Genetic epidemiology of major psychiatric disorders

We have worked for decades on epidemiologic studies, including the first studies showing familial overlap of Bipolar disorder (BD), Schizoaffective disorder and Schizophrenia (SZ), thus anticipating current genetic marker evidence on shared heritability. I also played a major role initiating and collaborating on the NIMH Genetics Initiative, which collected the first large-scale series of patients, relatives, and controls in Bipolar disorder. The Bipolar and Schizophrenia pedigree series I collected as an Intramural NIMH Branch Chief in the 1980s are still in use, and we recently published an article on rare variants associated with BD in those pedigrees and others in PNAS. A major current research activity is on application of the RDoCs concept to psychosis, as a PI on a multi-site collaboration on the study of Bipolar and Schizophrenia Intermediate Phenotypes (BSNIP), which has recently developed a new nosology of psychosis based on various cognitive, electrophysiological, neuropsychiatric, and other phenomena.

1. Gershon ES, Liebowitz JH. Sociocultural and demographic correlates of affective disorders in Jerusalem. J Psychiatr Res. 1975;12(1):37-50. PubMed PMID: 1142308.
2. Mazure C, Gershon ES. Blindness and reliability in lifetime psychiatric diagnosis. Arch Gen Psychiatry. 1979;36(5):521-5. PubMed PMID: 435012.
3. Gershon ES, Hamovit J, Guroff JJ, Dibble E, Leckman JF, Sceery W, Targum SD, Nurnberger JI, Jr., Goldin LR, Bunney WE, Jr. A family study of schizoaffective, bipolar I, bipolar II, unipolar, and normal control probands. Arch Gen Psychiatry. 1982;39(10):1157-67. Epub 1982/10/01. PubMed PMID: 7125846.
4. Ament SA, Szelinger S, Glusman G, Ashworth J, Hou L, Akula N, Shekhtman T, Badner JA, Brunkow ME, Mauldin DE, Stittrich AB, Rouleau K, Detera-Wadleigh SD, Nurnberger JI, Jr., Edenberg HJ, Gershon ES, Schork N, Bipolar Genome S, Price ND, Gelinas R, Hood L, Craig D, McMahon FJ, Kelsoe JR, Roach JC. Rare variants in neuronal excitability genes influence risk for bipolar disorder. Proc Natl Acad Sci U S A. 2015;112(11):3576-81. doi: 10.1073/pnas.1424958112. PubMed PMID: 25730879 PMCID: PMC4371952.

Rare Copy Number Variants (CNVs)

Rare CNVs arise as new mutations very frequently at specific genomic locations, and among these are the most potent risk factors known for several psychiatric disorders. For nearly 10 years, I have been actively involved in studies of CNVs in SZ and BD, including studies on QC of CNVs, and reports of CNV burden in BD and Autism Spectrum Disorder, and of the role of de novo CNVs as a major epidemiological contributor to risk of BD and SZ.

1. Christian SL, Brune CW, Sudi J, Kumar RA, Liu S, Karamohamed S, et al. Novel submicroscopic chromosomal abnormalities detected in autism spectrum disorder. Biol Psychiatry. 2008;63(12):1111-7. PMCID: PMC2440346.
2. Zhang D, Cheng L, Qian Y, Alliey-Rodriguez N, Kelsoe JR, Greenwood T, Nievergelt C, Barrett TB, McKinney R, Schork N, Smith EN, Bloss C, Nurnberger J, Edenberg HJ, Foroud T, Sheftner W, Lawson WB, Nwulia EA, Hipolito M, Coryell W, Rice J, Byerley W, McMahon F, Schulze TG, Berrettini W, Potash JB, Belmonte PL, Zandi PP, McInnis MG, Zollner S, Craig D, Szelinger S, Koller D, Christian SL, Liu C, Gershon ES. Singleton deletions throughout the genome increase risk of bipolar disorder. Mol Psychiatry. 2009;14(4):376-80. doi: 10.1038/mp.2008.144. PubMed PMID: 19114987 PMCID: PMC2735188.
3. Zhang D, Qian Y, Akula N, Alliey-Rodriguez N, Tang J, Bipolar Genome S, Gershon ES, Liu C. Accuracy of CNV Detection from GWAS Data. PLoS One. 2011;6(1):e14511. doi: 10.1371/journal.pone.0014511. PubMed PMID: 21249187 PMCID: PMC3020939.
4. Malhotra D, McCarthy S, Michaelson JJ, Vacic V, Burdick KE, Yoon S, Cichon S, Corvin A, Gary S, Gershon ES, Gill M, Karayiorgou M, Kelsoe JR, Krastoshevsky O, Krause V, Leibenluft E, Levy DL, Makarov V, Bhandari A, Malhotra AK, McMahon FJ, Nothen MM, Potash JB, Rietschel M, Schulze TG, Sebat J. High frequencies of de novo CNVs in bipolar disorder and schizophrenia. Neuron. 2011;72(6):951-63. doi: 10.1016/j.neuron.2011.11.007. PubMed PMID: 22196331 PMCID: PMC3921625.1.

Genetic variation in regulation of functional genomics of human brain

My major collaborator is my former postdoc Chunyu Liu, at University of Illinois at Chicago. He and I and other collaborators performed the first systematic study of genetic regulation of gene expression and methylation in human brain. We used GWAS to reveal quantitative trait loci for expression and methylation, and using Horvaths weighted gene correlation network analysis (WGCNA) we developed reproducible networks of gene expression associated with SZ and BD. We are currently engaged in sequence-based studies of gene regulation, and of somatic mutation in brain in neuropsychiatric disorders.

1. Liu C, Cheng L, Badner JA, Zhang D, Craig DW, Redman M, Gershon ES. Whole-genome association mapping of gene expression in the human prefrontal cortex. Mol Psychiatry. 2010;15(8):779-84. doi: 10.1038/mp.2009.128. PubMed PMID: 20351726 PMCID: PMC3057235.
2. Zhang D, Cheng L, Badner JA, Chen C, Chen Q, Luo W, Craig DW, Redman M, Gershon ES, Liu C. Genetic control of individual differences in gene-specific methylation in human brain. Am J Hum Genet. 2010;86(3):411-9. doi: 10.1016/j.ajhg.2010.02.005. PubMed PMID: 20215007 PMCID: PMC2833385.
3. Chen C, Cheng L, Grennan K, Pibiri F, Zhang C, Badner JA, Members of the Bipolar Disorder Genome Study C, Gershon ES, Liu C. Two gene co-expression modules differentiate psychotics and controls. Mol Psychiatry. 2013;18(12):1308-14. doi: 10.1038/mp.2012.146. PubMed PMID: 23147385 PMCID: PMC4018461.
4. Chen C, Zhang C, Cheng L, Reilly JL, Bishop JR, Sweeney JA, Chen HY, Gershon ES, Liu C. Correlation between DNA methylation and gene expression in the brains of patients with bipolar disorder and schizophrenia. Bipolar Disord. 2014;16(8):790-9. doi: 10.1111/bdi.12255. PubMed PMID: 25243493 PMCID: PMC4302408.
5. Gamazon ER, Badner JA, Cheng L, Zhang C, Zhang D, Cox NJ, Gershon ES, Kelsoe JR, Greenwood TA, Nievergelt CM, Chen C, McKinney R, Shilling PD, Schork NJ, Smith EN, Bloss CS, Nurnberger JI, Edenberg HJ, Foroud T, Koller DL, Scheftner WA, Coryell W, Rice J, Lawson WB, Nwulia EA, Hipolito M, Byerley W, McMahon FJ, Schulze TG, Berrettini WH, Potash JB, Zandi PP, Mahon PB, McInnis MG, Zollner S, Zhang P, Craig DW, Szelinger S, Barrett TB, Liu C. Enrichment of cis-regulatory gene expression SNPs and methylation quantitative trait loci among bipolar disorder susceptibility variants. Mol Psychiatry. 2013;18(3):340-6. doi: 10.1038/mp.2011.174. PubMed PMID: 22212596 PMCID: PMC3601550.