B) the Brain?
Autistic savants sometimes have mental abilities which are almost unbelievable.
One calculated the cube root of a 6 figure number; one could double
a 7 digit number 24 times in several seconds; one blind boy incapable
of tying shoes could play any piece of music like a professional after
one listen, some produce wonderful artwork as children, and one could
give the exact time of day to the second without a clock (even mumbling
in his sleep). Are genes responsible for autism? Although at some level,
genes are responsible for virtually everything in the body, it may be
the environment which changes which genes are active.
The brain's activity is not only guided by its genetic makeup, but also
by experience. Experience changes the structure and activity of the
brain (nurture determines nature)and these changes then affect future
interactions with the environment (more nurture). For example; drug
abuse can alter neurotransmitter secretion patterns and the loss of
limb causes a reorganization of neuronal projections onto the sensory
cortex. In children, damage to the left hemisphere causes the right
to take over the language capabilities and the commissures in children
(but not adults) enlarge in response to a damaged corpus callosum to
allow communication between hemispheres. One child even suffered the
removal of his entire left hemisphere (due to deterioration) but later
scored above average on intelligence tests, completed college and grad
school, and became an executive even though half his skull is full of
cerebrospinal fluid only.
It should be stressed that although a specific feature of the brain
might be biological and involve genes, it is not necessarily an inherited
3) Interaction between Nature and Nurture
Genes commonly interact with the environment before determining phenotype.
Frequently the most important question is not whether a given feature
is due to nature or nurture, but rather in what way have nature and
nurture interacted to produce this phenotype. In the following examples,
note that the genes do not determine the characteristics of the individual
themselves: individuals in one environment would develop one way, while
those in a different environment would develop a different way.
In humans, nutrition obviously affects final height and brain development,
traits which are also affected by genetic makeup. The condition xeroderma
pigmentosum can lead to skin cancer after sun exposure but humans who
inherit this gene can, by staying out of the sun, prevent cancer.
All infants born in the U.S. are tested for phenylketonuria. If a child
has this genetic disorder, there is an amino acid byproduct which they
cannot break down. It accumulates to levels in their brain which will
cause retardation. However, children who are placed on a special diet
The presence of certain DRD2 receptors may predispose an individual
to a variety of addictions and genes affecting alcohol metabolism can
predispose an individual to alcoholism. Obviously neither of these phenotypes
will be displayed if the individual avoids alcohol and drugs.
4) Nature can Influence Nurture
Anxiety, temperament, harm-avoidance, risk-taking, shyness, sexuality,
libido are not only aspects of personality which have a genetic component
(nature), they also influence the life situations we later find ourselves
in (nurture). For example, there may be a genetic component in determining
the degree of colic in infants. What effect does extreme colic in a
child have on parental interaction with the child? Can anyone say that
parents would treat a happy child and a child who is always crying exactly
the same? If not, then the environment of the child (nurture) will be
influenced by his or her nature.
5) Nature and Nurture are difficult to study separately
Often the nature/nurture distinction is difficult since relatives often
grow up in similar environments. For example, one study once concluded
the following that if one individual is homosexual, the likelihood of
an identical twin being homosexual is 52%, a fraternal twin 22%, and
nonrelated adopted sibling of same age 11%. Does this answer the question
as to whether sexuality is determined by genes or the environment? No.
Not only does genetic relatedness decrease as one considers, identical
twins, fraternal twins, and adopted siblings, the shared aspects of
their environment might also decrease as well.
Nurture can determine nature, nature can determine nurture, nature and
nurture must interact to produce some phenotypes, and the two are difficult
to study separately. In studying behavior and the brain, some traits
may have a strong genetic component while others primarily determined
by the environment.
--A 1997 book raised an interesting question. There are many genes which
interact with environmental variables to control height, producing a
Bell curve of phenotypes. Even if only the upper 1% of the curve are
called giants, there are individuals in the upper third of the distribution
that have a number of the tall alleles and share some of the phenotype.
Does this principle apply to personality traits?
--Is a sad personality a shadow form of depression?
--Is hypomania (over-elation) with its upswings and downswings a shadow
form of bipolar disorder in which the swings can be devastating?
--Is intermittent rage disorder a shadow form of more psychotic forms
--Is hyperactivity in adults a shadow form of attention deficit disorder?
--Is a lifetime of being socially awkward a shadow form of autism?
If these personality traits are influenced by multiple genes, what would
mild forms of these disorders look like? Would it ever be helpful to
have a bit of the elation of mania or be a bit pessimistic as in depression
or be not too slow to anger? What shadow syndromes might you have?
OTHER ASPECTS OF BEHAVIOR WHICH CAN BE MODIFIED THROUGHOUT LIFE
1) fetal environment
A number of factors can affect the development of a fetus' brain during
development such as alcohol, cocaine, lead, and toxic compounds of metabolism
(i.e. in phenylketonuric women who aren't sticking to their special
diet). Fetal alcohol syndrome often includes lifelong brain abnormalities,
including retardation. "Crack babies" undergo withdrawal and
schools report them to be withdrawn, impulsive, and hyperactive. Events
at birth can affect the fetal brain such as low oxygen (cocaine may
also cause this).
Similar fetuses exposed to different hormones will express different
behaviors; some of these hormones may come from a maternal disorder,
anabolic steroids or other medication, etc.
3) critical periods
Much of the nervous system is not "hard wired" but develops
according to early inputs. For some traits, critical stimuli must occur
during a certain developmental stage or else normal development can
never be attained.
a) Vision: Covering an eye or leaving a crossed eye uncorrected during
the first two years of life
b) Language: If language does not develop by a certain stage (often
about age 6), it will never be normal. Some children have been raised
in isolation (even as part of experiments: an Egyptian pharaoh wanted
to determine if Egyptian was humanity's innate language, a Scottish
king had similar ideas about Hebrew). Children who gradually become
deaf by the age of 2 but were exposed to language learn sign language
more quickly than those deaf from birth.
c) Attachment: there is an optimal period shortly after birth in which
a young animal attaches to a mother (or imprints on any figure in some
species) if normal development is to occur afterwards.
d) Sexual differentiation: in 4 mammals studied (including rhesus monkey),
there is a critical period for the effects of sex hormones on the brain.
In children (and to a lesser degree in adults although women fare better
than men) the brain retains plasticity: brain areas may compensate for
damage in other areas and perform processing that they otherwise would
4) infant care and beyond:
In mice, neurons are smaller and there are fewer glial cells when mice
mature in solitary confinement; neurological development (and weight
gain) is more rapid in animals (including human babies) that are handled.
Unresponsive mothers may increase "insecure attachment" in
their children (from human and primate studies) in which the young are
less likely to explore a new environment and more easily frightened;
secure attachment has been shown to promote social competence in toddlers.
In sad cases where children have been raised in neglect, children are
often withdrawn, frightened, even speechless; despite adoption, they
may have permanent psychological scars. Monkeys raised in total isolation
react aggressively to other monkeys; most were incapable of mating as
adults; artificially impregnated females often neglectful, cruel, or
even murderous of children; most abusive parents admit that they had
also been abused.
The frequency of psychological disorders (e.g. depression, anxiety,
post-traumatic distress disorder) increases after traumatic experiences
such as a natural disaster, war, or a sexual assault.
These are examples of how nurture can become nature--the early environment
of a child may guide brain development during critical periods and thus
become hard wired in the brain.
GENES, PERSONALITY, AND BEHAVIOR
NEUROTRANSMITTERS WHOSE RECEPTORS ARE GPCRs
While the messages which spread along a nerve cell electrical, the messages
which pass from nerve cells to muscle cells, gland cells, or other nerve
cells are chemical messages, transmitted by molecules called neurotransmitters
and neuropeptides. These molecules would be useless as messengers if
the cells receiving these messages did not have receptors for neurotransmitters
and neuropeptides. G protein coupled receptors (GPCRs) are the receptors
for most of these signals, and they mediate the signals of the nervous
system which result in muscle contraction, hormone secretion, sensory
awareness, emotions, memory, and personality.
The neurotransmitter dopamine is involved in the perception and pursuit
of pleasure. It is involved in almost every type of addiction and dopamine
treatment can decrease addiction. Its release increases sex drive, is
a factor in orgasm, and may cause premature ejaculation. Higher than
normal levels occur through cocaine use, sexual activity, periods of
increased sexual receptivity, and in response to testosterone. Much
of the feeling of euphoria associated with cocaine use results from
the blocking of the reabsorption of dopamine. Since dopamine receptors
are expressed in both the brain and on white blood cells, there may
be a link between personality and immune function (Czermak, 2004).
There are a number of dopamine receptors (DRD1 through DRD5). Different
alleles of these receptor genes affect a number of aspects of brain
function ranging from neurological disorders to normal personality traits.
DRD1 receptors are expressed in the brain's nucleus accumbens, caudate
nucleus, and the olfactory tubercle and are also expressed in the ovary.
Dopamine is used in the kidney to regulate sodium and DRD1 mutations
can affect sodium transport (OMIM). The DRD1 gene is located in the
region linked to bipolar disorder in some studies. Bipolar disorder
affects about 1% of the population and dopamine signaling is affected
by medications which treat bipolar disorder (Ni, 2002).
DRD2 alleles have been linked to schizophrenia, recurrent major depression,
and adolescent emotional disorders. Some studies have found associations
between certain alleles and alcoholism and Parkinson-like disorders.
DRD2 receptors function in the coordination of movement and mutations
may cause myoclonus dystonia. Some mutations in mice cause abnormalities
similar to those observed in Parkinsons disease. In mice some mutations
affect the response to morphine when used as a reward (but not other
rewards such as food). Some antipsychotic drugs act by blocking DRD2.
The A1 allele of DRD2 is more common in those addicted to alcohol, cigarettes,
opiates, and other substances and is associated with high novelty seeking
and high harm avoidance (Berman, 2002). The Ser311Cys allele of DRD2
is more common in those with persecution delusional disorder (Morimoto,
2002). The density of DRD2 receptors in the striatum is correlated with
the personality trait of detachment as are variants of the promoter
which affect the density of receptors produced. Novelty seeking is associated
with density of DRD2 receptors in the right insular cortex as is increased
blood flow to this region (Jonsson, 2003).
Investigations into the contribution of DRD2 in schizophrenia have led
to conflicting results, with some studies suggesting a link between
DRD2 polymorphisms and the disorder. A polymorphism in a gene located
3' to DRD2, named "X-kinase" is linked to schizophrenia (Dubertret,
2004). Different alleles of DRD2 seem to contribute to the difference
in the effectiveness of medication which treats post-traumatic stress
disorder (Lawford, 2003; Jonsson, 2003).
The first documentation of interaction between different alleles of
a gene and the environment was the 2000 report that children with minor
alleles of DRD2 had greater extraversion when living in an alcoholic
home while the opposite was true of children with major alleles of DRD2
DRD3 receptors are expressed in the limbic system and are involved in
cognition, emotions, and hormone release. Drugs which treat Parkinsons
disease and psychosis may act on DRD3 receptors. Increased expression
of DRD3 receptors may be a factor in causing schizophrenia. Polymorphisms
in DRD3 and DRD4 are linked to avoidant and obsessive personality traits
(Joyce, 2003). Reduction in the density of D3 receptors is involved
in antipsychotic treatment (Seretti, 2000). The DRD3 gene is highly
concentrated in the parts of the limbic system associated with reward.
It doesn't seem to be involved in alcohol addiction (Gorwood, 2001).
DRD3 polymorphisms linked to the trait of persistence (Czermak, 2004).
The BalI polymorphism (which converts a serime to a glycine in condon
9 of the first exon of DRD3) is linked to schizophrenia (Petronis, 2000).
Studies have linked the 102T/C polymorphism of DRD3 to schizophrenia
with the C allele being more frequently found in schizophrenics (Petronis,
DRD4 receptors are expressed in the limbic system and affect cognition,
emotions, and anger. This gene is one of the most variable human genes
known with most of the variation occurring in exon 3. Different alleles
of DRD4 are associated with scores on personality tests related to novelty
seeking (high scores with novelty seeking are correlated with impulsive
and exploratory behaviors; low scores are correlated with being stoic,
loyal, and frugal). Increased expression of receptors may be a factor
in schizophrenia and certain alleles may affect ADHD. Some mutations
in humans affect the functioning of the autonomic nervous system and
some mutations in mice affect activity levels and sensitivity to drugs
(OMIM). Although DRD4 alleles were associated with variations in smoking
prevalence in humans, this link was lost after controlling for novelty-seeking
Several drugs used to treat schizophrenia act on DRD4 and analysis of
the brains of schizophrenics indicates that DRD4 expression is higher
in schizophrenics (Xing, 2003). A polymorphism upstream of the DRD4
region which may affect transcription rates is linked to schizophrenia.
This may explain the inconsistent findings of polymorphisms within the
gene contributing to schizophrenia (Xing, 2003).
DRD5 receptors are expressed in the cortex, dentate gyrus, hippocampus,
and substantia nigra. There are a number of pseudogenes of DRD5, some
of which are still transcribed in some tissues. One allele of DRD5 is
associated with a disorder which affects the eye muscles known as plepharospasm
(Misbahuddin, 2002). The human genome contains 2 DRD5 pseudogenes (Nguyen,
Epinephrine is not only a neurotransmitter, but it also functions as
a hormone when released from the adrenal glands during the fight or
flight response. Blood concentrations of neurepinephrine increase in
ADHD. Some learning disabilities and some of the variations in NE receptors
are correlated with ADHD, especially when accompanied with learning
disabilities. Antidepressants such as Elavil prevent the reuptake of
NE and serotonin form the synaptic cleft; prolonging their elevating
effects. Some antihypertensive drugs act in the PNS, blocking NE's stimulation
of smooth muscle by binding to NE receptors. Amphetamines resemble NE
and dopamine which are used at pleasure center (OMIM).
GABA (gamma amino butyric acid)
GABA is the major inhibitory neurotransmitter of the vertebrate brain.
More than a dozen genes code for the subunits which can be combined
to form the receptor protein. GABA receptors interact with barbituates,
ethanol, and benzodiapezine. Tranquilizers such as valium and librium
bind to GABA receptors, enhancing its inhibitory effect (OMIM). GABA
receptor polymorphisms have been linked to anxiety and the effects of
alcoholism (Reif, 2003).
GABRA2 is expressed in the limbic system and it mediates the effects
of anti-anxiety drugs.
GABRA5 is located in the region which is deleted in the Prader-Willi
and Angelman syndromes and may be responsible for some of the effects
of these disorders. One study correlated a CA repeat in this gene to
GABRB3 mutations have been linked to insomnia and autism.
GABRE is expressed in the brain, heart, and placenta and alternate
splicing can produce tissue specific forms. Mutations may be involved
in retardation and early onset Parkinsons disease.
GABRG2 and GABRG1 mediate the effects of the drug benzodiapezine. One
of the splicing variants of GABRG2 interacts with ethanol. Mutations
can cause epilepsy and febrile seizures.
GABA B Receptor 1 GABBR1 is expressed throughout the brain, small intestine,
and uterus. Mutations in mice result in seizures, memory problems, and
Glutamate is the major excitory neurotransmitter in the mammalian brain.
There are two classes of glutamate receptor, ionotropic and metabotropic.
The ionotropic receptors are divided into the NMDA receptors and the
non-NMDA receptors (such as GRIA and GRIK). The metabotropic receptors
can be grouped on the basis of structure and function (GRM1 and 5 are
grouped together, as are GRM 2 and 3, and GRM 4 and 6).
1A) IONOTROPIC, NMDA
NMDA receptors are involved in associative memory.
GRIN1 is the major subunit in all NMDA receptors; one or more of the
following GRIN receptors are also incorporated into the protein. NMDA
receptors located at synapses increase the activity of CREB and BDNF
genes (involved in learning), and are antiapoptotic (prevent cell death).
NMDA receptors which are not located at synapses are activated in hypoxia,
inducing membrane potential changes in the mitochondria and apoptosis
(programmed cell death). A decrease in NMDA receptors may be a factor
GRIN2A mutations in mice interfere with memory.
GRIN2B mutations cause death in homozygous mice. Transgene mice which
expressed increased amounts of GRIN2B performed better at memory tasks
than wild type mice.
1B) Non-NMDA IONOTROPIC RECEPTORS
GRIA1 mutations in mice interfere with learning.
GRIA2 is essential for normal brain function and is also involved in
the perceived reward from cocaine.
GRIA3 mutations cause Rasmussen encephalitis whose effects include
inflammation, epilepsy, and dementia.
GRIK1 receptors are expressed in the ventral horn of the spinal chord.
Mutations can cause juvenile absence epilepsy.
GRIK2 polymorphisms affected the age of onset of Huntingdon disease.
2) METABOTROPIC RECEPTORS
GRM1 mutations cause learning and motor abnormalities.
GRM4 is expressed most highly in the cerebellum. Mutations affect learning.
Endorphins, enkalphins, and dynorphin are our brain's own opiates that
reduce our sensitivity to pain (may be felt during exercise ["runner's
high"] and the fight or flight response). Enkalphins are secreted
during labor. Opioid receptors mediate the effects of endogenous opiates
(enkalphins, endorphins, dynorphin) as well as those of morphine, heroin,
OPRM1 is the major receptor site for the binding of heroin, morphine,
and methadone. There are ethnic differences is the distribution of OPRM1
alleles and some alleles increase vulnerability to these drugs. One
mutant receptor binds beta-endorphin three times the degree observed
in wild type receptors. Mutations can cause epilepsy (OMIM).
The neurotransmitter serotonin inhibits sex drive and orgasm; promotes
contentment, causes cravings for sweets and has been used to treat depression,
obsessive-compulsive disorder, panic, anxiety, PMS. Prozac increases
serotonin levels and dieting decreases them. Receptors for serotonin
are involved in the regulation of sleep, appetite, thermoregulation,
pain, and sexual drives. Abnormalities in serotonin pathways can result
in depression, migraine, and obsessive-compulsive behavior. LSD binds
to serotonin receptors, blocking the inhibition of some pathways. Some
sensory information is no longer filtered resulting in a sensory overload
Serotonin receptors are expressed in the CNS, PNS, and other tissues
and are involved in depression, anxiety, schizophrenia, obsessive-compulsive
disorders, panic disorders, migraine, hypertension, eating disorders,
and irritable bowel syndrome (Hoyer, 2002). Studies have suggested that
abnormalities in the serotonin system may be a factor in aggression
and pedophilia (Maes, 2001).
Mutations in 5HT1A receptors in mice increased levels of anxiety (Reif,
HTR1B is most highly expressed in the striatum. Mutations in 5HT1B
receptors in mice increase aggression, exploratory behavior, and the
susceptibility to addition to cocaine and alcohol. Variants of the 5HT1B
receptor have been linked to increased frequency of alcoholism in two
human populations (Reif, 2003).
HTR1C variants can cause audiogenic seizures and visual hallucinations.
HTR2A receptors are imprinted and only the maternal allele is expressed.
One variant is associated with schizophrenia and with auditory and visual
hallucinations. A G/A polymorphism in the promoter of serotonin 2A receptor
gene (position -1438) has been correlated with seasonal affective disorder,
anorexia, and obsessive compulsive disorder (although other studies
have produced negative results). Studies of prison inmates have also
shown differences in the frequency of alleles at this site compared
to control populations (Beggard, 2003).
HTR2C mutations in mice cause seizures (including audiogenic seizures)
and weight gain. Variants in 5HT2c receptors and DRD4 receptors may
interact to determine reward dependence and persistence (Reif, 2003).
HTR3A is located on the region of chromosome 11 which some have linked
to schizophrenia and bipolar disorder.
NEUROPEPTIDES WHOSE RECEPTORS ARE GPCRs
There are more than 60 neuropeptides in the mammalian brain; most
of them act through GPCRs. In mammals, neuropeptides function in a variety
of neural pathways, including those involving feeding and sleep (Nathoo,
Galanin is expressed in the diencephalon and in other brain regions
and in the gastrointestinal tract. It effects neurotransmitter release,
pain, appetite, growth hormone secretion, heartbeat, gastric motility,
and sexual activity. GPRs 40 through 43 are located in a cluster on
Cannabinoid receptors respond to endogenous neuropeptides whose effects
are anti-inflammatory, immunosuppressive, anticonvulsive, and can relieve
intraocular pressure in glaucoma. They also affect memory. Both of the
receptors are involved in the extinction of aversive memories (OMIM).
CB1 and CB2 are the GPCRs which respond to marijuana and endocannibinoids
(those produced by the body). CB1 is most highly expressed in the hippocampus
and cerebellum but is also expressed outside the brain in the spleen,
testis, and white blood cells. CB2 is primarily expressed in white blood
cells. Both are expressed in the placenta (Onaivi, 2002).
Endocannibinoids are modified eicosinoid-like fatty acids. Given the
production of encannibinoids in the fetal brain, these substances may
function in development. Endocannibinoids also seem to function in immunity,
cell growth, learning, and inflammatory reactions. They may be produced
from cell membrane lipids after receptor-ligand interaction and function
as a retrograde signal (Onaivi, 2002). . Marijuana use can alter memory
and learning pathways (Onaivi, 2002).
Current evidence suggests that personality traits are not determined
by single genes but rather by the additive functions of a number of
genes, many of which are polymorphic in human populations (and which
will likely be shown to interact with the environment). Some personality
traits seem to be more affected by genes and others more affected by
the environment. Some personality disorders may reflect the extreme
expression of normal components of personality (Reif, 2003). It is thought
that any single gene does not typically cause more than 1-2% the observed
variance of a personality trait (Czermak, 2004).
Although variations in serotonin receptors can affect behavior, there
are other proteins involved in the use of serotonin as a neurotransmitter
whose variations are also significant. Low serotonin levels or turnover
have been linked to suicide, impulsive behavior, aggression, and low
social status (the latter observed in primates) (Reif, 2003). Harm avoidance
is determined by serotonin (Berman, 2002).
The enzyme tryptophan hydroxylase, located only in neurons of the
raphe nucleus, catalyzes the most important of the two reactions which
convert tryptophan to 5HT (serotonin). Variations in tryptophan hydroxylase
(TPH) have been linked to aggression and suicidal behavior (Reif, 2003).
Once serotonin is released as a neurotransmitter, it can be reabsorbed
for subsequent reuse by the neuron using a 5HT transporter (5HTT) or
degraded to 5HIAA by monoamine oxidase A (MAO-A) (Reif, 2003). The 5HTT
gene is regulated by an upstream polymorphic repetitive element (known
only in humans and simian primates). Variants in this transporter repetitive
element (5HTTLPR) have been linked to neuroticism, agreeableness, and
anxiety. The concentration of 5HIAA (the breakdown product of serotonin)
in cerebrospinal fluid has been shown to vary in monkeys depending on
whether young rhesus monkeys were raised by their mothers or their peers,
but only in monkeys the s allele of the serotonin reuptake transporter
repetitive element. These alleles also influence the age at which rhesus
monkeys leave their group (Reif, 2003).
Although variations in dopamine receptors can affect behavior, there
are other proteins involved in the use of dopamine as a neurotransmitter
whose variations are also significant.
Dopamine converted from tyrosine by the enzyme tyrosine hydroxylase
(TH) and aromatic amino acid decarboxylase (Reif, 2003). Variants in
the TH gene have been linked to neuroticism, angry hostility, vulnerability,
suicidal behavior, and alcoholism (Reif, 2003). Tyrosine hydroxylase
controls the synthesis of E and NE is a factor in some mood disorders
Catecol-O-methyltransferase (COMT) is an enzyme which breaks down dopamine,
epinephrine, and neurepinephrine. Deletions in the region of this gene
are associated with psychosis (Collier, 2003).
Although both serotonin and dopamine are perceived by multiple receptors,
both are reabsorbed into neurons by a single reuptake transporter. There
is some evidence that variations in the dopamine transporter (DAT) may
influence personality such as avoidant behavior (Reif, 2003).
Monoamines are deaminated by MAO-A and the catecholamines are methylated
by COMT. There are two genes for monoamine oxidase, MAO-A and MAO-B.
Deletions of MAO-A in humans result in mental retardation, autistic
behavior, and other abnormalities (Reif, 2003). Mutations in MAO-A and
5TTT affect the organization of the cerebral cortex in mice (Reif, 2003).
The absence of MAO-A expression in mice results in increased levels
of some neurotransmitters (dopamine, serotonin, and NE), higher aggression,
and inappropriate sexual activity in males. In humans, a mutation in
MAO-A causes Brunner syndrome in which males suffer from mild retardation
and display a variety of aggressive and hypersexual behaviors (in addition
to other behaviors ranging from arson to suicidal behavior). This is
the only example known which fulfills the OGOD (one gene, one disease)
model for behavioral disorders. Variations in the promoter region are
known to affect panic and depression in females and aggression in males
COMT variations have been shown to affect aggression in males and females.
Gene interaction (epistasis) has been observed between DRD4 and polymorphisms
of the 5HTTLPR and COMT (Reif, 2003).
GABA levels are inversely associated with aggression and the interaction
of GABAA receptors with alcohol, bezodiazepines, and barbiturates, can
increase aggressive behavior. The brain actually synthesizes steroid
hormones which can interact with GABAA receptors (Miezek, 2003).
The neurotransmitter norepinephrine is synthesized from dopamine by
dopamine ß-hydroxylase (DBH). Variant forms of this enzyme may
affect irritability (Reif, 2003).
Of course, there are many factors other than genetics which can affect
personality and the biochemistry of the brain. Schizophrenia may affect
up to 1% of the world's population. Non-genetic contributions may arise
from problems during pregnancy and delivery, urban environments, childhood
viral infections, marijuana use, and the age of the father (Collier,
2003). Season of birth has been implicated in variations in schizophrenia,
bipolar disorder, circadian rhythms, novelty seeking, neurotransmitter
metabolism, and suicidal tendency (Chotai, 2003).
OTHER PERSONALITY TRAITS AND DISORDERS
The nervous system depends on sodium, potassium, and calcium channels
to transmit electrical messages and a diversity of these channels can
be found throughout the nervous system. Mutations in individual channels
can have a range of effects, such as epilepsy, febrile seizures, migraines,
and hypertension (OMIM).
OBESITY (included here because of its frequent past association with
temptation, willpower, etc.)
The obese gene (that's the name of the gene in mice where it was discovered)
codes for the protein leptin. Leptin is a secreted protein from fat
cells that seems to serve as a "lipostat" (the human gene
is named leptin). The diabetic gene in mice and fatty gene in rats codes
for leptin receptor, OB-R, which is expressed in the hypothalamus (human
version LEPR). The hypothalamus responds to leptin by secreting neuropeptide
Y. Adipocyte fatty acid binding protein is in a pathway that links obesity
to insulin resistance and diabetes Other genes involved in fat metabolism
include UCP-3 (uncoupling proteins), ASIP, CPE, TUB, MC3R & MC4R
(meolanocortin receptors), POMC, MSTN, and TNFA (tumor necrosis factor).
The diverse features of Angelman syndrome (which include microcephaly,
abnormal movements, failure of speech development, and abnormally happy
disposition are caused by mutations in the ubiquitin ligase gene (Williams,
Among neurological disorders, autism spectrum disorders have a high
heritability. In monozygotic twins, the concordance for autism (if the
definition of autism spectrum includes language delay) has been reported
to be between 60% and 90%. While the general risk of autism spectrum
disorder is about 0.5%, the risk for an individual with an affected
sibling is 2 to 6%. The symptoms of autism can occur with other disorders
such as fragile X syndrome, tuberous sclerosis complex, Rett syndrome,
neurofibromatosis, and duplications of the 15q chromosomal region (Spence,
2004; Volkmar, 2003). A major factor in autism seems to be abnormal
fetal neural development. Genes (such as HOXA1) and drugs (such as ethanol,
valproic acid, thalidomide, and misoprostol) which mediate their effects
early in fetal development can cause autism (Conciatori, 2004).
Autism may involve brain abnormalities such as an increase of brain
size by 2-10% and abnormalities (such as fewer neurons or decreased
neuronal branching) in specific areas such as the amygdale, hippocampus,
septum and anterior cingulated. Autistic patients may also display abnormal
cerebellar development, consistent with the association of mutations
in the genes reelin and engrailed2 with autism. In monkeys, lesions
of the amygdale and hippocampus have produced behavior comparably to
those observed in autism (Volkmar, 2003; Bartlett, 2005).
Autism is not inherited in a Mendelian fashion and gender affects susceptibility
given that only 20% of those affected are female. The genes which have
been identified as being associated with autism include genes involved
in brain development (such as homeobox genes HoxA1 and engrailed 2,
the extracellular matrix gene reelin, and the forkhead transcription
factor FOXP2), genes involved in neurotransmitter action (such as the
serotonin transporter SCL6A4, GABA receptor GABRB3, glutamate receptor
GluR6, arginine vasopressin receptor AVPR1a, and serotonin precursor
enzyme tyrptophan 2,3 dioxygenase), genes involved in immune disorders
(such as HLA-DR4, HLA-DR13, and the MHC III complex complement gene
HLA C4B) and other genes expressed in the brain (such as adenosine deaminase
ADA and UBE2H which causes the Angelman syndrome) (Spence, 2004; Odell,
2005; Torres, 2002; Serajee, 2006; Bartlett, 2005; Li, 2005). Rare variants
of the secretin gene may contribute to autism (Yamagata, 2002).
Autistic patients frequently may possess an abnormal skull shape (trigonocephaly).
Hoxa1 and MECP2 mutations are both associated with autism (the latter
being the cause of Rett syndrome) and can cause abnormal skull shape
Oxytocin and vasopressin are known to mediate a variety of social behaviors
such as courtship and parental care in vertebrates as diverse as fish
and mammals. Oxytocin mutations in mice cause social deficits which
may be related to autism in humans as do mice with mutations in the
Fmr gene which causes fragile X syndrome (Winslow, 2002; Lim, 2005;
Fragile X syndrome, caused by a trinucleotide expansion of the FMR gene,
is the most common inherited disorder causing mental retardation and
is also associated with autism, attention deficit hyperactivity disorder,
delayed language development, anxiety, and abnormal social interactions
Schizophrenia is a serious genetic disorder affecting about 1% of the
population. Although a large number of genes have been associated with
increasing the risk of schizophrenia, many of these analyses have had
difficulty being replicated and few genes have strong support as causative
agents. The candidate genes include dysbindin (which interacts with
the dystrophin complex in hippocampal synapses), neuroregulin 1 (whose
diverse forms perform a variety of functions in the development of the
nervous system, neuronal cell interaction, and synapse function), disrupted
in schizophrenia 1 (a cytoskeletal protein functioning in neural development),
D-amino oxidase, interleukin-10, and regulator of G-protein signaling
4 (Owen, 2005; Harrison, 2006; Sawa, 2005; He, 2006). The onset of schizophrenia
is thought to demonstrate an environmental influence which may be mediated
by thyroid hormones and retinoids which a critical for brain development
and whose pathways have been associated with schizophrenia in genome
analyses (Palha, 2005). In patients with schizophrenia, abnormal expression
of cytomatrix proteins has been observed in the amygdale (Weidenhofer,
Bipolar disorder is a serious mood disorder both because of its worldwide
prevalence (estimated at 3-5%) and its implication in the suicide of
untreated patients. The regions of the brain which seem most responsible
for the features of bipolar disorder are the amygdale, hippocampus,
basal ganglia, and prefrontal cortex. Although it clearly has a genetic
component, causative genes have not yet been clearly identified. A number
of gene variants have been associated with bipolar which include serotonin
receptors (HTR3A and HTR4) and the serotonin transporter, GABA receptor
(GABRA5) hormones and neuropeptides (corticotrophin-releasing hormone
and proenkaphalin), and NCAM1 (Shastry, 2005; Otani, 2005).
Schizophrenia and bipolar disorder may share some of the same susceptibility
genes, such as the G72 protein (D-amino oxidase activator) which interacts
with D-amino acid oxidase (DAO) in the oxidation of D-serine (which
can subsequently interact with NMDA receptors) (Addington, 2004).
It is obvious that genes can affect intelligence, given the many mutations
which lead to retardation.
-- FMR-1 gene (fragile X syndrome), the most common form of inherited
--Rubinstein-Taybi syndrome: the cause of 1/300 institutionalized cases;
a gene on chromosome 16 involved in the switching on of other genes
--there are over 70 different x-linked conditions causing mental retardation;
over 100 different retardation causing mutations have been identified
BMRGH, FMR, SRS, MRX1, MRXA, MRX9, MRX14, MRX20, MRX23,MRX29, RAB,GDIA,
OPHN1, FRAXE, FRAXF, SHS, WTS, MRSD
--Mutations in the human homolog of the Drosophila Aristaless gene,
named Aristaless related homeobox gene ARX, can cause mental retardation,
epileptic seizures, and infantile spasms (Stromme, 2002).
--in laboratory organisms, mutations in certain genes (CREB genes,
dunce, rutabaga, turnip, and others) decrease learning potential
All heritability studies indicate a genetic component to IQ scores,
ranging between .6 and .8 (heritability is a measure of the percentage
of a variation in a given population that is caused by genetic factors;
it is not a measure of what percentage of intelligence in genetic in
origin). Unfortunately, this topic is certainly a difficult one to study
and is clouded by past failures. Measurements of intelligence in the
past (whether through phrenology, head circumference, or early forms
of IQ tests) have been highly erroneous and often based on (or reinforced)
Microcephaly is a disorder in which head and brain size are significantly
reduced. Microcephalic humans have brain sizes equivalent to those of
chimpanzees and gorillas. The cerebral cortex's gyral pattern is less
complex than normal. Primary microcephaly involves a reduction in the
number of neurons during fetal development while secondary microcephaly
involves a reduction in neuronal branching and synapse formation after
birth. Severe forms of human microcephaly may also involve lissencephaly,
the formation of a smooth cerebral surface.
Abnormal spindle-like microcephaly associated ASPM is a large protein
which interacts with microtubules and is expressed in areas where new
neurons are produced. Its homolog in flies is known to function in the
organization of microtubules during cell division. Microcephalin (MCPH1)
is related to topoisomerase II-binding protein and BRCA1. It regulates
chromosome condensation in mitosis and DNA repair. Homologs exist in
bilateran animals. Other genes which cause microcephaly function in
cell division and include cyclin dependent kinase 5 regulatory associated
protein (homologous to centrosomin in flies) and centromere associated
protein J (homologous to CENPJ in flies) (Woods, 2004; Bond, 2006; Ponting,