It has been generally accepted that evidence for inherited prediposition to a disease automatically implies involvement of DNA sequence variation (polymorphisms, mutations). Although this research program has been very productive in classical genetic disorders such as sickle cell anemia and Huntington’s disease, application of the DNA sequence-oriented paradigm to complex non-Mendelian diseases such as schizophrenia, asthma, diabetes, multiple sclerosis, among numerous others, has not led to significant breakthroughs thus far. Our laboratory has developed the epigenetic theory of complex disease which is based on two simple postulates: 1) (at least) some epigenetic factors (DNA and chromatin modification) are transmitted from one generation to another, along with the DNA sequences, and the former can account for heritability of (at least) some traits; ii) epigenetic factors play a critical role in the regulation of various genomic functions in the cell. The significant heuristic advantage is that putative epigenetic misregulation of genes, more so than DNA sequence-based ones, can explain a series of universal non-Mendelian features: i) environmental effects; ii) discordance of monozygotic twins; iii) differential susceptibility in males and females; iv) parental origin effects; v) in some complex diseases, fluctuating course and even recovery; vi) presence of familial and sporadic cases and unclear mode of inheritance.
The recently opened Krembil Family Epigenetics Research Laboratory of the Centre for Addiction and Mental Health is fully dedicated to the understanding of the role of epigenetic risk factors in complex diseases. We use a spectrum a molecular techniques from single nucleotide modification analysis to a large scale, full chromosome microarray- based screening for epigenetic changes in affected individuals and controls. Research in psychiatric disorders is the main mandate of the laboratory but we also interested in other non-Mendelian diseases such as diabetes and Crohn’s disease. It is expected that identification of epigenetic changes in human diseases will provide the basis for new, epigenetic modification- based therapeutic approaches.
1. Gagliano SA, Ptak C, Mak DY, Shamsi M, Oh G, Knight J, Boutros PC, Petronis A. Allele-Skewed DNA Modification in the Brain: Relevance to a Schizophrenia GWAS. Am J Hum Genet. 2016; 98(5):956-62.
2. Labrie V, Buske OJ, Oh E, Jeremian R, Ptak C, Gasiūnas G, Maleckas A, Petereit R, Žvirbliene A, Adamonis K, Kriukienė E, Koncevičius K, Gordevičius J, Nair A, Zhang A, Ebrahimi S, Oh G, Šikšnys V, Kupčinskas L, Brudno M, Petronis A. Lactase nonpersistence is directed by DNA-variation-dependent epigenetic aging. Nat Struct Mol Biol. 2016; 23(6):566-73.
3. Oh G, Ebrahimi S, Wang SC, Cortese R, Kaminsky ZA, Gottesman II, Burke JR, Plassman BL, Petronis A. Epigenetic assimilation in the aging human brain. Genome Biol. 2016; 17(1):76.
4. Oh G, Wang SC, Pal M, Chen ZF, Khare T, Tochigi M, Ng C, Yang YA, Kwan A, Kaminsky ZA, Mill J, Gunasinghe C, Tackett JL, Gottesman II, Willemsen G, de Geus EJ, Vink JM, Slagboom PE, Wray NR, Heath AC, Montgomery GW, Turecki G, Martin NG, Boomsma DI, McGuffin P, Kustra R, Petronis A. DNA modification study of major depressive disorder: beyond locus-by-locus comparisons. Biological Psychiatry. 2015; 77(3):246-55.
5. Kriukienė E, Labrie V, Khare T, Urbanavičiūtė G, Lapinaitė A, Koncevičius K, Li D, Wang T, Pai S, Ptak C, Gordevičius J, Wang SC, Petronis A, Klimašauskas S. DNA unmethylome profiling via covalent capture of CpG sites. Nature Communications, 23; 4:2190, 2013.
6. Khare T, Pai S, Koncevicius K, Pal M, Kriukiene E, Liutkeviciute Z, Irimia M, Jia P, Ptak C, Xia M, Tice R, Moréra S, Nazarians A, Belsham D, Wong AHC, Blencowe BJ, Wang SC, Kapranov P, Kustra R, Labrie V, Klimasauskas S, Petronis A. 5-hmC in the brain: abundance in synaptic genes and differences at the exon-intron boundary. Nature Structural and Molecular Biology 19(10):1037-43, 2012.
7. Labrie V, Pai S, Petronis A. Epigenetics of major psychosis: progress, problems, and perspectives. Trends in Genetics 28(9): 427-35, 2012.
8. Kaminsky Z, Tochigi M, Jia P, Pal M, Mill J, Kwan A, Ioshikhes I, Vincent JB, Kennedy JL, Strauss J, Pai S, Wang SC, Petronis A. A multi-tissue analysis identifies HLA complex group 9 gene methylation differences in bipolar disorder. Mol Psychiatry. 17(7):728-40; 2012
9. Petronis A. Epigenetics as a unifying principle in etiology of complex diseases and traits. Nature, 465(7299):721-7; 2010.
10. Kaminsky ZA, Tang T, Wang SC, Ptak C, Oh G, Wong AHC, Feldcamp LA, Virtanen C, Halfvarson J, Tysk C, McRae AF, Visscher PM, Montgomery GW, Gottesman II, Martin NG, Petronis A. DNA methylation profiles in monozygotic and dizygotic Twins. Nature Genetics, 41(2):240-5.
11. Mill J, Tang T, Kaminsky ZA, Khare T, Yazdanpanah S, Bouchard L, Assadzadeh A, Flanagan J, Schumacher A, Wang S-C, Petronis A. Epigenomic profiling reveals DNA methylation changes associated with major psychosis. American Journal of Human Genetics, 82(3): 696-711.
12. Ptak C, Petronis A. Epigenetics and complex disease: from etiology to new therapeutics. Annual Review in Pharmacology and Toxicology. 2008; 48: 48:257-76.