schizophrenia lies in the collective effect of hundreds or thousands of common
polygenic variants, each contributing small effects.^46
One of the most interesting results of GWAS for schizophrenia was the impli-
cation of the major histocompatibility complex (MHC) genes, encoding proteins
necessary for the immune system to recognize foreign substances, in the pathogen-
esis of the disease.^47 Other interesting genes found to be associated with schizo-
phrenia in GWAS are as follows: transcription factor 4 (TCF4) gene (has a role in
neurodevelopment); neuregulin 1 (NRG1) gene (has a role in the regulation of
expression and activation of glutamate receptors, neuronal migration, and oligo-
dendrocyte development); the disrupted-in-schizophrenia (DISC)locus; zinc finger
804A (ZNF804A) gene, showing significant ethnical association differences (for
exp. a significant association in Danish and Russian population, not in Irish,
Japanese, less in Chinese); etc.^48 It is interesting that there are important ethnical
genetic variations related also to other psychiatric diseases and disorders, which
may significantly influence the metabolism and action of psychotropic drugs in
different ethnic groups.^49
3.3 The Role of Environmental Exposures and Epigenetics
in Predisposition to Schizophrenia
The predisposition to psychiatric diseases, such as schizophrenia, is likely to be a
product of the interplay of genetic characteristics, epigenetic modifications, and
environmental exposures. It is interesting that monozygotic twins are concordant
for schizophrenia in only 45 % of cases despite having identical DNA.^50 Some
environmental exposures have been associated with psychiatric disease. For exam-
ple, stress, especially early life trauma (child abuse and neglect), is linked to many
psychiatric illnesses, probably by inducing the epigenetic modifications in gene
expression.^51
The beautiful illustration for the importance of genetics, but not only, in the
predisposition and development of schizophrenia is the famous case of “Genain
quadruplets,” identical female quadruplets born in 1930, all of whom have schizo-
phrenia.^52 The monozygotic quadruplets shared the same genetic predisposition to
schizophrenia, and they were raised in the same dysfunctional family.
(^46) International Schizophrenia Consortium et al. ( 2009 ).
(^47) Shi et al. ( 2009 ) and Stefansson et al. ( 2009 ).
(^48) Ozomaro et al. ( 2013 ).
(^49) Silva ( 2013 ).
(^50) Ozomaro et al. ( 2013 ).
(^51) Ozomaro et al. ( 2013 ).
(^52) Rosenthal ( 1963 ).
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