Isr J Psychiatry Relat Sci - Vol. 49 - No 2 (2012)
Evidence for an Association between Brain-Derived
Neurotrophic Factor Val66Met Gene Polymorphism
and General Intellectual Ability in Early-Onset
Schizophrenia
Nora S. Vyas, PhD, CSci, CPsychol, AFBPsS, 1,2 and Basant K. Puri, PhD, FRCPsych3
1
Child Psychiatry Branch, National Institutes of Health, Bethesda, Maryland, U.S.A.
2
King s College London, Institute of Psychiatry, SGDP Centre and Department of Psychosis Studies, London, U.K.
3
Department of Imaging, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, U.K.
INTRODUCTION
ABSTRACT
Brain-derived neurotrophic factor (BDNF), a gluta-
mate neurotrophic factor, is a member of the neuro-
Background: Brain-derived neurotrophic factor (BDNF)
trophin family that plays a crucial role in the survival
plays a crucial role in the survival, development and
and differentiation of particular neuronal systems, and
maintenance of neuronal systems, and the Val66Met
has a strong involvement in promoting brain growth
polymorphism has been implicated in memory
and development (1-3). BDNF also appears to medi-
functions.
ate activity-dependent synaptic plasticity and neuronal
Method: We examined the association of BDNF with
development (4-7), and is more widely distributed and
general intellectual ability in 161 individuals including
expressed in the central nervous system (CNS) and has
53 early-onset patients with schizophrenia (EOS),
survival-promoting functions on various CNS neurons
91 healthy biological relatives, and 17 relatives with
including human hippocampus and cerebral cortex (8).
major depressive disorder (MDD), using the Wechsler
Association studies have implicated BDNF as a
Intelligence Scales (WISC).
strong candidate gene in bipolar disorder (9-11),
schizophrenia (12, 13), Alzheimer s disease (14, 15),
Results: Regardless of diagnosis, individuals with the
eating disorders (16), neuroticism (17), and obsessive-
Met66 allele had a significantly higher performance score
compulsive disorder (18). BDNF has been implicated
than those homozygous for Val66 on vocabulary, block
in schizophrenia based on its effects on neurotrans-
design and object assembly subtests of the WISC. EOS
mitter systems that are dysregulated during the ill-
probands showed poor performance on all IQ subtests
ness and its involvement in the mechanism of action
compared with relatives with and without MDD.
of antipsychotic drugs (19, 20). BDNF is involved in
Limitations: Relatively smaller sample size of
the development and survival of dopaminergic and
individual genotypes.
serotonergic neurons (21). An increase in BDNF
mRNA levels has been reported in the hippocampus
Conclusions: BDNF genotype may play a role in specific
in schizophrenia (22). High concentrations of BDNF
cognitive functions and dimensions of intelligence. The Met
in cortical areas and reductions of neurotrophins in
allele appears to be associated with superior performance
the hippocampus have been reported in patients with
in IQ compared with relatives Val/Val genotype.
schizophrenic psychosis in comparison with normal
Address for Correspondence: N.S. Vyas, PhD, Child Psychiatry Branch, National Institute of Mental Health, NIH, Building 10, Rm 3N202,
Bethesda, MD, U.S.A. [e-mail]
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NORA S. VYAS AND BASANT K. PURI
controls (23). In contrast, two further studies showed difference in a sentence completion task between Val/
reduced BDNF levels in schizophrenia (24, 25). Val and Met carriers in young subjects at high risk of
However, Shimizu et al. (26) showed no significant developing schizophrenia, although the former group
differences in serum BDNF levels between antipsy- showed relatively increased activation of the anterior
chotic-naïve and medicated patients with schizophre- cingulate cortex. Rosa et al. (13) showed a preferen-
nia and healthy individuals. In addition, there was no tial transmission of the Val allele from heterozygous
correlation between BDNF levels and duration of ill- parents to offspring affected with psychosis, suggest-
ness, age of onset, clinical symptoms. ing a possible role of this gene in the vulnerability to
The BDNF gene, located on 11p13, has a non- schizophrenia spectrum disorder.
conservative exonic single nucleotide polymorphism Individuals with early-onset and adult-onset schizo-
(SNP) at nucleotide 196 (dbSNP number rs6265, phrenia show intellectual deficits across the lifespan
G/A), which results in a valine (Val) to methionine (34-38). Early onset schizophrenia (EOS; onset before
(Met) substitution within the 5 proBDNF protein at age 18 years) is a rare, chronic, and relatively severe
codon 66 (Val66Met). This SNP may be related to hip- variant of the adult-onset counterpart of the disorder
pocampus-mediated memory performance in humans. (39, 40). Intelligence scores in patients with EOS often
Several studies have reported that BDNF Met66 car- range between 80 and 90 (approximately 1-1.5 stan-
riers with a diagnosis of schizophrenia may be at a dard deviations below the normative mean), which
substantially greater risk of hippocampal dysfunction is significantly lower than adult-onset cases (41-44).
(27, 28). Pezawas et al. (29) reported 12-15% volume Individuals with a genetic predisposition to schizo-
reductions in the hippocampus in Met66 carriers rela- phrenia show a significant difference in IQ scores in
tive to Val66 homozygotes; significant reductions were comparison to normal controls (45-51), including pre-
observed in the dorsolateral prefrontal cortex. The morbid periods (50). One study showed an associa-
association of BDNF and hippocampal function raised tion of BDNF Val55Met polymorphism with general
concerns about whether the Val66Met polymorphism intellectual ability in healthy individuals (32), but no
influenced intelligence scores in schizophrenia. studies to date have investigated the association of this
The Val allele of the BDNF Val66Met polymor- polymorphism with intelligence in schizophrenia. The
phism is expressed more frequently in patients with lower than average IQ scores of EOS patients informed
psychosis (13), schizophrenia (30), and schizoaffec- our choice of examining the association of the BDNF
tive disorder or other affective disorders (31), linking Val66Met polymorphism and general intellectual abil-
genetic variation of the BDNF polymorphism with ity in EOS probands and their first-degree relatives.
symptoms of psychosis. In a Chinese cohort study,
Tsai and colleagues (32) examined the association of
METHODS
BDNF gene polymorphism with general intellectual
ability in a healthy female population (aged 18-21
years, n=114) using the Wechsler Adult Intelligence PARTICIPANTS
Scale - Revised version (WAIS-R). Individuals with Patients were identified by clinicians referrals from
the Val/Val genotype showed modest increases in secondary care services within the South London and
performance intelligence quotient (IQ)scores in com- Maudsley NHS Trust and were included if they: (a) were
parison with individuals with the Met/Met genotype aged between 13-18 years; (b) fulfilled Diagnostic and
and the heterozygous group, suggesting a relation- Statistical Manual of Mental Disorders, Fourth Edition
ship between BDNF and dimensions of general intel- (DSM-IV) (52) criteria for schizophrenia; and (c) had
lectual ability. Egan et al. (27) reported that the Met at least one first-degree relative unaffected by schizo-
allele of the functional polymorphism was associated phrenia. Eligible first-degree relatives were invited to
with poor performance on human episodic memory participate, with the patients consent, if aged 13-65
and abnormality in hippocampal function in patients years and without a personal history of schizophrenia
with schizophrenia (n=106), their unaffected siblings spectrum disorders.
(n=138) and healthy controls (n=59). However, the Exclusion criteria for the entire sample (patients
authors reported no association of BDNF Val66Met and healthy relatives) included: (a) head injury lead-
polymorphism on IQ. Whalley et al. (33) reported no ing to a loss of consciousness for > 1 hour; (b) a per-
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BRAIN-DERIVED NEUROTROPHIC FACTOR VAL66MET GENE POLYMORPHISM IN EARLY-ONSET SCHIZOPHRENIA
sonal history of neurological or medical disorders; (c) tives with major depressive disorder (MDD). All par-
a family history of hereditary neurological disorders; ticipants were assessed on the following IQ subtests of
and (d) fulfilling DSM-IV criteria for lifetime drug or the Wechsler Intelligence Scales (WISC-III or WAIS-R):
alcohol dependence and drug or alcohol abuse in the vocabulary, comprehension, similarities, object assembly,
preceding six months. and block design. The age-appropriate scaled scores for
All participants were recruited as part of the each subtest were inputted for statistical analysis.
Vulnerability Indicators in Psychosis Study (VIPS)
from January 2003 to January 2007. This study exam- GENOTYPING PROCEDURES
ines clinical, cognitive, and genetic liability and dis- Buccal swab DNA was obtained from 161 participants.
ease expressivity in schizophrenia. The study proce- The GA SNP encoding the amino acid substitution
dures were in accordance with the Joint South London Val66Met (dbSNP rs6265) was genotyped. Genotype for
and Maudsley and the Institute of Psychiatry NHS rs6265 was determined by a TaqMan SNP genotyping
Research Ethics Committee. Written informed consent assay (assay ID: C_11592758_10) (Applied Biosystems,
or assent was obtained from all participants. 850 Lincoln Centre Drive, Foster City, California
94404, U.S.A.). 10 ng DNA was used in a 10-źl reac-
CLINICAL EVALUATION AND NEUROPSYCHOLOGICAL tion, according to the manufacturers instructions. End-
ASSESSMENT point analysis was performed on an AB Prism 7900HT
All participants underwent an interview by a trained Sequence Detection System (SDS) and a probability
child and adolescent psychiatrist who was initially blind > 95% was attained for the SDS package. Genotype
to diagnosis but not family status, using the Structured frequencies for rs6265 were 0.22, 0.76, and 0.02 for
Clinical Interview for DSM-IV (SCID) for Axis I disor- Val66Met, Val66Val, and Met66Met, respectively. The
ders (patient and non-patient version) (53, 54). genotype frequencies were comparable with Hap-Map
General intellectual ability was measured using age- population genome build dbSNP (http://www.ncbi.
appropriate Wechsler Intelligence Scales. The Wechsler nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=6265). The
Adult Intelligence Scale Revised edition (WAIS-R) (55) genotype distribution of the rs6265 SNP in BDNF was
was used for individuals aged 16 years and above and in Hardy-Weinberg equilibrium. There were 21 unde-
the Wechsler Intelligence Scale for Children Third edi- termined BDNF genotypes in the full sample, owing
tion (WISC-III) (56) was used for younger subjects. Five to amplification failure. One hundred and seven sub-
healthy relatives and eight EOS probands were assessed jects had the Val/Val genotype, 33 the Val/Met geno-
using the WISC-III, and the WAIS-R was performed type, and three the Met/Met genotype. Owing to the
on 86 healthy relatives, 45 EOS probands and 17 rela- low frequency of the Met66 homozygotes (~2%), the
Table 1. Group comparisons of IQ subtest scores
Variable EOS Patients Relatives with MDD Healthy Relatives Test Statistic P-value *
(n = 53) (n = 19) (n = 91)
Age (yr) 17.25 (1.31) 43.27 (8.16) 34.87 (14.67) Wald Ç2 =610.36 <0.01
2
Years of Education 10.47 (1.04) 12/0 (2.59) 12.32 (2.41) Wald Ç2 =40.32 <0.01
2
Gender (m/f) 29/24 4/13 42/29 Ç2=7.73 <0.05
GAF score 56.2Ä…1.99 65.9Ä…1.77 81.6Ä…0.81 Wald Ç2 =89.34 <0.01
2
IQ subtests
Vocabulary 7.2Ä…3.07 9.6Ä…3.51 8.6Ä…3.57 Wald Ç2 =10.02 <0.01
2
Comprehension 7.1Ä…3.49 10Ä…3.21 10Ä…2.72 Wald Ç2 =18.38 <0.01
2
Similarities 8.1Ä…2.59 10Ä…2.92 9.4Ä…3.05 Wald Ç2 =7.14 <0.01
2
Block Design 8.6Ä…3.39 9.2Ä…3.03 10.1Ä…3.61 Wald Ç2 =3.31 0.19
2
Object Assembly 8.0Ä…2.75 7.8Ä…2.64 8.2Ä…3.02 Wald Ç2 =5.42 0.83
2
*Uncorrected P values.
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NORA S. VYAS AND BASANT K. PURI
genotypes Val/Met and Met/Met were combined for the agents (n=46); one was taking typical medication and
analysis (n = 36), and known as  Met carriers. six were unmedicated at the time of assessment. The
mean time since onset of positive symptoms, as docu-
STATISTICAL ANALYSIS mented in the medical notes, to study entry was 1.77
Statistical analyses were carried out using the Statistical years (SD 0.93).
Package for the Social Science (SPSS) version 18. To
study the effect of genotype and diagnosis on IQ we GROUP COMPARISONS
used generalized estimating equation (GEE) with Group differences across IQ subtests are presented in
an exchangeable within-subject working correlation Table 1. As there was a significant difference between
structure and robust standard errors covariates (57, groups for age and years of education, these variables
58) approach to account for familial inter-correlation were inputted as covariates. As shown in Table 1,
between the EOS probands and their first-degree rela- there was a significant main effect of diagnosis prior
tives. The Hubert White sandwich estimator was used to Bonferroni correction (uncorrected p-values pre-
which provides standard errors that are robust to pos- sented) on all IQ subtests, except the block design sub-
sible misspecification of the correlation matrix. Unlike test. Specifically, there was a main effect of diagnosis on
repeated measurement ANOVA a GEE allows for sev- vocabulary, where EOS probands performed less well
eral observations per case (i.e., observations of two than healthy relatives (P=0.07, Cohen s d=0.40) and
parents) and uses a full case analysis in the presence MDD relatives (P=0.01, Cohen s d=0.77). Similarly,
of missing data. We used a factorial design to study EOS probands performed significantly less well on the
genotype (Val/Val vs. Met carriers) × diagnosis (EOS comprehension subtest than healthy relatives (P<0.001,
vs. healthy relatives vs. MDD) interaction on IQ sub- Cohen s d=0.82) and MDD relatives (P<0.05, Cohen s
tests. Following a significant main effect of genotype or d=0.03). A trend was observed for a diagnosis effect
genotype × diagnosis interaction, Bonferroni correction on similarities in which EOS probands showed below
(p-value multiplied by the number of pairwise com- average performance than healthy relatives (P=0.095,
parisons) was performed. We calculated the effect sizes Cohen s d=0.44) and MDD relatives (P=0.07, Cohen s
using Cohen s d for measures that survived Bonferroni d=0.39). There was no difference in performance IQ
correction. across groups.
EFFECT OF GENOTYPE
RESULTS Table 2 shows the means and standard deviations of
IQ subtests in relation to BDNF genotype. There was a
SAMPLE CHARACTERISTICS significant main effect of genotype on vocabulary (Wald
One hundred and one families of schizophrenia patients Ç2=5.66, df=1, P=0.017), with Met carriers outperform-
were assessed. The age entry criterion was between 13 ing Val/Val genotype (Cohen s d=0.39). With regard to
and 65 years for all participants. Fourteen families did performance IQ measures, there was a significant main
not meet the inclusion criteria for the study, and 23
families refused to participate. In total, 64 patients with
schizophrenia and 179 relatives were enrolled into the
Table 2. Effect of BDNF genotype on IQ across diagnostic groups
study. Of these, 32 relatives were excluded for not meet-
IQ subtest BDNF (Val66Met)
ing the inclusion criteria (substance abuse), 39 relatives
withdrew or were unavailable to participate in the study, Val/Val Met carriers
(n = 109) (n = 36)
and 11 patients with schizophrenia did not meet the cri-
Vocabulary 7.8Ä…0.3* 9.2Ä…0.6*
teria for remission. The total sample used in the analysis
Comprehension 8.8Ä…0.3 9.8Ä…0.6
constituted 161 individuals: 53 patients with schizophre-
nia and 108 of their first-degree relatives. Seventeen rela- Similarities 8.9Ä…0.2 9.5Ä…0.5
tives were diagnosed with MDD (two relatives had bipo- Block Design 9.3Ä…0.3* 10.5Ä…0.6*
lar disorder), and 91 relatives had no psychiatric disorder.
Object Assembly 7.8Ä…0.2* 8.9Ä…0.4*
The majority of schizophrenia patients were pre-
*p < 0.05
scribed antipsychotics, most commonly atypical
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BRAIN-DERIVED NEUROTROPHIC FACTOR VAL66MET GENE POLYMORPHISM IN EARLY-ONSET SCHIZOPHRENIA
effect of genotype on block design (Wald Ç2=4.48, df=1, ciation of the BDNF polymorphism with intelligence
P=0.034, Cohen s d=0.40) and object assembly scaled (32) and generalized cognitive functioning (27, 59).
score (Wald Ç2=5.42, df=1, P=0.02, Cohen s d=0.39), Rosa and colleagues (13) recently showed that indi-
revealing significantly higher scores for Met carriers viduals with the Met/Met genotype performed better on
compared with the Val/Val genotype. Figure 1 depicts prefrontal-cortical related tasks (as measured using the
the association of BDNF on these IQ subtests. As shown Wisconsin card sorting task and the Trail Making Test)
in Table 2, there was no evidence for any association in comparison with the Val/Met and Val/Val genotypes.
between the BDNF Val66Met polymorphism and com- With respect to intelligence scores, our results follow a
prehension (Wald Ç2=2.03, df=1, P=0.15) or similarities similar trend in which individuals with the Met allele
(Wald Ç2=2.53, df=1, P=0.11). are associated with better performance on specific IQ
measures compared with the Val/Val genotype. Our
GENOTYPE BY DIAGNOSIS INTERACTION findings harmonize with those of Harris et al. (60) who
We found no significant genotype × diagnosis interac- observed an association of the BDNF Met66 allele with
tions for vocabulary (Wald Ç2=3.86, df=2, P=0.145), enhanced verbal reasoning ability, which correlated
comprehension (Wald Ç2=2.19, df=2, P=0.33), simi- with IQ, in community-dwelling elderly volunteers. In
larities (Wald Ç2=2.47, df=2, P=0.29), block design contrast, Tsai et al. (32) reported that Val66 homozy-
(Wald Ç2=0.93, df=2, P=0.62) or object assembly (Wald gotes had significantly higher performance IQ scores
Ç2=0.36, df=2, P=0.83). than heterozygotes; a parsimonious explanation of
these findings may reflect the cohort studied: the cohort
involved only females, they were all ethnically Han
DISCUSSION
Chinese, and they were all young healthy nursing stu-
The BDNF Val66Met gene polymorphism has been dents who were not predisposed to a lower IQ. Previous
found to be associated with performance on specific IQ studies have shown that the Met allele of the Val66Met
subtests in EOS probands and their first-degree rela- polymorphism is associated with poor IQ scores (27,
tives. Regardless of diagnosis, individuals with the Met/ 61, 62). Our findings are supported by previous studies
Met or Val/Met genotype demonstrated enhanced per- that demonstrate an association of the Met allele with
formance on the vocabulary, block design, and object better performance on general intellectual ability and
assembly subtests of the Wechsler Intelligence scale. other cognitive functions (13, 33, 62). However, owing
Our findings support previous studies showing an asso- to the small sample size and the family-based design
of this investigation, further studies with larger sample
sizes are needed to confirm these associations.
Fig. 1: Association of BDNF Genotype on vocabulary, block
Previous studies showed an association between
design and object assembly subtests regardless of diagnosis
BDNF and hippocampal function, which led to inves-
11.00
tigations into the influence of BDNF on intelligence
in schizophrenia (27, 32). Semantic memory has been
shown to be associated with verbal IQ in clinical and
10.00
research settings (63), although some reports consider
semantic memory to be hippocampally-independent
9.00
(64, 65). Our findings showed that, compared with the
Val/Val genotype, Met66 carriers achieved the highest
8.00 score in the vocabulary subtest, which is a measure
of an individual s general mental ability articulately to
describe the meaning of words. Egan and colleagues
7.00
(27) reported an association of the BDNF genotype
Block Design
on episodic memory in patients with schizophrenia,
Object Assembly
6.00
their siblings, and normal controls. Although the hip-
Vocabulary
pocampal system is considered to be a common path-
way between semantic memory and episodic memory
5.00
Val/Val Met carriers
(66), the expressivity of BDNF and the accumulation
141
NORA S. VYAS AND BASANT K. PURI
of different effects on cognitive functions in different to the hypothesis that BDNF may play a critical role
psychotic disorders points to a general effect of the in the neurodevelopment of brain circuitry involved
polymorphism on cognitive abilities, and more spe- in general cognitive abilities, and more specifically to
cifically to memory performance and IQ. However, memory and dimensions of IQ. Further investigation
further replication is warranted to confirm this result. is warranted to provide a more validated conclusion.
The lack of a genotype × diagnosis interaction may at
least partly result from a lack of diagnostic specificity of
Acknowledgements
BDNF genotype in relation to general intellectual abil- This work was supported by a departmental fund at King s College London,
Institute of Psychiatry, London, U.K. We are grateful to the patients and
ity. Indeed, it has been argued that the nosological clas-
relatives who participated in the VIPS project. We thank child and adolescent
sification of DSM-IV-TR (67) may be somewhat arbi-
consultant psychiatrists from the adolescent services who referred suitable
trary (68). As noted by Owen and colleagues (68), there
participants for this study.
Dr. Nora S. Vyas was supported by the Fulbright Distinguished Scholar
is an absence of a distinctive  zone of rarity between
Award by the US-UK Fulbright Commission and is currently supported by the
schizophrenia and mood disorders, which may explain
Lindemann Trust Fellowship.
our findings. In addition, the additive actions of sev-
eral susceptibility genes, which could either be multiple
Contributions
risk genes or protective gene variants, may be associated
NSV was involved in the design, analysis and interpretation of data, and wrote the
with the differential expression of general intelligence.
first draft of the manuscript. BKP was involved in the interpretation of the data
and critically revised the manuscript. Both authors approved the final version.
There are some limitations in this study. In view of
the critical role of activity-dependent secretion of BDNF
in hippocampus-based synaptic plasticity and learning
Conflicts of Interest
None.
and memory (27), antipsychotic medication could have
contributed to impairments in general intellectual abil-
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