Literature review of the candidate genes, Supplemental Digital Content 2
LRRTM1 (Leucine Rich Repeat Transmembrane Neuronal 1)
The gene region was first discovered by linkage (Francks, Fisher et al. 2002, Francks, DeLisi et al. 2003a,
Francks, DeLisi et al. 2003b) and later the gene was associated with schizophrenia and handedness (Francks,
Maegawa et al. 2007). Schizophrenia patients are statistically more frequently non-right-handed (Sommer,
Ramsey et al. 2001) which points to a possible link between handedness and schizophrenia. Handedness is
reflected in brain structural or functional LR asymmetry, the central sulcus is being regarded as a potential
anatomical correlate of hand preference (Renteria 2012). Therefore, the genes, responsible for the asymmetric
development of brain areas that govern the hand use, might also be important for LR asymmetry, in other brain
structures, that is affected in case of schizophrenia. LRRTM1 is believed to be one of such genes. Its specific
role in brain function is still not completely clear, but the protein product seems to be important for maintaining
synaptic integrity; mice with this gene being knocked out show significant cognitive impairment (Linhoff,
Lauren et al. 2009, Takashima, Odaka et al. 2011).
FOXP2 (Forkhead Box P2)
This is a transcription factor, expressed in the human brain, mutated in case of Speech-language disorder 1 (Lai,
Fisher et al. 2001). Two SNP in this gene are associated with hemispheric asymmetries for speech perception
(Ocklenburg, Arning et al. 2013). Since language areas of the human brain are asymmetric on the LR axis, and
since structural and functional LR asymmetry is compromised in case of schizophrenia, language and
schizophrenia might have common mechanisms.
There is also additional opinion among many authors that language, cerebral asymmetry and schizophrenia are
specific only to humans, appeared with the emergence of Homo sapiens and therefore they could all depend on
a common genetic factor (reviewed in (Crow 2008)). This point of view – one language-schizophrenia gene
present only in humans – is rather debatable, since chimpanzees and bonobos also use various ways of
language-like communication (Corballis 2002, Pollick, de Waal 2007), while language cortical areas are present
and are asymmetric in all great apes (Cantalupo, Hopkins 2001, Spocter, Hopkins et al. 2010) (some authors
contest these findings (Schenker, Hopkins et al. 2010, Chance, Sawyer et al. 2012)). Moreover, even frogs
possess a vocal generator localized asymmetrically in the left brain hemisphere (Bauer 1993), suggesting early
evolution of common prerequisites for the vocal communication in all vertebrates. The role of FOXP2 in vocal
production and learning has strong parallels between humans and birds: the reduced level of expression of
FOXP2 in basal ganglia by RNAi leads to inaccurate vocal imitation in zebra finches (Haesler, Rochefort et al.
2007). Also, FOXP2 expression in the developing brain of mouse and human was found to be strikingly similar
(Lai, Gerrelli et al. 2003). Hence, cerebral lateralization and vocal communication in lower animals, although
not as evolved as in humans, are not specific only to humans. Moreover, researchers have managed to create
rodent models with elements of schizophrenia (Powell, Miyakawa 2006). If the schizophrenia gene (or genes)
has some role in cerebral asymmetry and language, then the gene is present not only in humans.
The previous genetic studies of FOXP2 in schizophrenia patients were somewhat contradictory (Sanjuan,
Tolosa et al. 2005, Sanjuan, Tolosa et al. 2006, Tolosa, Sanjuan et al. 2010, Spaniel, Horacek et al. 2011, Li,
Zeng et al. 2012), not always reporting significant association between schizophrenia and SNPs in FOXP2. On
the other hand, DISC1 (Disrupted in schizophrenia 1) gene, one of the best candidates for genes, playing a role
in schizophrenia, was found to be inhibited by the transcription factor FOXP2 (Walker, Hill et al. 2012), which
traces another link between FOXP2 and schizophrenia. Also, FOXP2 appears to regulate neuronal maturation
and migration during brain development in mice, although the results of different studies indicate either
negative (Clovis, Enard et al. 2012), or positive (Vernes, Oliver et al. 2011) regulation of neuronal
development. Finally, FOXP2 was found to be expressed in the cortical plate, basal ganglia, thalamus, inferior
olives and cerebellum in the developing brain of mouse and human. These findings support a role for FOXP2 in
the development of corticostriatal and olivocerebellar circuits involved in motor control, and this in turn can be
related to the speech (articulation) deficits, and probably also to linguistic and grammatical (cognitive)
impairments, observed in Speech-language disorder 1 (Lai, Gerrelli et al. 2003). Incorrect development of brain
areas, involved in some aspects of the language faculty, could have consequences on development of
asymmetric areas of the brain. This can make FOXP2 a candidate of choice for a gene, important in LR
asymmetry of the human brain and in schizophrenia.
LMO4 (Lim Domain Only 4)
LMO4 is required for neural tube closure, neural crest formation, as well as for maturation and migration of
neurons in the developing brain cortex in mice and frogs (Lee, Jurata et al. 2005, Asprer, Lee et al. 2011,
Ochoa, Salvador et al. 2012). Additionally, this transcription co-factor was found to be consistently
asymmetrically expressed in the perisylvian human cortex (Sun, Patoine et al. 2005) that includes Wernicke’s
language comprehension area, one of the most clearly asymmetric areas of the human brain (Renteria 2012).
This expression asymmetry – higher expression on the right side – was found only in 12-, 14-, and 17-week old,
but not in 19-week old human embryonic brains, so LMO4 could be one of the genes, involved in development
of LR asymmetry of the human brain cortex. Moreover, LMO4 knockout or suppression in mice points to a role
of LMO4 in formation of cortical areas, important for sensory perception and motor coordination (Kashani, Qiu
et al. 2006, Huang, Kawase-Koga et al. 2009), and LMO4 knockdown only on the right side in embryonic
cortices in mice, that normally do not exhibit brain functional asymmetry, results in the right paw preference, as
well as suppression of early neurogenesis in the right hemisphere (Li, Bian et al. 2013). Again, if this gene’s
function is compromised, it could lead to abnormalities in LR asymmetry of the brain and therefore to
schizophrenia.
PCDH11X/Y (protocadherin 11 X-linked and protocadherin 11 Y-linked gene pair)
The gene pair is found in the region of homology between the human sex chromosomes (Xq21.3/Yp11.2), is
expressed predominantly in the brain – in the adult, as well as in the embryo – and seems to take part in the
brain circuit formation and maintenance by determining the cell-cell recognition (Blanco, Sargent et al. 2000,
Kim, Yasuda et al. 2011, Priddle, Crow 2012). A role in schizophrenia for this gene pair was proposed by the
British psychiatrist Timothy J. Crow, who also proposed the notion that schizophrenia is a genetic disorder of
altered LR asymmetry of the brain (Crow, Ball et al. 1989, Crow 2002, Crow 2008). The argument of T.J. Crow
is the following: schizophrenia is a human-specific illness; language is a human-specific faculty; in
schizophrenia, LR asymmetry of the cortical structures is reduced or reversed; language ability is determined by
the highly asymmetric brain structures in humans; schizophrenia therefore could be the consequence of humans
acquiring the faculty of language; schizophrenia is an illness, arising from altered LR asymmetry of the brain;
LR brain asymmetry profiles in men and women are different; in men, the age of onset of schizophrenia is
earlier and the incidence of the illness is more frequent (Boshes, Manschreck et al. 2012, Cascio, Cella et al.
2012); sex-chromosome aneuploidies are characterized by verbal and spatial deficits, related to LR brain
asymmetry alteration; the genetic factor, underlying schizophrenia, language, and LR brain asymmetry has to be
unique to humans and has to be on sex chromosomes, but in a region of similarity between the two sex
chromosomes (so there would be two similar, but not identical versions of the gene). The only such genetic
candidate is the PCDH11X/Y gene pair: because it appeared as a result of duplication from X chromosome at
the time of the chimpanzee and hominid separation, it is now present only in humans (Williams, Close et al.
2006). Each gene in the pair has numerous (5 to 16) changes in the coding sequence, leading to amino acid
substitutions, in comparison with the sequence of PCDH11X in the great apes. Because the gene pair is
expressed in the brain, male and female neurons have a different gene content: men have PCDH11X and
PCDH11Y and women have 2 copies of PCDH11X, since the gene escapes X-chromosome inactivation (Lopes,
Ross et al. 2006). Both genes are highly expressed in the developing cerebral cortex: in fetal (12–34 weeks
postconception) and adult human brains PCDH11X/Y expression was detected in developing neurons as they
migrated from the ventricular zone, through the subplate and into the cortical plate; both proteins interact with
β-catenin, a protein that plays a role in determining axis formation and regulating cortical size (reviewed in
(Priddle, Crow 2013)).
WNT pathway, which includes β-catenin and GSK3β (glycogen synthase kinase 3 beta), was found to be
directly implicated in schizophrenia (reviewed in (Lovestone, Killick et al. 2007, Emamian 2012)) and in
cerebral asymmetry: WNT pathway determines habenula asymmetry in zebrafish (Husken, Carl 2012). In
particular, atypical and typical antipsychotic drugs alter GSK3 (GSK3α and β) activity, as do drugs that induce
psychosis; many of the genes statistically associated with schizophrenia directly or indirectly regulate GSK3
activity (Lovestone, Killick et al. 2007). GSK3β is also statistically associated with schizophrenia and other
psychiatric disorders (Benedetti, Bernasconi et al. 2004, Li, Mo et al. 2011). This indicates a possible role of
PCDH11X/Y gene pair in determining cerebral asymmetry and playing a role in pathogenesis of schizophrenia.
Genetic studies of this gene pair in schizophrenia patients were not numerous and did not show an involvement
of the gene pair in schizophrenia. In particular, T.J. Crow and colleagues (Giouzeli, Williams et al. 2004) did
not find disease-causing mutations in the gene pair in 214 affected individuals, when compared to their
unaffected relatives from 99 families, using the DHPLC. Also, an association study of two non-synonymous
SNPs in the PCDH11Y gene did not show any association with schizophrenia (Durand, Kappeler et al. 2006).
Nevertheless, the gene pair deserves attention when studying the genetics of schizophrenia in the light of altered
LR asymmetry of the brain.
SRY (sex determining region Y)
This is a transcription factor, found on Y chromosome, which participates in the testis determination (Marshall
Graves 2002, Wilhelm, Palmer et al. 2007). Known mutations in this gene lead to gonadal dysgenesis (Filges,
Kunz et al. 2011). Additionally, the gene evolutionally derives from the X chromosome-linked SOX3 (SRYbox 3) gene (Marshall Graves 2002), part of the SOX gene family, responsible, among other functions, for the
nervous system development. SRY might therefore confer different properties to male neurons, in comparison
with female neurons, expressing only SOX3 (Turner, Ely et al. 2011). In particular, SRY may play a role as a
positive regulator of dopamine synthesis and metabolism in the human male midbrain, being expressed in a subpopulation of tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta and in the ventral
tegmental area (Czech, Lee et al. 2012). Also, SRY was found to be expressed in the rodent substantia nigra, in
dopaminergic neurons, and regulates tyrosine hydroxylase expression (Dewing, Chiang et al. 2006). Therefore,
SRY could determine a different pattern of activity in dopaminergic neurons in the male brain and different
brain morphology in general in men, in comparison with women. This can be linked to the fact that
schizophrenia has a different incidence in male and female patients (Boshes, Manschreck et al. 2012, Cascio,
Cella et al. 2012): SRY could play a role in a “male-specific” schizophrenia phenotype (in a way, similar to
PCDH11Y), which tends to have an earlier age of onset and a greater incidence of the illness. The SRY gene,
apart from possibly determining the different brain morphology in men, could also determine the male-specific
profile of LR brain asymmetry. In addition, the involvement of the dopaminergic system in schizophrenia is
well characterized (Freedman 2003), which adds another possible link between schizophrenia and SRY.
Although known mutations lead to gonadal dysgenesis, sex-chromosome aneuploidies are characterized by
verbal and spatial deficits, related to LR brain asymmetry abnormalities (reviewed in (Crow 2008)). This
indicates that these verbal and spatial deficits, related to LR brain asymmetry abnormalities, could be due to a
loss of SRY. In case of this gene, the genetic transmission would be in the males only within a family.
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