Mood disorders, like bipolar disorder (BPD), are life-wrenching diseases. Current therapies help many, but not every patient responds favorably. Treating this disease more effectively will require a deeper understanding of its causes. Jun Li, Ph.D., Associate Professor of Human Genetics at the University of Michigan is probing the genetics and gene function of BPD in fundamentally original ways. Li tells us that “extensive genetic complexity remains a major barrier to identifying bipolar disorder’s genetic basis”. Li aims to break this barrier. Already his lab has made great strides in identifying genes for bipolar disorder susceptibility since receiving the Johnson & Johnson / One Mind (IMHRO) Rising Star Translational Research Award in 2011.
Through his research, Li attempts to pinpoint the rare genetic variants found among people diagnosed with bipolar disorder by genotyping 344 individuals in 34 different families. In each of these families, BPD has impacted more than one individual and has been present over generations. These multiplex BPD families may manifest a “highly penetrant subset of BPD by transmitting one or a few high-impact coding variants” (Li). Because Li has found many different candidate genes in different families, his approach aims to support the hypothesis that even when different genes are implicated, these different genes can have the same effect on the pathway level and can ultimately lead to symptoms of BPD.
After sifting through rare coding variants, Li focused in on the unique genetic differences found within the multiplex BPD families. The tests yielded more than 300 genes with damaging mutations that were rare in the general population but passed on among BPD cases through these families. Pathway analysis of these genes revealed a multiplicity of genes involved in circadian rhythms (daily sleep/wake cycles). Circadian rhythm irregularities have long been associated with BPD and Jun Li’s findings provide a strong genetic basis for this connection and a possibility of directly targeting this pathway with treatment. Other genes found with damaging mutations were genes impacting childhood brain development.
Li’s groundbreaking findings present genetic commonality among multiplex BPD families, highlighting targetable pathways in circadian regulation and early neurodevelopmental processes. Looking towards the future, further studies would aim to narrow in on the specific causal genes in each family and develop therapies to more effectively treat BPD.
We at One Mind remain deeply impressed with Dr. Li’s contributions toward understanding the biology behind bipolar disorder, and thank our donors for enabling us to fund his valuable research.
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