James A. Knowles
Professor and Associate Chair for Research
Psychiatry & The Behavioral Sciences
Zilkha Neurogenetic Institute
Keck School of Medicine
Discovery of genetic factors that predispose individuals to disease, with a focus on the psychiatric illnesses. We have ongoing projects for the following disorders:
- Panic Disorder
- Obsessive-Compulsive Disorder (OCD)
- Nicotine Addiction
- Opiate Addiction
- Major Depression
- Pulmonary Arterial Hypertension (PAH) / Primary Pulmonary Hypertension (PPH)
Research OverviewMy overriding interest is the genetic basis of behavior, cognition and affect. I have pursued this interest by completing both a Ph.D. in genetics, and a residency and research fellowship in psychiatry. Using this training, I have embarked on a research career to search for the genetic factors that have an etiological role in psychiatric illness. To do so, I have participated in both large genetic studies of the “complex” (non-Mendelian) genetic disorders and in studying several simple or Mendelian disorders.
The study of Mendelian disorders has been a useful “testbed” to hone the laboratory techniques for finding the genes for the psychiatric disorders, which are complex genetic disorders. I have discovered the genes for two Mendelian disorders. The first was RP14, a gene for autosomal recessive Retinitis pigmentosa (RP) on chromosome 6p. The second is PPH1, the gene for familial Primary Pulmonary Hypertension (now called PAH-Pulmonary Arterial Hypertension), an autosomal dominant disorder. My collaborators and I also found that the gene for PAH, BMPR2 (bone morphogenetic protein receptor II), is also mutated in: some individuals with congenital heart disease; approximately 5-10% of individuals with sporadic PAH; and some individuals who developed PAH after taking the diet drug fenfluramine. We have also shown that BMPR2 interacts with the c-Src signaling pathway and have developed an assay for high-throughput drug discovery to look for new treatments for PAH. Both the RP and the PAH projects have enabled me to build a genetics laboratory with state-of-art equipment, and personnel trained in the techniques of genomic analysis, mutation detection, and bioinformatics to enable us to find the genetic loci for the psychiatric disorders.
Finding genes for the psychiatric disorders is by necessity a collaborative effort. These are large-scale studies that require multiple sites to collect the sample sizes necessary to have adequate power. These studies also require teams of clinicians, geneticists and statisticians, working together, to make progress. I am the geneticist/molecular biologist on several such teams. My work with these investigators has focused on the anxiety disorders, depression and the addictive disorders. I published the first genome-wide scan for linkage to panic disorder, which ruled out the likely existence of a single major gene for the disorder and demonstrated the need for larger sample sizes in psychiatric genetics. More recently, our collaborative group has found two loci for panic disorder, one on chromosome 15q and a second, sex-specific locus on chromosome 2q. Both are significant at when corrected for genome-wide testing. I have also worked on another anxiety disorder, obsessive-compulsive disorder (OCD). Our genome-wide scan for linkage to OCD found suggestive linkage to chromosomes 1q, 3q, 6q, 7p, and 15q. Genome-wide significant linkage to chromosome 15q has also been observed for major depression by another collaborative group I am a member of. I also have two addictive disorder projects, opiate addiction and nicotine dependence. We have observed genome-wide suggestive linkage to chromosome 14q for opiate addiction and are in the process of analyzing the data from a genome-wide scan for linkage of nicotine dependence. Lastly, since coming to USC, I have joined with Drs. Carlos and Michele Pato to discover genes for both schizophrenia and bipolar disorder using the unique sample they have collected in the Azores.
Levinson,D.F., Evgrafov,O.V., Knowles,J.A., Potash,J.B., Weissman,M.M., Scheftner,W.A., DePaulo,J.R., Jr., Crowe,R.R., Murphy-Eberenz,K., Marta,D.H., McInnis,M.G., Adams,P., Gladis,M., Miller,E.B., Thomas,J., and Holmans,P. (2007). Genetics of recurrent early-onset major depression (GenRED): significant linkage on chromosome 15q25-q26 after fine mapping with single nucleotide polymorphism markers. Am J Psychiatry 164, 259-264.
Samuels,J., Shugart,Y.Y., Grados,M.A., Willour,V.L., Bienvenu,O.J., Greenberg,B.D., Knowles,J.A., McCracken,J.T., Rauch,S.L., Murphy,D.L., Wang,Y., Pinto,A., Fyer,A.J., Piacentini,J., Pauls,D.L., Cullen,B., Rasmussen,S.A., Hoehn-Saric,R., Valle,D., Liang,K.Y., Riddle,M.A., and Nestadt,G. (2007). Significant linkage to compulsive hoarding on chromosome 14 in families with obsessive-compulsive disorder: results from the OCD Collaborative Genetics Study. Am J Psychiatry 164, 493-499.
Fyer,A.J., Hamilton,S.P., Durner,M., Haghighi,F., Heiman,G.A., Costa,R., Evgrafov,O., Adams,P., De Leon,A.B., Taveras,N., Klein,D.F., Hodge,S.E., Weissman,M.M., and Knowles,J.A. (2006). A third-pass genome scan in panic disorder: evidence for multiple susceptibility loci. Biol. Psychiatry 60, 388-401.
Shugart,Y.Y., Samuels,J., Willour,V.L., Grados,M.A., Greenberg,B.D., Knowles,J.A., McCracken,J.T., Rauch,S.L., Murphy,D.L., Wang,Y., Pinto,A., Fyer,A.J., Piacentini,J., Pauls,D.L., Cullen,B., Page,J., Rasmussen,S.A., Bienvenu,O.J., Hoehn-Saric,R., Valle,D., Liang,K.Y., Riddle,M.A., and Nestadt,G. (2006). Genomewide linkage scan for obsessive-compulsive disorder: evidence for susceptibility loci on chromosomes 3q, 7p, 1q, 15q, and 6q. Mol. Psychiatry 11, 763-770.
Wong,W.K., Morse,J.H., and Knowles,J.A. (2006). Evolutionary conservation and mutational spectrum of BMPR2 gene. Gene 368, 84-93.
Wong,W.K., Knowles,J.A., and Morse,J.H. (2005). Bone Morphogenetic Protein Receptor Type II C-Terminus Interacts with c-Src: Implication for a Role in Pulmonary Arterial Hypertension. Am. J Respir. Cell Mol. Biol. 33, 438-446.
Roberts,K.E., McElroy,J.J., Wong,W.P., Yen,E., Widlitz,A., Barst,R.J., Knowles,J.A., and Morse,J.H. (2004). BMPR2 mutations in pulmonary arterial hypertension with congenital heart disease. Eur. Respir. J. 24, 371-374.
Hamilton,S.P., Fyer,A.J., Durner,M., Heiman,G.A., Baisre,d.L., Hodge,S.E., Knowles,J.A., and Weissman,M.M. (2003). Further genetic evidence for a panic disorder syndrome mapping to chromosome 13q. Proc. Natl. Acad. Sci. U. S. A 100, 2550-2555.
Humbert,M., Deng,Z., Simonneau,G., Barst,R.J., Sitbon,O., Wolf,M., Cuervo,N., Moore,K.J., Hodge,S.E., Knowles,J.A., and Morse,J.H. (2002). BMPR2 germline mutations in pulmonary hypertension associated with fenfluramine derivatives. Eur. Respir. J 20, 518-523.
Deng,Z., Morse,J.H., Slager,S.L., Cuervo,N., Moore,K.J., Venetos,G., Kalachikov,S., Cayanis,E., Fischer,S.G., Barst,R.J., Hodge,S.E., and Knowles,J.A. (2000). Familial Primary Pulmonary Hypertension (Gene PPH1) Is Caused by Mutations in the Bone Morphogenetic Protein Receptor-II Gene. Am J. Hum. Genet. 67, 737-744.