Neuregulin I: A Gene Linking Mental Illness and Creativity?

Caleb He1

Steven Lippmann, M.D.2

  1. University Student, University of Louisville, School of Arts and Sciences, Louisville, KY
  2. Emeritus Professor, University of Louisville, School of Medicine, Louisville, KY

Corresponding Author

Steven Lippmann, M.D.

University of Louisville School of Medicine

401 East Chestnut Street, #610

Louisville, KY 40202


The neuregulin 1 (NRG1) gene has associations with psychotic symptoms in individuals with schizophrenia.1High levels of creativity and intelligence are other possible polymorphisms associated with this gene. This may partially explain the persistence of schizophrenia in the gene pool despite adverse health effects affecting patients with this condition.

Among 200 subjects with high intellectual achievement (mean IQ = 124.7, SD = 9.5), those with the promoter gene for the NRG1 genotype had higher creativity scores as compared to controls.2 This may be the only known experiment demonstrating a correlation between positive psychological function and polymorphisms associated with severe mental illness.2

Low latent inhibition (LI), which refers to the inability to distinguish the relevance between novel and familiar stimuli, is associated with NRG1. People with schizophrenia demonstrated a low or absent LI.3 There is also a link between high IQ and low LI with greater creativity; high-IQ university students with excellent creative achievement were seven times more likely to have low LI.4 Creative achievement and psychotic tendencies might be positively correlated.

Persons with schizophrenia and also high intelligence often have less disorganization and better-preserved functioning. Patients with schizophrenia and superior premorbid and current IQ (mean = 120) performed just as well on neurocognitive tests as healthy controls with similar scores.5

 Individuals affected by schizophrenia have elevated levels of NRG1 and receptor ERBB4 activity in the prefrontal cortex.6 NRG1 and ERBB4 receptors play a significant role in regulating neurotransmission within the prefrontal cortex.7,8 The prefrontal cortex has a critical role in creativity;9,10 individuals with decreased prefrontal cortex function due to focal brain injury can have evidence of creative activity. This may be explained by the prefrontal cortex’s association with LI capabilities.11

Schizophrenia affects approximately 1% of all populations, but an elevated risk of schizotypal symptoms exists in first-degree relatives of individuals with schizophrenia.12 Genes coding for serious illnesses in homogeneous carriers may confer beneficial, adaptive traits to relatives who are heterozygous carriers.13 Perhaps increased creativity and intelligence is one of these traits. Parallels include that sickle-cell anemia can confer tolerance to malarial infection,14 Ashkenazi Jewish carriers of Tay-Sachs genes have elevated resistance against tuberculosis,15 and heterozygote carriers of cystic fibrosis have decreased susceptibility to cholera.16,17

These observations indicate the need for further research into the role of beneficial traits for survival of people with schizophrenia as a condition counter to evolutionary selection. Any correlation between increased creativity and heterozygous carriers of schizophrenia remains yet unclarified.


  1. Yang JZ, Si TM, Ruan Y, et al: Association study of neuregulin 1 gene with schizophrenia. Molecular Psychiatry 2003; 8:706–709.
  2. Kéri S: Genes for psychosis and creativity: a promoter polymorphism of the neuregulin 1 gene is related to creativity in people with high intellectual achievement. Psychological Science 2009; 20(9):1070-1073.
  3. Rascle C, Mazas O, Vaiva G, et al: Clinical features of latent inhibition in schizophrenia. Schizophrenia Research 2001; 51:149-161.
  4. Carson SH, Peterson JB, Higgins DM: Decreased latent inhibition is associated with increased creative achievement in high-functioning individuals. Journal of Personality and Social Psychology 2003; 85(3):499-506.
  5. Černis E, Vassos E, Brébion G, et al: Schizophrenia patients with high intelligence: A clinically distinct sub-type of schizophrenia? European Psychiatry 2015; 30(5):628-632.
  6. MacCabe J, Brébion G, Reichenberg A: Superior intellectual ability in schizophrenia: neuropsychological characteristics. Neuropsychology 2012; 26(2):181-190.
  7. Chong VZ, Thompson M, Beltaifa S, et al: Elevated neuregulin-1 and ErbB4 protein in the prefrontal cortex of schizophrenic patients. Schizophrenia Research 2008; 100(1-3):270-280.
  8. Woo RS, Li XM, Tao YM, et al: Neuregulin-1 Enhances Depolarization-Induced GABA Release. Neuron 2007; 54(4):599-610.
  9. Stefansson H, Petursson H, Sigurdsson E, et al: Neuregulin 1 and Susceptibility to Schizophrenia. American Journal of Human Genetics 2002; 71(4):877-892.
  10. Dietrich A: The cognitive neuroscience of creativity. Psychonomic Bulletin & Review 2004; 11:1011-1026.
  11. Wei DT, Yang JY, Li WF, et al: Increased resting functional connectivity of the medial prefrontal cortex in creativity by means of cognitive stimulation. Cortex 2014; 51:92-102.
  12. Walter EE, Fernandez F, Snelling M, et al: Genetic Consideration of Schizotypal Traits: A Review. Frontiers in Psychology 2016; 7:1769.
  13. Withrock IC, Anderson SJ, Jefferson MA, et al: Genetic diseases conferring resistance to infectious diseases. Genes & Diseases 2015; 2(3):247-254.
  14. Ferreira A, Marguti I, Bechmann I, et al: Sickle Hemoglobin Confers Tolerance to Plasmodium Infection. Cell 2011; 145(3):398-309.
  15. Spyropoulos B, Moens PB, Davidson J, et al: Heterozygote advantage in Tay-Sachs carriers? American Journal of Human Genetics 1981; 33(3):375-380.
  16. Gabriel SE, Brigamn KN, Koller BH, et al: Cystic fibrosis heterozygote resistance to cholera toxin in the cystic fibrosis mouse model. Science 1994; 266(5182):107-109.
  17. Asimi A: “Cystic fibrotics could survive cholera, choleraics could survive cystic fibrosis”; hypothesis that explores new horizons in treatment of cystic fibrosis. Medical Hypotheses 2015; 85(6):715-717.