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The molecular genetics of cognition: dopamine, COMT and BDNF

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DOI: 10.1111/j.1601-183X.2005.00163.x · Source: PubMed

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Genes, Brain and Behavior (2006) 5: 311–328 Copyright # Blackwell Munksgaard 2006

Review

The molecular genetics of cognition: dopamine, COMT

and BDNF

J. Savitz*,†, M. Solms‡ and R. Ramesar† hat genes play in the development of the intellect. While
†
Galton’s conceptualization of intelligence as an instinct (see
MRC/UCT Human Genetics Research Unit, Institute of
Plotkin 1997) is no longer tenable, most modern studies
Infectious Disease and Molecular Medicine, ‡ Departments of
Psychology and Neurology, University of Cape Town, South acknowledge the importance of genetic factors, with herit-
Africa ability estimates of standardized intelligence quotient (IQ)
*Corresponding author: J. Savitz, MRC/UCT Human Genetics tests converging on the 50–80% range (Bouchard 1998).
Research Unit, University of Cape Town Medical School, Discrete (as opposed to global) cognitive processes such as
Observatory, 7925, South Africa. E-mail: js@cormack.uct.ac.za processing speed, short-term and working memory have
also been shown to be significantly influenced by genes
The important contribution of genetic factors to the
with heritability values ranging from 30 to 60% (Luciano
development of cognition and intelligence is widely
et al. 2001).
acknowledged, but identification of these genes has
Cognition is a complex trait and is therefore likely to be
proven to be difficult. Given a variety of evidence impli-
underpinned by many genes, each with a relatively small
cating the prefrontal cortex and its dopaminergic cir-
effect. To reduce the complexity involved, most investigators
cuits in cognition, most of the research conducted to
have attempted to fractionate global cognitive function into
date has focused on genes regulating dopaminergic
discrete cognitive processes via neuropsychological investi-
function. Here we review the genetic association studies
gations. Performance in these specific domains can then be
carried out on catechol-O-methyltransferase (COMT)
statistically linked to the functional activity of particular pro-
and the dopamine receptor genes, D1, D2 and D4. In
teins, and by extension to the genetic variants accounting for
addition, the evidence implicating another promising
these functional differences. This is known as an association
candidate gene, brain-derived neurotrophic factor
study and accounts for a major component of genetic
(BDNF) in neuropsychological function, is assessed.
research into complex traits like cognition. Genes are usually
Both the COMT val158met polymorphism and the
considered good contenders for involvement in the genesis
BDNF val66met variant appear to influence cognitive
of a particular phenotype, if they are functionally polymorphic
function, but the specific neurocognitive processes
and have some prima facie physiological relevance to the
involved continue to be a matter of debate. Part of the
cognitive trait under consideration (Glatt & Freimer 2002).
difficulty is distinguishing between false positives,
These criteria will inform our evaluation of two of the most
pleiotropy and the influence of a general intelligence
promising genes implicated in neurocognitive function, cate-
factor, g. Also at issue is the complexity of the relevant
chol-O-methyltransferase (COMT) and brain-derived neuro-
neuromolecular pathways, which make the inference of
trophic factor (BDNF). Given the pivotal role of dopamine
simple causal relationships difficult. The implications of
(DA) in the functioning of the prefrontal cortex (PFC) (vide
molecular genetic cognitive research for psychiatry are
infra), the burgeoning database of genetic association stu-
discussed in light of these data.
dies involving DA receptor genes will also be covered here.
Keywords: BDNF, cognition, COMT, dopamine, genetics,
neuropsychological, prefrontal cortex
Dopamine and the prefrontal cortex
Received 18 April 2005, revised 25 May 2005, accepted for
publication 25 May 2005 Our linguistic and cognitive abilities are the characteristics
that set us apart from other primates, and these distinctive
functional differences presumably have neurological correl-
The genetics of cognition and intelligence have long fasci- ates. Rilling and Insel (1999), in a magnetic resonance ima-
nated both the scientific community and society at large. ging (MRI) investigation, compared neuroanatomical data
Ever since Francis Galton’s famous study of eminent across 11 different species of primates. Humans were
families, the pièce de résistance of the 1865 ‘Hereditary found to have significantly larger neocortices and had signifi-
Talent and Character’, controversy has raged over the role cantly more gyrified (a measure of cortical folding) prefrontal

doi: 10.1111/j.1601-183X.2005.00163.x 311

Savitz et al.
cortices than expected for a non-human primate of the same
size (Rilling & Insel 1999). Secondly, a plethora of data from
neuropsychological studies of brain-injured patients and
more recently neuroimaging work has indicated that the
PFC is critical for ‘executive functioning’, a miscellaneous
category of cognitive processes that includes working mem-
ory, response inhibition, planning, concentration, attention,
perceptual organization, judgement, decision making and
self-monitoring (Benton 1994).
Genes and gene families that are expressed in the PFC are
therefore obvious candidates for involvement in cognition.
Unfortunately, with approximately half of the 32 000 Homo
sapiens genes expressed in the brain and significant portion
of these genes expressed in the PFC, narrowing down the
list of candidates becomes a speculative exercise. Previc
(1999) has hypothesized that DA is the key regulator of six
predominantly left-hemisphere cognitive skills – the ‘execu-
tive functions’ that are critical to human language and
thought. In Previc’s schema, physiological adaptations to
ecological changes in sub-Saharan Africa catalysed the
expansion of dopaminergic pathways and with it our ascend-
ing intellectual abilities. While this hypothesis may be specu-
lative, the evidence linking DA to prefrontal function and
cognition is well established (Cools & Robbins 2004). Given
the pivotal role of DA in the mediation of PFC function (vide
infra) and the empirical evidence garnered from genetic asso-
ciation studies, we have in the first part of the paper
focussed our attention on three candidates, COMT and the
DA receptors, D2 and D4.
One of the first clues that DA is involved in cognition came
from studies of patients with Parkinson’s disease (PD).
Working memory and executive type deficits are often pre-
sent in the early stages of PD (Cools & Robbins 2004).
Dubois and Pillon (1997) presented data indicating that
about 93% of PD patients present with cognitive – mostly
executive – deficits. Administration of L-DOPA to PD
patients has been reported to improve working memory
(Mattay et al. 2002), cognitive flexibility (Cools et al. 2001)
and planning as evinced by the Tower of London (TOL)
(Cools et al. 2002). In addition, the neurotoxin 1-methyl-
4-phenyl-1,2,3,6-tetrohydropyridine, which results in a
degeneration of the nigrostriatal pathway, produces similar
executive dysfunction to PD (Stern & Langston 1985).
The second strand of evidence implicating DA in cognition
comes from animal studies. Non-human primate studies of
working memory make widespread use of the delayed
response task. The animal is shown the location of a piece
of food, the food is then hidden from view by an opaque
screen, and the primate must then choose the correct loca-
tion of the treat from two or more options (Goldman-Rakic
1995). Working memory deficits on this task were shown to
result from experimental depletion of PFC DA in rhesus
monkeys (Brozoski et al. 1979), and more contemporary
studies have shown that deficits on tests of working mem-
ory can be reversed with DA agonists (Goldman-Rakic 1995).
312
In addition, spatial working memory tasks have been shown
to increase dopaminergic activity in the dorsolateral PFC of
primates (Kodoma et al. 1997).
In human studies, Luciana et al. (1998) improved the work-
ing memory performance of individuals by using the DA
agonist bromocriptine, while set-shifting ability was reduced
by DA antagonists (Lange et al. 1992). Ageing populations
with decreased PFC DA levels and cognitive inflexibility have
also been shown to benefit from the administration of DA
agonists (Ollat 1992). More contemporary neuroimaging stu-
dies have demonstrated a correlation between the density of
dopaminergic fibres in the caudate nucleus and performance
on a range of executive and memory tests (Remy & Samson
2003). Recent data suggest, however, that there is not a
simple linear relationship between DA and cognition.
Dopamine does not always enhance cognitive perform-
ance and may in fact retard it (Cools & Robbins 2004).
Bromocriptine, a DA D2 receptor agonist, was demonstrated
to improve cognition in individuals with a low-baseline mem-
ory capacity but impair performance in high performers
(Kimberg et al. 1997). Similarly, Mattay et al. (2000) showed
that dextroamphetamine, a drug that potentiates dopaminer-
gic activity, improved cognitive performance in subjects with
low-baseline levels of DA but that once DA receptor stimula-
tion reached a certain threshold, working memory function
deteriorated. Thus, an inverted ‘U’ shaped curve charac-
terizes the relationship between DA levels and cognitive
performance, with both suboptimal and supra-optimal DA
activity impairing prefrontal function (Cools & Robbins 2004).
These hypothesized effects may be mediated by the dif-
ferential effects of D1 and D2 receptor binding. Theoretically,
D2 receptor binding signals the presence of important (often
reward-based) information and allows the PFC network to
respond to this new information by updating its working
memory system (Weinberger et al. 2001). D1 receptor sti-
mulation, on the other hand, plays a gating role by controlling
the threshold of significance above which information must
pass before it can be admitted to working memory and
processed by the PFC. D1 receptor activation thus stabilizes
the pattern of activity within the PFC neural network and
protects the system from distracters until the appropriate
behavioural response is generated (Weinberger et al. 2001).
When the D1/D2-binding ratio is disturbed, cognitive per-
formance is theoretically impaired in one of two directions:
(a) A lack of D1-mediated signalling in the PFC (a hypodopa-
minergic state) theoretically causes neural representations to
be vulnerable to decay and competing inputs, resulting in
poor differentiation of target from background (Winterer &
Weinberger 2004). This may be manifested in impulsive and
distractible behaviours and poor working memory and plan-
ning, abilities which are mediated by the PFC. Attention is
drawn to contextually weak stimuli, leading perhaps in
extreme cases to the delusions, paranoia and neurocognitive
dysfunction characteristic of schizophrenia (Winterer &
Weinberger 2004). (b) Hyperdopaminergic states associated
Genes, Brain and Behavior (2006) 5: 311–328

with excessive D1 stimulation, on the other hand, may allow
representations in the PFC to be maintained but not effec-
tively updated, leading in extreme cases to perseverative or
stereotypic behaviour (Weinberger et al. 2001) and reduced
performance on tasks requiring cognitive flexibility (Cools &
Robbins 2004).
Given the delicate balancing act that the regulators of PFC DA
activity need to achieve for optimal cognitive function, these
enzymes make excellent candidate genes for influencing inter-
individual variation in cognition. Dopamine catabolism in the PFC
is regulated by monoamine oxidase which is found on the
mitochondrial membranes of catecholamine neurons and
COMT which is concentrated in the extrasynaptic spaces
(Deutch & Roth 1999). The dopamine transporter (DAT) is
found primarily in dopaminergic neurons of the substantia
nigra and ventral tegmental area (VTA) and allows for the rapid
reuptake of DA from the synaptic cleft (Deutch & Roth 1999).
While all three of these enzymes are important regulators
of subcortical and cortical DA transmission, COMT appears
to play the pivotal role in the modulation of fronto-striatal
networks. An evolutionary recent functional single nucleotide
polymorphism (SNP) of the COMT gene (val158met) located
on chromosome 22q11 that results in the substitution of
valine (val) with methionine (met) at codon 158 of the protein
sequence has been described (GenBank accession no.
Z26491). The met allele produces an enzyme that is unstable
at body temperature and has only a quarter the activity of the
val-containing polypeptide (Egan et al. 2001).
In the PFC, burst firing of VTA neurons causes synaptic DA
release in pyramidal cells, but these cortical neurons contain
very little DAT (Dougherty et al. 1999), allowing high levels of
DA to diffuse out of the synaptic cleft and bind to
extrasynaptic D1 receptors where the neurotransmitter is
inactivated principally by COMT (Bilder et al. 2004). The
high-activity val allele decreases extrasynaptic DA concentra-
tions and therefore D1 activation, shifting the balance in
favour of intrasynaptic D2 receptor activation (Bilder et al.
2004; Winterer & Weinberger 2004).
Given the hypothetical differential effects of D1 and D2
receptor stimulation discussed above, the effect of COMT
genotype on PFC-mediated cognitive functions may be as
follows: The val (high-activity) allele theoretically results in
lowered stability of PFC neural networks which may mani-
fest in decreased ability to maintain information in working
memory (Bilder et al. 2004; Winterer & Weinberger 2004) but
enhanced ability to update the contents of working memory
with new information or switch cognitive sets (Cools &
Robbins 2004). The met allele, which is associated with an
elevated PFC DA level and increased D1 receptor binding, is
predicted to enhance the stability of PFC networks and thus
the performance of cognitive tasks involving maintenance of
information, but lead to decreased cognitive flexibility (Bilder
et al. 2004; Winterer & Weinberger 2004).
This hypothesis offers an elegant model of PFC modula-
tion and cognition, but are these theoretical speculations
Genes, Brain and Behavior (2006) 5: 311–328
The molecular genetics of cognition
congruent with empirical data linking genotype with cogni-
tive performance? We are aware of 26 studies that have
examined the association between the COMT val158met
polymorphism and cognitive function, and these data are
summarized in Table 1. The results are impressive even if
one acknowledges the possible effects of publication bias.
Twenty out of 26 studies report an association between the
COMT val158met polymorphism and cognitive function, and
all of them bar two suggest that the low-activity met allele
allows for better performance on cognitive tasks that have a
working memory component.
The latter point is important, because if all the positive
findings reported to date were spurious, then it would be
expected that the relevant studies would implicate all alleles
of COMT with equal frequency. In fact, 90% of statistically
significant results reported in the literature suggest that the
low-activity met allele is associated with enhanced working
memory. Assuming that no publication bias exists, these
data suggest that the COMT val158met polymorphism may
exert a genuine effect on cognition.
Egan et al. (2001), in the original study, reported that the
high-activity val allele was associated with poorer perform-
ance on the Wisconsin Card Sorting Test (WCST), a putative
measure of ‘executive’ function, reduced efficiency of phy-
siological response in the dorsolateral PFC during a working
memory task and was transmitted more often than expected
by chance to probands with schizophrenia. Egan et al. (2001)
suggested that the COMT genotype accounted for 4% of the
variance in performance on the WCST, and this was echoed
by Joober et al. (2002), Bilder et al. (2002) and Goldberg et al.
(2003). Despite this seemingly small effect size, however,
positive results have been generated by studies with very
modest sample sizes. Fourteen of the 20 studies reporting
significant genotype – cognition associations – made use of
sample sizes below 100 (Table 1). Whether this is a tribute to
the sensitivity of the neuropsychological and neuroimaging
techniques or whether the COMT val158met polymorphism
exerts a more significant effect on cognition is unclear.
There is some evidence for the latter possibility. Bilder
et al. (2002) reported that the COMT genotype accounted
for 11% of the variance in processing speed and attention.
Diamond et al. (2004) found that 26% of the variance on their
dots-mixed task was due to the effects of genotype, while
Nolan et al. (2004) suggested that 28–41% of the statistical
variance on their competing programs task was due to
COMT variants.
Despite the impressive congruency in genotype-cognition
correlations, the specific cognitive functions or modules that
are sensitive to dopaminergic modulation remain a source of
debate. Most of the initial studies used the WCST as a
measure of prefrontal cognitive function. The original test
developed by Berg in 1948 was designed to assess cognitive
flexibility, hypothesis testing and problem solving. Frontal
cortex dysfunction may interfere with the planning of tasks
and the ability to generate and select alternative hypotheses
313
 Table 1: Association between the Catechol-O-methyltransferase (COMT) val158met polymorphism and cognitive performance
314
Study Sample (mean age)
Eisenberg et al. (1999) 48 ADHD triads (9.4)
Egan et al. (2001) 175 schizophrenics (36), 219
unaffected siblings and 55 C (34)
Bilder et al. (2002) 58 individuals with chronic
schizophrenia (40.5)
Fossella et al. (2002) 220 healthy adults (18–50)
Joober et al. (2002) 94 schizophrenics
(not given) þ 31 C (not given)
Malhotra et al. (2002) 73 healthy subjects (31.3)
Bates et al. (2003) 79 healthy subjects
Gallinat et al. (2003) 49 schizophrenics
(32.8) þ 170 C (43.9)
Goldberg et al. (2003) 74 schizophrenics (37), 108
siblings (37) and 68 C (35)
Mattay et al. (2003) 25 healthy subjects (33)
imaged on amphetamine
Tsai et al. 2003) 120 healthy females (19–21)
Bearden et al. (2004) 44 children (11.1) with 22q11
deletion syndrome
Genes, Brain and Behavior (2006) 5: 311–328
Ethnicity Cognitive tasks Outcome
Savitz et al.
Ashkenazi and CPT Met/met subjects made less errors of commission
non-Ashkenazi jews (false alarms) on the CPT, indicating
lower levels of impulsivity
Caucasian (USA) WCST Valine allele is associated with a greater number of
perseverative errors on the WCST and reduced
efficacy of prefrontal function during a
working memory task
Mixed (USA) Executive (digit-span, WCST, letter Met allele associated with better performance in
fluency, block design, visual reproductions); the processing speed and attention domain
declarative memory (paragraph recall,
word-list learning); processing speed and
attention (TMT A þ B, DSST); simple
motor (tapping)
Not stated (USA) Attention network test (ANT) There was a non-significant trend towards higher
executive attention scores in the met/met
homozygotes
Not stated (Canadian) WCST Met/met homozygotes performed better on the
WCST compared with heterozygotes
or val/val subjects
Mixed (USA) WCST Met/met homozygotes performed better on the
WCST compared with heterozygotes or
val/val subjects
Not stated (USA) Not stated (long-term visual memory) Met/met homozygotes performed better than
val/val homozygotes on the visual memory task
Caucasian (German) Auditory oddball ERP Met/met subjects had lower frontal P300 amplitudes
than val/val homozygotes. Frontal P300 amplitude
correlates negatively with prefrontal cognitive
task performance
94% Caucasian (USA) N-back working memory task þ CPT CPT and 0-back performance (attention) not related
to genotype. Val/val genotype associated with
worst performance in 1 þ 2-back conditions
(working memory)
Not stated (USA) WCST and N-back working memory task Val/val subjects on placebo made more errors on
the WCST than met/met subjects. Val/val subjects
improved on the amphetamine, while met/met
subjects performed worse on the
WCST and N-back task
Han Chinese WAIS þ WCST Met/met homozygotes showed reduced P300
response latencies. There was no difference
between the groups on the cognitive tasks
Predominantly Animal naming, TMT-B, arithmetic (WISC), Met hemizygotes performed better than val
Caucasian (USA) digit span hemizygotes on digit span and TMT-B
 Bertolino et al. (2004) 30 schizophrenics (28.6)
treated with olanzapine over 8 weeks
de Frias et al. (2004) 286 men (57.8)
Diamond et al. (2004) 39 healthy children (9)
Foltynie et al. (2004) 288 patients with Parkinson’s
disease (65.5)
Not stated (Italian) N-back working memory task No difference between groups at 4 weeks
treatment. At 8 weeks, met carriers performed
better on 2-back task. Met/met homozygotes
showed least dorsolateral prefrontal
activation on fMRI
Not stated (Swedish) Episodic and semantic memory (battery) Met/met homozygotes performed better than
heterozygotes or val/val homozygotes on the
episodic and semantic memory tasks
Predominantly Dots-mixed (working memory and inhibition); Met/met homozygotes performed better than
Caucasian (USA) self-ordered pointing task (working memory val/val subjects on the dots-mixed task only.
only); recall memory; mental rotation There was no genotype effect on the other tasks
(posterior parietal lobe)
Not stated (British) TOL, CANTAB (pattern and spatial Met allele associated with poorer performance
recognition), verbal fluency on the TOL only

Genes, Brain and Behavior (2006) 5: 311–328

Mills et al. (2004) 114 children with ADHD (9.2)
Nolan et al. (2004) 26 schizophrenics (41.4)
Rosa et al. (2004) 89 sibling pairs discordant for
schizophrenia (not given)
Stefanis et al. (2004) 543 males from the general
population (21)
Strauss et al. (2004) 63 young adults with
childhood-onset mood disorder (18.4)
Taerk et al. (2004) 118 ADHD children (9)
Tsai et al. (2004) 154 schizophrenics (43.5)
Weickert et al. (2004) 20 schizophrenics (approximately 32) Not stated
given antipsychotics or placebo
Bellgrove et al. (2005) 61 children and adolescents
with ADHD (12)
Ho et al. (2005) 159 schizophrenics (26.5)
and 84 C (27)
Caucasian (British) Digit span, MFFT, CPT, Go No Go (MARS) No significant differences
Predominantly Competing programs task (tests imitation Met allele associated with better imitation
Caucasian (USA) and reversal of rule) (cognitive stability) but val allele associated with
better performance in the reversal condition
(flexibility)
Not stated (Spanish) WCST No association between genotype and
performance in schizophrenics.Val/val genotype
associated with greater number of perseverative
errors in healthy siblings
Caucasian (Greek) N-back working memory task; CPT; No significant association between genotype and
antisaccade task task performance
65% Caucasian (USA) Logical memory tests from the WMS; No significant association between genotype and
paired associates (delayed recall); task performance
RCF; WAIS; WISC
Not stated (Caucasian) SOPT, TOL, WCST No significant association between genotype and
task performance
Chinese MMSE No significant differences reported
N-back working memory task; WCST; Met/met subjects on medication improved on
verbal fluency; WAIS; WMS the N-back task. Val/val subjects showed no
improvement with treatment and were more
impaired than met/met homozygotes
Caucasian (Irish) WISC; TEA-Ch Val/val homozygotes performed better than
heterozygotes or met/met homozygotes on the
‘Walk Don’t Walk’ subtest which measures
sustained attention and response inhibition
Caucasian (USA). WCST, digit span (R), No significant differences reported
TMT (A þ B); N-back working
memory task

ADHD, attention deficit hyperactivity disorder; C, controls; CANTAB, Cambridge neuropsychological test automated battery; CPT, continuous performance test; DSST, digit symbol
substitution test; ERP, event related potential; MARS, maudsley attention and response suppression battery; MFFT, matching familiar figures test; MMSE, mini mental state examination;
RCF, rey complex figure; SOPT, self-ordered pointing task; TEA-Ch, tests of everyday attention for children; TMT, trail-making test; TOL, tower of London; WAIS, Wechsler adult intelligence
test; WCST, Wisconsin card sorting test; WISC, Wechsler intelligence scale for children; WMS, Wechsler memory scale.
The molecular genetics of cognition

315
Savitz et al.
after negative feedback (shifting cognitive set), traits which
the WCST putatively measures (Lezak 1995). The inability to
shift cognitive set is usually recorded as ‘percentage of per-
severative errors’ made by the individual.
A consistent association between the val/val genotype and
greater percentage of perseverative errors on the WCST
characterizes the literature (Egan et al. 2001; Joober et al.
2002; Malhotra et al. 2002; Mattay et al. 2003; Rosa et al.
2004), a trend that appears to run counter to the hypothe-
sized sequelae of hypodopaminergic states, discussed
above. The val allele, reducing D1 receptor binding, should
allow for more cognitive flexibility, the negative aspect of
which may be greater distractibility as evinced by a WCST
measure such as ‘failure to maintain cognitive set’. On the
other hand, individuals with the met/met genotype should
theoretically be more cognitively stable, less distractible and
in certain cases therefore more likely to make perseverative
errors.
The difficulty with the WCST is that it is a complex pro-
blem-solving task with multiple cognitive components and
thus reasons for failure (Bilder et al. 2004; Goldberg et al.
2003). Nevertheless, the complexity of the task does not
explain the consistent association (five studies) between
the presence of the val allele and the increased number of
perseverative errors on the WCST. Perhaps val/val homo-
zygotes are less able to inhibit prepotent responses (see
below) – in this case, the prepotent response may be the
tendency to continue with the same strategy – than met
allele carriers, and therefore make more perseverative errors.
The lack of specificity of the WCST has led to the use of
simpler neuropsychological tasks with more focussed
effects. Goldberg et al. (2003) made use of the N-back-
working memory test in which the individual must continu-
ously recall information that is 0 or 1, or more, back in a
sequence. Catechol-O-methyltransferase genotype was not
related to performance in the 0-back condition, which is more
a measure of attention than working memory (Goldberg et al.
2003). In the 1-back and 2-back conditions, however,
individuals with the met allele outperformed their counter-
parts, suggesting that the process of information updating
and maintenance in the face of competing stimuli is sensitive
to prefrontal DA levels (Goldberg et al. 2003). In a sample of
schizophrenics treated with olanzapine, met carriers also
performed better than val/val individuals on the 2-back task
(Bertolino et al. 2004). Bilder et al. (2004), however, argue
that the N-back task requires both stability (the maintenance
of information) and flexibility (updating the currently relevant
stimulus with new information) and thus suffers from some
of the same drawbacks as the WCST.
Diamond et al. (2004) tested a group of children on a task
that putatively requires both working memory and inhibition
(the dots-mixed task) and a task that requires working mem-
ory only (self-ordered pointing). The dots-mixed task pre-
sents subjects with two types of dots, shaded or striped.
For the shaded dots, the person is required to press a button
316
with the left or right hand according to the side of the screen
that the dot appears on, while for the striped dots, the sub-
ject is required to use the opposite hand (Diamond et al.
2004). In the self-ordered pointing task, a series of line draw-
ings or abstract designs are presented. The subject’s task is
to touch each stimulus only once, but after each response,
the computer screen refreshes, and the order of the stimuli
changes (Diamond et al. 2004). Although both tasks depend
on the integrity of the dorsolateral PFC, only the dots-mixed
test was associated with genotype (met homozygotes per-
formed better), and this led Diamond et al. (2004) to propose
that working memory per se is not sensitive to PFC DA
levels and COMT genotype. It is the ability to inhibit prepo-
tent responses and shut out distracting stimuli, along with
working memory that is sensitive to DA regulation (Diamond
et al. 2004).
Nolan et al. (2004) examined the effect of the COMT
genotype on a computerized task that requires shifting
between two rules of responding, imitation and reversal. In
the imitation condition, the subject presses once on a key in
response to a single stimulus and twice in the case of two
stimuli. The rules are then reversed, and the individual is
required to press once in response to two stimuli and twice
in the case of a single stimulus. Acquisition and maintenance
of the imitation rule reportedly requires cognitive stability,
whereas the reversal condition requires flexibility and the
ability to inhibit the previously learned, more intuitive
response (Nolan et al. 2004). In line with the hypothesized
effects of D1 and D2 receptor binding, Nolan et al. (2004)
found that the met allele was associated with better cogni-
tive stability but poorer flexibility.
While it may be premature on the basis of a small number
of studies to engage in theoretical speculation about the
evolutionary trade-off between these two alleles, the high
frequency of the low performance val allele in most popula-
tions may be explained by hypothesizing that greater cogni-
tive stability and enhanced working memory makes the PFC
system less sensitive to internal or external stimuli, a trade-
off that presumably incurred costs in a hostile evolutionary
environment.
A recent report has suggested that the influence of COMT
on cognition may extend beyond working memory and inhib-
ition. de Frias et al. (2004) found an association between the
COMT genotype and episodic and semantic memory. The
effect was specific to recall rather than recognition, with
met/met individuals outperforming heterozygotes, but not
val/val homozygotes (de Frias et al. 2004). In an earlier
paper, Bates et al. (2003) found that met/met homozygotes
performed better than val/val homozygotes on a delayed
visual memory-recall task. Whether these are false-positive
results or are indicative of a role for DA in memory function
remains to be seen. Diamond et al. (2004) and Strauss et al.
(2004) failed to implicate COMT in memory performance,
although these studies may have been under-powered with
sample sizes of 39 and 63, respectively.
Genes, Brain and Behavior (2006) 5: 311–328

Ho et al. (2005) have hypothesized that age differences
between samples may be responsible for the failure to
detect a significant gene – cognition association in some
studies. The rationale behind this argument is a putative
decline in frontal lobe DA function of 11–13% per decade,
which may render older groups more sensitive to a gene-
tically mediated (val allele) increase in DA catabolism (Ho
et al. 2005). Because the mean age of the sample of Ho
et al. (2005) was approximately 26, we divided the data in
Table 1 into two groups: those studies that sampled indivi-
duals below 30 and those studies with a mean subject age of
greater than 30. We excluded the data derived from children
with attention-deficit hyperactivity disorder (ADHD) and stu-
dies where age was not reported.
Preliminary support for the hypothesis of Ho et al. was
detected. Three out of five studies including individuals with
a mean age of less than 30 were unable to detect a signifi-
cant gene – neurocognitive function relationship, while 10
out of 11 studies with a mean sample age of more than 30
reported positive results. However, the effect of COMT vari-
ants on cognitive function in children is not entirely consist-
ent with this hypothesis. Out of six studies that sampled
children, three reported the met allele to be associated
with better performance on tests of ‘executive’ function,
one found the met allele to be associated with worse cogni-
tive function, and two studies were non-significant.
The difficulty with the interpretation of childhood studies
of cognition is that the PFC is yet to reach full maturity.
Segalowitz & Davies (2004) hypothesized that the PFC devel-
ops until late adolescence, while Welsh et al. (1991)
extended this neurodevelopmental process until early adult-
hood. In the absence, therefore, of a lucid understanding of
the developmental status of these inchoate dopaminergic
pathways, extrapolating genetic association data from chil-
dren to adults may be problematic.
In summary then, on the basis of the genetics literature,
neurocognitive tasks that require the individual to hold infor-
mation ‘on-line’ (i.e. working memory) and perhaps inhibit
responses to prepotent or distracting stimuli appear to be
most sensitive to differential COMT activity. Some prelimin-
ary evidence suggests that the effect of COMT variants may
extend to other cognitive domains such as memory (Bates
et al. 2003; de Frias et al. 2004). The problem with simply
reporting scores obtained on neuropsychological tests of
memory in isolation, however, is that low scores may be
indicative of poor executive functioning rather than a bona
fide memory deficit (that is a deficit mediated by hippocam-
pal dysfunction). In our opinion, therefore, the balance of
evidence indicates that it may be premature at this stage to
invoke a role for COMT in mediating medial temporal
function.
While debate will doubtless continue over the nature of
the neurocircuitry modulated by COMT, important implica-
tions for the treatment of a variety of psychiatric conditions
loom on the horizon. Mattay et al. (2003) demonstrated that
Genes, Brain and Behavior (2006) 5: 311–328
The molecular genetics of cognition
amphetamine, which blocks the action of dopamine, seroto-
nin and noradrenaline transporters, improves working mem-
ory in individuals with suboptimal D1 receptor activation (i.e.
val/val individuals) but has a detrimental effect on PFC cogni-
tion in met/met individuals. In contrast, antipsychotics were
found to improve cognitive function as evinced by the N-back
task in met homozygotes, but val/val individuals did not
improve cognitively on treatment (Weickert et al. 2004).
Inada et al. (2003) examined the response of 100 schizo-
phrenics to neuroleptics and found that met/met homozy-
gotes were on a significantly higher dose of maintenance
therapy than the other patients. This effect was partially
replicated by Illi et al. (2003) who detected a significantly
higher rate of conventional neuroleptic treatment resistance
in met/met patients. Thus, the effect of the met allele which
shifts the D1/D2 activation ratio in favour of D1 is presumably
accentuated by D2 receptor antagonists.
DRD1 and DRD2
The important influence of COMT variants on the D1/D2
receptor-activation ratio raises the possibility that functional
polymorphisms of these two receptor genes may also con-
tribute to population variation in cognitive performance. The
D1 receptor is highly expressed in the glutamatergic pyrami-
dal cells of the PFC (Lidow et al. 1991). Arnsten et al. (1994)
demonstrated that a D1 receptor antagonist impaired the
working memory of monkeys, while a D1 agonist improved
memory performance. Similarly, D1 receptor knockout mice
display spatial learning deficits (El-Ghundi et al. 1999), and
antipsychotic induced downregulation of PFC D1 receptors
was shown to produce severe working memory deficits
which could be reversed by D1 receptor stimulation
(Castner et al. 2000). Okubo et al. (1997) reported a positive
correlation between the density of prefrontal D1 receptors
and performance on the WCST in a schizophrenic population,
and Muller et al. (1998) showed that visuospatial working
memory improved in individuals administered pergolide, a
D1 and D2 receptor agonist.
D2 receptors are most commonly found on the GABAergic
interneurons of the PFC and appear to play a role in depres-
sing N-Methyl-D-Aspartate (NMDA) receptor-mediated exci-
tatory neurotransmission (Kotecha et al. 2002). Mehta et al.
(1999) administered sulpiride, a D2 receptor antagonist, to
healthy volunteers and found that the drug impaired spatial
working memory, planning and attentional set-shifting. In a
follow-up study, the same group showed that shifting of
cognitive set is particularly sensitive to D2 receptor antagon-
ism (Mehta et al. 2004). Kimberg et al. (1997) demonstrated
that a D2 receptor agonist improved cognition in individuals
with a low-baseline memory capacity. In addition, an age-
related decrease in D2 receptors has been hypothesized to
contribute to cognitive decline in the elderly. As a result, the
D2 agonist piribedil has been used in the treatment of
317
Savitz et al.
patients with mild cognitive impairment, apparently with
some success (Peretti et al. 2004).
On the basis of the pharmacological data described above,
it is entirely plausible that executive functions such as work-
ing memory are influenced by functional variation in both the
D1 and D2 receptors. We were unable to find any studies
that made reference to a relationship between cognitive
performance and polymorphisms of the D1 receptor. A hand-
ful of publications have, however, addressed the role of D2
receptor polymorphisms on cognition (Table 2). All of these
studies concentrated on one particular SNP within the DRD2
gene, the TaqIA polymorphism.
The DRD2 gene is about 270 kb long and contains eight
exons, with the TaqIA locus located in the 30 untranslated
region of the gene (Noble 2000). The functional status of the
TaqIA variant is not entirely clear, but some preliminary evi-
dence indicated that A1 allele was associated with reduced
density of DRD2 receptors in the striatum (Pohjalainen et al.
1998). More recently, Duan et al. (2003) found that a synon-
ymous SNP (C957T) affects mRNA stability and therefore
receptor expression, and this was confirmed in vivo by
Hirvonen et al. (2004). The C957T variant was found to be
in linkage disequilibrium with the TaqI A variant in a
Caucasian but not an African-American sample (Duan et al.
2003).
Five studies examining the effect of the DRD2 TaqIA poly-
morphism and cognition are listed in Table 2. Tsai et al. 2002)
and Petrill et al. (1997) made use of standardized IQ tests.
The former reported that A1 homozygotes outperformed
their counterparts on the performance subscale of the
Wechsler Adult Intelligence Scale (WAIS)-R, while the latter
found no significant association between genotype and IQ.
Table 2: Relationship between dopamine D2 variants and cognitive performance
Study Sample Ethnicity
Noble et al. (1994) 98 10–14-year-old boys Caucasian (USA)
Berman and Noble 182 10–14-year-old boys Caucasian (USA)
(1995)
Petrill et al. (1997) 51 high IQ, 51 average IQ, Caucasian (USA)
and 35 low IQ children
Bartres-Faz et al. 49 memory impaired subjects Not stated (Spanish) MMSE, RAVLT,
(2002) (mean age 65 years)
Tsai et al. (2002) 112 female volunteers, Han Chinese
19–21 years old
CPT, continuous performance test; ERP, event related potential; JLO, judgement of line orientation; MMSE, mini mental status examination;
RAVLT, Rey auditory verbal learning test; TMT, trail making test; TOH, tower of Hanoi; WAIS-R, Weschler adult intelligence scale (revised);
WISC-R, Wechsler intelligence scale for children (revised).
318
Using the Rey Auditory Verbal Learning Test, a measure of
verbal memory and learning, Bartres-Faz et al. (2002)
reported a result in the same direction as Tsai et al. (2002):
reduced performance in A2 homozygotes. However, in a
sample of 10–14-year-old boys, Noble et al. (1994) and
Berman and Noble (1995) reported prolonged P300 latency
and reduced visuospatial performance in A1 allele carriers.
These contradictory findings together with the modest sam-
ple sizes of the relevant studies suggest the possibility of
false positives. Nevertheless, given the wide distribution of
the DRD2 receptor in the caudate, putamen, nucleus accum-
bens, amygdala, hippocampus and cerebral cortex and the
effect of COMT on the D1/D2 receptor-activation ratio,
further investigation of this gene may prove worthwhile.
We suggest that because of its putative functional effect,
use of the C957T polymorphism may provide more decisive
results than have been achieved up to now.
DRD4
Wang et al. (2002) proposed that DRD4 impacts prefrontal
cognition by virtue of its effects on GABAergic signalling. The
authors demonstrated that activation of DRD4 receptors,
located in the vicinity of GABAA receptors on dendrites,
reduces GABAA receptor-mediated currents in the PFC
(Wang et al. 2002). GABAergic activity in the PFC has been
shown to modulate the processing of information and the
planning of future actions (Constantinidis et al. 2002). Thus,
both DRD4 and genes coding for components of the
GABAergic system are also candidates for influencing cogni-
tion. Egan et al. (2004) showed that a potentially functional
variant in the metabotropic glutamate receptor, GRM3,
Cognitive tasks Outcome
CPT ERP-derived P300 latency was prolonged
in Taq A1 allele 1 carriers
JLO Reduced visuospatial performance
associated with the Taq A1 allele
WISC-R No significant association between IQ
and genotype
Subjects homozygous for the Taq A2
logical memory, allele exhibited reduced left caudate
visual reproduction, volumes and performed worse on the
visual paired associates, RAVLT and MMSE
TMT-A þ B; FAS;
TOH; JLO
WAIS-R The A1/A1 group scored significantly
higher on the performance scale than the
A2/A2 group
Genes, Brain and Behavior (2006) 5: 311–328

impacts verbal fluency and memory and is associated with
abnormal PFC and hippocampal activation as evinced by
functional magnetic resonance imaging (fMRI). To our know-
ledge, this is the only genetic association study that has
correlated GRM3 variants with cognition. More work has
been carried out on DRD4, most probably because of its
hypothesized role in ADHD.
Attention-deficit hyperactivity disorder is characterized by
deficits in impulse control, attention, working memory, plan-
ning and self-regulation (Barkley 1997), traits that are usually
associated with damage to or dysfunction of PFC circuits.
The treatment of choice, methylphenidate (Ritalin), which
promotes the release of DA and blocks its reuptake, is sug-
gestive of an intimate link between this neurotransmitter and
ADHD. Thus, any genes involved in the aetiology of ADHD
may be good candidates for modulating cognitive function.
One such candidate is the DA D4 receptor gene. The asso-
ciation between an exonic DRD4 variable number tandem
repeat (VNTR) variant (see below) and ADHD is one of the
most robust findings in psychiatric genetics (DiMaio et al.
2003). Both case-control and family-based association stud-
ies have suggested that the longer or 7R allele is a risk factor
for ADHD (DiMaio et al. 2003).
The DRD4 belongs to the same class of receptor as DRD2,
exerting an inhibitory effect on the adenylyl cyclase-mediated
secondary messenger system and is found primarily in the
limbic regions and on PFC pyramidal neurons (Wang et al.
2002). The DRD4 gene is located on the short arm of chro-
mosome 11 and contains a 48 bp VNTR polymorphism in the
third exon of the gene which has been widely typed in
genetic association studies (Ding et al. 2002). Between 2
and 11 repeated elements have been reported in the litera-
ture, although the two predominant alleles in Caucasians
consist of four (4R) and seven repeats (7R), respectively
(Ding et al. 2002). The polymorphic repeated segment
codes for amino acids in the third intracellular loop of the
receptor, a region that couples to G proteins and therefore
Table 3: Associations between the dopamine D4 receptor gene and cognition
Study Sample Ethnicity Cognitive tasks
Swanson et al. (2000) 32 ADHD 68% Caucasian (USA) Stroop,
subjects cued detection task,
go-change task
Fossella et al. (2002) 200 adults Not stated (USA) ANT
Manor et al. (2002) 178 ADHD Not stated (Israeli) CPT (TOVA)
triads
Langley et al. (2004) 133 children Caucasian (British) CPT, MFFT,
with ADHD Go/No Go Task,
Stop Task
ADHD, attention deficit hyperactivity disorder; ANT, attention network test; CPT, continuous performance test; MFFT, matching familiar figures
test; TOVA, test of variables of attention
Genes, Brain and Behavior (2006) 5: 311–328
The molecular genetics of cognition
mediates intracellular signalling (Asghari et al. 1995). The
strategic position of the polymorphism suggests that the
DRD4 receptor variants may exert a functional effect.
Asghari et al. (1995) found differences in cyclic adenosine
monophosphate inhibition between the 4R and 7R alleles, as
well as between a 2R and 4R combined group, and the 7R
allele. It is unclear whether the various alleles in question are
differentially sensitive to endogenous DA, although the 4R
allele has been reported to be more responsive to pharma-
cological DA agonists (Fossella et al. 2002).
We are aware of four papers that have described an asso-
ciation between alleles of the DRD4 48 bp VNTR polymorph-
ism and cognitive functioning (see Table 3). Interestingly,
three out of the four studies were carried out on individuals
with ADHD, possibly because the DRD4 gene is a candidate
gene for this disorder. While Swanson et al. (2000), Fossella
et al. (2002) and Manor et al. (2002) found that children with
a 4R allele or other shorter (2–5R) alleles performed more
poorly on tests of attention and executive functioning,
Langley et al. (2004) report increased impulsivity and there-
fore worse performance on a test of behavioural inhibition in
carriers of the 7R allele.
If the 4R variant does indeed increase sensitivity to DA,
then one would expect more efficient signal transduction in
4R carriers and a subsensitive response to DA in 7R carriers.
Theoretically, the 7R allele could therefore be associated
with under-activity of the mesocorticolimbic DA pathway
(Swanson et al. 2000), although, to our knowledge, this
remains to be conclusively demonstrated. However, this
hypothesis will have to reconcile better neurocognitive per-
formance in ADHD individuals with the DRD4 7R allele (pre-
sumably with an under-active mesocortical DA pathway) and
the association between improved cognition and the COMT
met allele (which elevates the PFC DA level).
The interpretation of these results is further complicated
by the hypothesis of Swanson et al. (2000) that there may be
two basic aetiological subtypes of ADHD. One sector of the
Outcome
Individuals with a 7R allele performed at the same level as
the control group. ADHD children without a 7R allele
performed poorly on the battery
Individuals without a 4R allele performed better on the
executive attention component than carriers of the allele
Children with the short (2–5) exon III repeats performed
worse on the CPT
Children with the 7-R allele were more impulsive on the
MFFT and stop task
319
Savitz et al.
ADHD population displays a profile suggestive of significant
cognitive (and neuropsychological task) impairment. The bal-
ance of the population is hypothesized to carry the 7R poly-
morphism implicated in novelty-seeking behaviour (Savitz &
Ramesar 2004). This genetic subtype may represent an
extreme of temperament, manifesting the behavioural but
not the neurocognitive problems associated with ADHD
(Swanson et al. 2000). If this postulate is correct, then
those individuals with a ‘genetic subtype’ of ADHD (i.e.
carriers of the 7R allele) may outperform their counterparts
who have sustained some exogenous form of damage to the
brain during development. This latter ADHD group will prob-
ably not display an excess of any particular DRD4 VNTR
allele. Thus, in ADHD samples, although the 7R allele may
be associated with better cognitive performance, it may play
no role in cognition and may simply be a proxy for ADHD
aetiology.
In addition, a C to T transition 521 bp upstream from the
transcription-initiation site has attracted attention because of
its possible functional effect. According to Okuyama et al.
(1999), the T variant is transcribed with 40% less efficiency
than the C allele. More recently, D’Souza et al. (2004)
reported that the longer allele of a 120-bp tandem repeat in
the 50 -flanking region of the DRD4 gene, which is known to
contain predicted consensus sequence transcription factor-
binding sites, has lower levels of transcriptional activity than
the shorter allele. These variants have also been implicated
in ADHD (Kustanovich et al. 2004) and novelty-seeking
behaviour (Rogers et al. 2004) and may be worthwhile geno-
typing in future investigations of the genetics of cognition.
Theoretically, the 48 bp VNTR could be in linkage disequili-
brium with either or both of these polymorphisms (or some
other unknown variant), although no linkage disequilibrium
between the 521 C/T polymorphism and the 48 bp VNTR
was detected by Fossella et al. (2002) in their sample.
Brain-derived neurotrophic factor
Neurotrophins are regulatory factors that mediate the differ-
entiation, proliferation and survival of cholinergic, dopaminer-
gic and serotonergic neurons (Poo 2001). Brain-derived
neurotrophic factor, one of these neurotrophins, is
expressed throughout the brain, particularly in the PFC and
hippocampus (Pezawas et al. 2004) where it exerts long-
term effects on neuronal survival, migration, dendritic and
axonal growth (Pang & Lu 2004). Brain-derived neurotrophic
factor has been shown to prevent the spontaneous death of
dopaminergic rat neurons (Hyman et al. 1994), exert a pro-
tective effect in the presence of neurotoxins (Hung & Lee
1996) and elevate forebrain 5-HT neuronal fiber density
(Mamounas et al. 1995).
Brain-derived neurotrophic factor also appears to act on a
much shorter temporal scale. In vitro experiments demon-
strate that BDNF application causes rapid changes in
320
synaptic transmission at both excitatory and inhibitory
synapses (Baldelli et al. 2002). Brain-derived neurotrophic
factor is also secreted in response to neuronal activity
(Farhadi et al. 2000; Goodman et al. 1996, cited in Egan
et al. 2003) where it acts as a retrograde or paracrine mes-
senger allowing neuronal activity to modify synaptic connec-
tions (Egan et al. 2003; Poo 2001). This modulation of
synaptic plasticity and neuronal transmission is particularly
salient in the hippocampus where BDNF-mediated enhance-
ment of long-term potentiation (LTP) has been shown to
facilitate memory formation (Poo 2001).
Brain-derived neurotrophic factor is widely expressed in
the rat hippocampus, and studies of BDNF knockout mice
have demonstrated impairment of hippocampal LTP (Pozzo-
Miller et al. 1999), and treatment with antisense BDNF oli-
gonucleotide or anti-BDNF antibody impaired spatial memory
formation in rats (Mu et al. 1999). Knockout mice, with a
deletion of the TrkB gene which codes for the BDNF recep-
tor, show LTP and maze-learning deficits (Minichiello et al.
1999). The causal mechanism behind BDNF-mediated modu-
lation of LTP is not clear, but one suggestion is that the
protein enhances synaptic vesicle docking by phosphorylat-
ing synaptic proteins (Pang & Lu 2004).
The BDNF gene is located on chromosome 11p13 and is
composed of five or more exons, each with its own promoter
region allowing for differential mRNA splicing (Jiang et al.
2005). A frequent, non-conservative SNP in the gene (dbSNP
number rs6265), producing a val to met amino acid substitu-
tion at codon 66 (val66met) of the pro-BDNF sequence, was
shown by Egan et al. (2003) to affect the activity-dependent
secretion of BDNF. Depolarization-dependent secretion of
BDNF is impaired by the met allele. The met-BDNF may
not be correctly transferred from the Golgi apparatus to its
appropriate secretory granules, despite the fact that mature
protein function is unaltered by the polymorphism (Egan
et al. 2003).
On the basis of these data, Egan et al. (2003) and Hariri
et al. (2003) reasoned that the val66met variant may impact
human hippocampal function and memory. In a sample of
schizophrenic and healthy subjects, the met allele was asso-
ciated with poorer episodic memory as evinced by immedi-
ate and delayed recall of Wechsler Memory Scale stories, a
disruption of the normal hippocampal fMRI disengagement
pattern during a working memory task, and lower hippocam-
pal n-acetyl aspartate, an intracellular marker of neuronal
function (Egan et al. 2003). Similarly, Hariri et al. (2003)
demonstrated that met-BDNF carriers displayed reduced hip-
pocampal engagement during both the encoding and retrie-
val of a spatial task and made significantly more recognition
errors on this task than val/val homozygotes. These results
were partially replicated by Dempster et al. (2005). Another
study of declarative memory in affectively ill individuals,
however, failed to confirm these original findings (Strauss
et al. 2004). In MRI investigations, Pezawas et al. (2004)
and Szeszko et al. (2005) extended the findings of Egan
Genes, Brain and Behavior (2006) 5: 311–328

et al. (2003) and Hariri et al. (2003) by demonstrating that val/
met heterozygotes displayed lower hippocampal volumes
than their val/val counterparts.
The putative effects of the val66met variant on working
memory and retrieval of encoded information suggest that
the influence of BDNF may extend beyond its role in LTP
(see Table 4). Rybakowski et al. (2003) found that carriers of
the met allele performed significantly worse than val/val
homozygotes on the WCST, a measure of PFC function.
This was confirmed by the recent Pezawas et al. (2004)
report, demonstrating that met-BDNF carriers display age-
and gender-independent dorsolateral PFC gray matter
volume reductions. Pezawas et al. (2004) propose that this
variation in cortical morphology is at least partly the result of
long-term BDNF-mediated effects on the developmental pro-
cess and is not simply a reflection of transient val66met-
moderated neurotransmitter fluctuations during memory
formation.
Tsai et al. (2004) presented data indicating that val/val
homozygotes performed significantly better than carriers of
the met allele on the performance scale of the WAIS,
although the statistical significance was marginal, and the
result stands in contradistinction to that of Egan et al.
(2003). On the other hand, Foltynie et al. (2005) reported
that in patients with PD, the met allele was associated with
better performance on the TOL, a measure of planning abil-
ity. The apparently differential effect of the BDNF val66met
polymorphism in PD may possibly be explained by the com-
plex interactions between BDNF secretion and degeneration
of the nigro-striatal dopaminergic neurons which may result
in a prefrontal-striatal DA imbalance (Foltynie et al. 2005).
Thus, out of six studies that have implicated BDNF variants
in cognition, four have reported an association between the
met allele and worse performance on sundry neurocognitive
tasks. One study is equivocal (Tsai et al. 2004), and one
study (Foltynie et al. 2005) finds evidence for improved per-
formance in met carriers (see Table 4).
A potentially confounding variable is the discovery by Jiang
et al. (2005) of a functional polymorphism 281 bp upstream
from the putative transcription-initiation site of exon 1 of
BDNF. The ‘A’ variant which may be protective against anxi-
ety and psychiatric illness appears to exert an independent,
but opposite effect to the met 66 allele which has been
implicated in psychopathology (Jiang et al. 2005). The two
genetic variants may, however, be in linkage disequilibrium
with each other, although, given the differential anxiety-
related effects of the 281C>A variant on the val 66 haplo-
type background (Jiang et al. 2005), future research may
benefit from controlling for this SNP.
There appear to be at least three different mechanisms
through which BDNF impacts cognition. One possibility is
that stress, especially chronic stress, may result in excessive
release of glucocorticoids from the adrenal gland, directly
and indirectly causing atrophy and death of vulnerable neu-
rons through the actions of cortisol and the inhibition of
Genes, Brain and Behavior (2006) 5: 311–328
The molecular genetics of cognition
BDNF synthesis, respectively (Duman et al. 1997). Because
the hippocampus is particularly vulnerable to the action of
glucocorticoids (Nestler et al. 2002), this may explain the
memory deficits described above. A potentially useful future
study would be to examine the effects of the val66met
polymorphism on cortisol release and hypothalamic pitui-
tary-adrenal axis dysfunction.
A second possibility is that the val66met variant influences
the efficacy of both early- and late-phase LTP in the hippo-
campus (Egan et al. 2003; Hariri et al. 2003), consistent with
reported BDNF-driven variation in verbal and visual declara-
tive memory. Interestingly, three out of four studies hypothe-
sizing a significant role for BDNF in neurocognition have
reported that heterozygotes perform more poorly on cogni-
tive tasks than val/val homozygotes. Whether this is an arte-
fact of the low frequency of met homozygotes in the
population, limiting potential group comparisons in genetic
association studies, or indicative of the sensitivity of LTP to
BDNF level is debatable.
Thirdly, BDNF has diffuse effects on monoaminergic neu-
rotransmitter systems. It promotes the sprouting of mature
serotonergic neurons (Mamounas et al. 1995), augments
central serotonergic activity following a midbrain infusion
(Siuciak et al. 1996), moderates the firing of neurons in the
dorsal raphe nucleus (Celada et al. 1996) and modulates
serotonin transporter function (Mossner et al. 2000). Brain-
derived neurotrophic factor has also been shown to influence
dopaminergic activity (Narita et al. 2003). Administration of
BDNF has been shown to potentiate nigrostriatal dopaminer-
gic function and locomotor activity (Horger et al. 1999; Pierce
et al. 1999, cited in Narita et al. 2003), and chronic BDNF
treatment enhances the reward response to cocaine (Horger
et al. 1999).
In summary, (a) Animal studies suggest that BDNF pro-
tects neurons from the effects of damage, plays a role in
modifying synaptic connections and modulates hippocampal
LTP. (b) Human studies have demonstrated that the met
allele is associated with lower hippocampal volume or func-
tional activity. (c) Genetic studies with the functional val66-
met variant have indicated that the met allele is associated
with weaker performance on tests of memory and ‘execu-
tive’ function. Given these parallel sources of evidence, we
suggest that it is likely that val66met BDNF variant exerts an
effect on memory performance and perhaps executive func-
tion, although more evidence is required for the latter.
Caveats
A number of theoretical obstacles may impede the resolution
of gene-cognition relationships.
(a) Gene-cognition correlations reported in the literature
usually rest on the assumption that the effect of the genetic
variant in question is specific to a particular cognitive process
and is not reflective of variation in a general intelligence
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Savitz et al.

Table 4: Association between the BDNF val66met polymorphism and cognition

Study Sample Ethnicity Cognitive tasks Outcome

Egan et al. (2003) 203 schizophrenics and 305
siblings and 133 C
Hariri et al. (2003) 28 healthy subjects
Rybakowski et al. (2003) 54 bipolar patients
Nacmias et al. (2004) 83 Alzheimer patients and 97 C
Strauss et al. (2004) 63 adults with childhood
-onset mood disorder
Tsai et al. (2004b) 114 healthy females
Dempster et al. (2005) 92 schizophrenics and 114
unaffected relatives
Foltynie et al. (2005) 291 individuals with
Parkinson’s disease
90% Caucasian (USA) WMS (episodic memory)
and CVLT
Predominantly Caucasian Visual declarative memory (IAPS)
(USA)
Not stated (Polish) WCST
Caucasian (Italian) IMCT, digit span, CTT,
babcock story,
paired words
(Canadian) Declarative memory
Han Chinese WAIS
Not stated (British) WMS
Not stated (British) TOL, verbal fluency, spatial and
pattern recognition (CANTAB)
Met/met homozygotes performed worse thanheterozygotes or
val/val homozygotes on WMS. No difference on CVLT
Memory-related hippocampal activity greaterduring both
encoding þ retrieval in val/val
homozygotes. Met carriers made more errors
on recognition memory task
Val/val subjects performed significantly better than
met allele carriers
NS
NS
Val/met heterozygotes but not met/met homozygotes
performed worse than the val/val group on the performance
scale of the WAIS
The met allele was associated with worse performance on the
delayed score of the logical memory subscale
Patients with a met allele performed better on the TOL than val/
val homozygotes

C, controls; CANTAB, Cambridge neuropsychological test automated battery; CTT, corsi tapping task; CVLT, California verbal learning test; IAPS, international affective picture system; IMCT,
international memory and concentration test; NS, not significant; Schiz, schizophrenics; Sibs, siblings; TOL, tower of London: WAIS, Wechsler adult intelligence test; WCST, Wisconsin card
sorting test; WMS, Wechsler memory scale.

Genes, Brain and Behavior (2006) 5: 311–328


factor. It has long been recognized that scores on different
IQ tests emphasizing distinctive types of cognitive tasks are
positively correlated with each other, suggesting the exist-
ence of a general intelligence factor eponymously named
Spearman’s g (Spearman 1904). Persuasive evidence that
IQ scores predict concurrent neuropsychological perfor-
mance across the entire spectrum of intelligence in neurolo-
gically normal individuals has also been mustered (Jung et al.
2000). As the number of discrete cognition-genotype correla-
tions reported in the literature grows, so does the difficulty of
distinguishing between (a) false positives, (b) the potentially
pleiotropic influence of the polymorphism on multiple but
discrete cognitive processes and (c) the possible effect of
genotype on g – that is a higher-order over-arching cognitive
process. This can be seen in the data reviewed above. While
the COMT val158met variant has been reported to impact
general executive function (Egan et al. 2001), working mem-
ory (Goldberg et al. 2003), working memory and inhibition
(Diamond et al. 2004) and episodic and semantic memory (de
Frias et al. 2004), the BDNF val66met polymorphism has
been postulated to influence hippocampal function and
memory (Egan et al. 2003; Hariri et al. 2003) and different
components of executive function (Foltynie et al. 2005;
Rybakowski et al. 2003).
A related problem is that the use of neuropsychological
tests to pinpoint cognitive modules that are sensitive to
genetic variation is limited by the absence of a simple linear
relationship between task performance and activation of a
particular neural circuit. This is because there are many rea-
sons for failure on a neuropsychological task. Goldberg and
Weinberger (2004) suggest that the use of an alternative
phenotype, such as fMRI activity, which may be more clo-
sely related than psychological testing to the underlying
function of the neural system, may ameliorate this difficulty.
(b) The complexity of neuromolecular pathways makes it
dangerous to draw simple causal relationships between a
genetic variant and a cognitive process. The putative relation-
ship between, for example, the COMT val158met SNP and
working memory probably indicates that COMT is one cog in
a complex circuit involved in PFC function. Does the COMT
val158met variant exert a direct causal effect on PFC func-
tion, or is it simply correlated with a true causal factor such
as the efficacy of DA receptor binding or the developmental
trajectory taken by the embryonic brain?
(c) If a true but weak relationship between COMT and
BDNF variants and cognitive function exists, then it would
be expected that a greater percentage of positive findings
would have been derived from studies employing large num-
bers of participants. In fact, in the case of COMT, the pattern
is diametrical. Four of the largest studies with sample sizes
of 159 schizophrenics and 84 controls (Ho et al. 2005), 154
schizophrenics (Tsai et al. 2004), 543 healthy males (Stefanis
et al. 2004) and 220 healthy adults (Fossella et al. 2002) failed
to show statistically significant gene-cognition associations.
On the other hand, 15 studies making use of sample sizes of
Genes, Brain and Behavior (2006) 5: 311–328
The molecular genetics of cognition
100 or less report positive results (see Table 1). The rela-
tively low rate of positive findings in studies with large sam-
ple sizes and statistical power is a cause for concern and
raises the possibility that some of these results may be
spurious. Concerning BDNF, the two studies with the largest
sample sizes, 203 schizophrenics, 305 siblings and 133 con-
trols (Egan et al. 2003), and 291 patients with PD (Foltynie
et al. 2005) both reported significant results, while the two
non-significant findings were obtained with sample sizes of
less than 100 (see Table 4). This picture is more consistent
with a small but genuine effect of the val66met BDNF variant
on cognition.
These crude estimates of publication bias are best
assessed with a formal meta analysis or funnel plot. The
difficulty in this field is the diversity of tasks used to measure
cognition. Different neuropsychological tasks vary in their
properties and therefore exert a differential influence on
effect size and study outcome. Secondly, results are differ-
entially reported across studies: for example, the homozy-
gote and heterozygote groups are sometimes grouped
together and sometimes considered separately in the statis-
tical analyses. Given the additional frustration that the data
required to calculate effect size and mean standard error are
not always available, more formal estimates of publication
bias are not presented here.
(d) False-positive results due to lack of correction for multi-
ple testing is a potential problem when many different neu-
ropsychological measures are being used. Theoretically, the
cut-off value for significance (a value) should be divided by
the number of comparisons being made in order to avoid
Type I errors. Some researchers, however, contend that
conservative corrections such as the Bonferonni method
are unnecessary when the research is driven by an a priori
hypothesis and hampers the detection of weak effects. The
best approach is probably some kind of compromise
between the two extremes. Numerous multiple compar-
isons will be problematic for the interpretation of results,
but unnecessarily strict methodological requirements will
hamper the detection of weak effects.
The genetics of cognition: implications for
psychiatry
The détente between the once disparate worlds of cognition
and emotion research (see Damasio 1994; Panksepp 1998)
has coincided with the growing recognition that cognitive
impairment is a central facet of many psychiatric disorders.
Deficits of executive function, working memory and declara-
tive memory are widely reported in the schizophrenia litera-
ture (Hoff & Kremen 2003). Similarly, two recent reviews of
the neuropsychology of bipolar disorder concluded that
executive dysfunction and verbal memory deficits are
pathognomonic of a bipolar diathesis (Glahn et al. 2004;
Savitz et al. 2005). Cognitive dysfunction has also been
reported in a multitude of other psychiatric conditions
323
Savitz et al.
including ADHD (Barkley 1997), unipolar depression
(Davidson et al. 2002), eating disorders (Lena et al. 2004),
obsessive compulsive disorder (Shin et al. 2004) and border-
line personality disorder (Monarch et al. 2004).
Given the extensive iterative connections between the
PFC and the limbic system, these data suggest that an occult
biological anomaly in the aforementioned neural networks
underpins both a disruption of cognition and affect. Another
possibility is that a primary affective or cognitive disturbance
leads to dysfunction of the other modality. Regardless of
which possibility turns out to be correct, ‘cognitive genetics’,
far from being an esoteric backwater of modern psychiatry,
is most probably indispensable to a comprehensive account
of both the aetiology and pathophysiology of psychiatric
illness.
Conclusion
Traditional behavioural genetics methodologies have long
suggested a role for genes in cognition, but it is only in the
past few years with the rapid evolution of molecular and
computational technology for genetic analysis, coupled with
the extraordinary flow of data from the human genome pro-
ject, that identification of these genes has become a viable
proposition. One of the defining features of our species is a
significantly enlarged neocortex and gyrified PFC, and this
together with a plethora of evidence implicating in particular,
the PFC in cognition, suggests that the genes expressed in
this part of the brain are good candidates for involvement in
cognitive function.
One such of these candidates is COMT, an enzyme which
influences the activity of DA in the PFC by virtue of its
catabolic effects on the neurotransmitter. Given its pivotal
role in the regulation of dopaminergic activity and the large
number of studies that have implicated the val158met SNP
in cognition, we suggest that functional variation in this gene
contributes to inter-individual differences in cognitive func-
tion. The DA receptor genes, in particular D1, D2 and D4, are
all theoretically good candidates for a role in cognition, but
the number of genetic association studies carried out thus
far is too small to draw any firm conclusions. Another candi-
date gene is BDNF which appears to exert a more diffuse
effect via its role in LTP and neuronal survival and repair.
Physiological, genetic and neuroimaging data all favour the
hypothesis that BDNF influences neurocognitive function. As
is the case with COMT though, a resolution of the precise
cognitive processes regulated by BDNF remains elusive.
Acknowledgment
The support of the Medical Research Council of South Africa is
acknowledged.
324
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