in four individuals with bipolar disorder not found in controls. We used a Drosophila overexpression system to evaluate these bipolar disorder-associated variants in RAB5A. We determined that when bipolar disorder-associated RAB5A variants are expressed in fruit flies, synaptic neurotransmission, endolysosomal trafficking, viability, survival and wing morphology are all disrupted. We confirmed that certain bipolar disorder-associated RAB5A variants also disrupt early endosomal trafficking in mammalian cells. This confirms bipolar disorder-associated variants in RAB5A disrupt its normal function. Moreover, Drosophila melanogaster is a viable experimental system to test the pathogenicity of genomic variants associated with psychiatric disorders.