We commend the work performed by Zhu et al. providing additional insights into the pathogenesis of myasthenia gravis (1). In essence, they applied Mendelian randomization to genome-wide data that we recently made public for a large cohort of patients diagnosed with the neuromuscular disorder (2). This powerful approach identified genetic variants increasing the risk of developing myasthenia gravis by influencing gene expression. Their most exciting observations centered on CHRNB1 and ERBB2, two loci we discovered in our genomic and transcriptomic analyses (2). Their data corroborated our conclusions in that they found rs4151121 to influence the expression of CHRNB1 in skeletal muscle. ERBB2 was also implicated in their search, though the lead variant and tissue involved differed between the two studies. We had identified rs2102928 in skeletal muscle as the candidate variant affecting ERBB2 expression, whereas rs1565922 in peripheral nerves was implicated in this current analysis. These findings are not mutually exclusive and point to this myasthenia gravis–related gene operating across multiple tissues.
Regardless of these subtle differences, the two studies hint at CHRNB1 and ERBB2 playing a prominent role in the pathobiology of myasthenia gravis. Given that ERBB2 can modulate the expression of acetylcholine receptor subunits (3, 4), future studies should explore how the expression of these genes in nerves and skeletal muscle mediate the disease process. Our findings also have clinical implications as patients carrying the risk allele could have persistently lower expression of acetylcholine receptors, which may explain why some patients fail to enter remission (4). These observations suggest that new therapies modulating CHRNB1 and ERBB2 expression may benefit treatment-refractory patients. To demonstrate how genomic information can provide useful starting points to consider for therapeutic interventions, we performed in silico druggability testing on additional gene targets identified from the prioritization analysis of our genome-wide association study data (5). This approach identified 14 gene targets as potentially druggable, three of which have existing approved drugs or therapeutic agents in clinical testing (milatuzumab, forigerimod, and oprozomib; see Table 1) (6–8).
Table 1.
List of prioritized druggable genes ranked according to their priority index (PI) scores
| Drug | Current disease indication | Mechanism of action | Gene | PI rank | PI rating | Druggability | Seed gene |
|---|---|---|---|---|---|---|---|
| Milatuzumab | Orphan drug status for MM and CLL | HLA-DR antigens- associated invariant chain antagonist | CD74 | 2 | 4.59 | 1 | N |
| Forigerimod | Phase III trial for SLE | Heat-shock cognate 71-kDa protein inhibitor | HSPA8 | 12 | 4.11 | 8 | N |
| Oprozomib | Orphan drug status for MM and Waldenstrom's macroglobulinaemia | 26S proteosome inhibitor | PSMD4 | 20 | 3.96 | 15 | N |
| — | — | — | HLA-DRA | 4 | 4.48 | 21 | Y |
| — | — | — | HLA-DQA1 | 5 | 4.44 | 8 | Y |
| — | — | — | UBA52 | 6 | 4.42 | 19 | N |
| — | — | — | HLA-DQB1 | 17 | 4.05 | 8 | N |
| — | — | — | AP1G1 | 18 | 4.00 | 1 | N |
| — | — | — | SH3GL2 | 19 | 3.96 | 3 | N |
| — | — | — | ARF1 | 22 | 3.93 | 4 | N |
| — | — | — | AP2B1 | 23 | 3.92 | 2 | N |
| — | — | — | AP1B1 | 25 | 3.87 | 1 | N |
| — | — | — | HLA-C | 28 | 3.76 | 1 | Y |
| — | — | — | AP1S3 | 29 | 3.75 | 1 | N |
Drugs that are approved or in clinical testing are highlighted in yellow. MM, multiple myeloma; CLL, chronic lymphocytic leukemia; SLE, systemic lupus erythematosus; Seed gene indicates if the prioritized gene was used as a seed gene (yes [Y] or no [N]).
The work presented by Zhu et al. (1), together with our recent publication (2), demonstrates the value of genomic research in unraveling the pathogenesis of neurological diseases. Most notably, the insights provided by such large collaborative efforts pave the way for rational drug development and precision medicine efforts.
Acknowledgments
This work was supported in part by the Intramural Research Programs of the NIH, National Institute on Aging (Z01-AG000949-02). The work was also supported by the Myasthenia Gravis Foundation (D.B.D. and B.J.T.), a generous bequest by Geraldine Weinrib, and a gift from Philip Swift. Support was provided by Mr. and Mrs. Don Brandon and the Department of Neurology, University of Kansas Medical Center. We thank the Laboratory of Neurogenetics (NIH) staff for their collegial support and technical assistance.
Footnotes
Competing interest statement: B.J.T. holds patents on the clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of C9orf72 and has received research grants from The Myasthenia Gravis Foundation, the Robert Packard Center for ALS Research, the ALS Association (ALSA), the Italian Football Federation (FIGC), the Center for Disease Control and Prevention (CDC), the Muscular Dystrophy Association (MDA), Merck, and Microsoft Research. B.J.T. receives funding through the Intramural Research Program at the NIH.
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