ResearchIn Canada, approximately 250,000 people suffer from schizophrenia, a severe psychiatric disease of unknown origin. Identification of the primary causes would be of critical importance in diagnostic, treatment, and preventative applications in schizophrenia. In an attempt to unlock the primary risk factors for this disease, the last 30 years of research effort has focused on identification of DNA sequence mutations and environmental hazards, but why are these elements believed to be so important?

Like other human diseases, schizophrenia exhibits significant heritability. Twin-based populational studies revealed that 60-70% of predisposition to schizophrenia is due to inherited risk factors. Traditionally, it has been assumed that only DNA sequence controls heritability. Over the last 30 years, numerous molecular genetic studies have been performed in order to identify disease-specific DNA mutations. Despite significant effort, such DNA sequence variants can only explain a minor portion of heritability in psychiatric diseases thus far.

Another potential source of risk for schizophrenia is thought to be environmental. The idea that environmental hazards may act independently or interact with mutant genes is based on the observation that identical (monozygotic) twins, who have virtually identical DNA sequences, quite often exhibit discordance, i.e. only one twin has an illness and the co-twin does not. In schizophrenia, if one twin has the disease there is only a 50% chance the co-twin will also be affected. Traditionally, such discordance is attributed to the “non-shared” environment. The assumption is that there must be some non-genetic factors driving this phenotypic difference, and thus, some environmental exposure unique to one of the twins must be responsible for the presence or absence of the disease. Unfortunately, the particular components of the environment producing the discordance have remained elusive.

We propose that a third group of factors, namely epigenetic marks, may play a critical role in causing schizophrenia. Epigenetics refers to the regulation of various genomic functions by heritable and potentially reversible chemical modifications of DNA and chromatin structure, rather than changes in DNA sequences. In other words, epigenetic factors do not change the structure of DNA, but affect the way genes function, often reducing or enhancing the product a gene normally produces. Aberrant cytosine modifications, which are the target of study in our lab, could have the same effect as DNA mutations since proper epigenetic regulations are critical; precise timing, location, and level of gene expression are crucial for normal cell function.

We performed a detailed re-analysis of the scientific literature on psychiatric diseases and concluded that numerous features of schizophrenia are consistent with putative epigenetic dysregulations. Such features include the age of onset between 16 and 25 years of age (which follow major hormonal changes in the body of a teenager), discordance between monozygotic twins, differences between males and females in the clinical course of the disease, disease fluctuations (remission and relapse), and the cases of partial recovery. The epigenetic theory can also explain the inherited basis of schizophrenia, providing a non-DNA sequence-based mechanism of heritability. Finally, epigenetics can offer a fresh alternative approach to understand how environmental hazards increase disease risk. Some environmental factors do interact with epigenomes and leave epigenetic vestiges that may last for long periods of time.

At the Krembil Family Epigenetics Laboratory, we perform large-scale epigenome-wide studies of schizophrenia and other psychiatric diseases. We use powerful and informative high-throughput technologies, such as microarrays and next generation sequencing, to identify epigenetic aberrations that are involved in the disease etiology. We also develop new technologies and experimental tools to test and characterize the role of cytosine modifications in the context of human diseases, as well as basic biology. We are a cutting edge lab working towards identifying causal, rather the correlational, factors in human morbid biology.

Our effort may contribute to the understanding of the fundamental etiological principles of schizophrenia, and may also be used to improve its clinical management. First, molecular epigenetic markers would serve as novel pre-symptomatic diagnostic tools, enabling physicians to identify individuals at risk for schizophrenia and enroll them in prevention and early intervention programs. Second, identification of the primary molecular causes of schizophrenia will lead to new therapeutic opportunities through rational drug design, such as high-throughput, high-content screening of small molecules that will rectify the specific epigenetic problem in specific patients (‘custom’ drugs). Third, the research principles developed in our studies will facilitate epigenomic studies of other psychiatric and non-psychiatric diseases. Fourth, our schizophrenia epigenomics project may also contribute to the revision of the current paradigm of human morbid biology, which attempts to explain complex disease exclusively by DNA sequence variation and environmental factors.

Download the Tapscott Chair Final Report From Dr. Art Petronis 2015-2020 here.
Download the Tapscott Chair Research Plans for 2015-2020 here.
Download the Tapscott Chair Impact Summary for 2015-2016 here.
Download the Tapscott Chair Impact Summary for 2010-2015 here.

Currently there are seven graduate students receiving training in the lab.

Topics Include:

  • Epigenetics and cancer
  • Genetic – epigentic interactions
  • Epigenetics and complex disease
  • Epigenomics of DNA recombination
  • Epicgenetics and disease
  • Epicgenetic-genetic interactions
  • Epigenomics of major psychosis
  • Meiotic mapping in disease
  • Animal models and epigenetics
  • Epigenomic methods

Selected Papers:

  1. Petronis A. Epigenetics as a unifying principle in etiology of complex diseases and traits. Nature, 465(7299):721-7; 2010.
  2. Vedadi M, Barsyte-Lovejoy D, Liu F, Rival-Gervier S, Allali-Hassani A, Labrie V, Wigle TJ, Dimaggio PA, Wasney GA, Siarheyeva A, Dong A, Tempel W, Wang SC, Chen X, Chau I, Mangano TJ, Huang XP, Simpson CD, Pattenden SG, Norris JL, Kireev DB, Tripathy A, Edwards A, Roth BL, Janzen WP, Garcia BA, Petronis A, Ellis J, Brown PJ, Frye SV, Arrowsmith CH, Jin J. A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells. Nat Chem Biol. 2011; 7(8):566-74.
  3. 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
  4. Labrie V, Pai S, Petronis A. Epigenetics of major psychosis: progress, problems, and perspectives. Trends in Genetics 28(9): 427-35, 2012.
  5. Cortese R, Kwan A, Lalonde E, Bryzgunova O, Bondar A, Wu Y, Gordevicius J, Park M, Oh G, Kaminsky Z, Tverkuviene J, Laurinavicius A, Jankevicius F, Sendorek D, Haider S, Wang SC, Jarmalaite S, Laktionov P, Boutros PC, Petronis A. Epigenetic markers of prostate cancer in plasma circulating DNA. Human Molecular Genetics 21(16): 3619-31; 2012.
  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. 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.
  8. 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.
  9. Pal M, Ebrahimi S, Oh G, Khare T, Zhang A, Kaminsky ZA, Wang SC, Petronis A. High precision DNA modification analysis of HCG9 in major psychosis. Schizophr Bull. 2016 Jan;42(1):170-7.
  10. 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.
  11. 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.
  12. 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.
  13. Oh G, Ebrahimi S, Carlucci M, Zhang A, Nair A, Groot DE, Labrie V, Jia P, Oh ES, Jeremian RH, Susic M, Shrestha TC, Ralph MR, Gordevičius J, Koncevičius K, Petronis A. Cytosine modifications exhibit circadian oscillations that are involved in epigenetic diversity and aging. Nature Communications 2018 Feb 13;9(1):644.


Petronis A and Mill J (eds). Brain, Behavior and Epigenetics.

Series: Epigenetics and Human Health. Springer, 2011; 317p.