A common variant in Myosin-18B contributes to
mathematical abilities in children with dyslexia and
intraparietal sulcus variability in adults
KU Ludwig1,2, P Sa ¨mann3, M Alexander1,2, J Becker1,2, J Bruder4, K Moll5,10, D Spieler3,6, M Czisch3, A Warnke7, SJ Docherty8,
OSP Davis8, R Plomin8, MM No ¨then1,2, K Landerl9, B Mu ¨ller-Myhsok3, P Hoffmann1,2,11, J Schumacher2,11, G Schulte-Ko ¨rne4,11
and D Czamara3,11
The ability to perform mathematical tasks is required in everyday life. Although heritability estimates suggest a genetic
contribution, no previous study has conclusively identified a genetic risk variant for mathematical performance. Research has
shown that the prevalence of mathematical disabilities is increased in children with dyslexia. We therefore correlated genome-
wide data of 200 German children with spelling disability, with available quantitative data on mathematic ability. Replication of
the top findings in additional dyslexia samples revealed that rs133885 was a genome-wide significant marker for mathematical
abilities (Pcomb¼7.71?10?10, n¼699), with an effect size of 4.87%. This association was also found in a sample from the
in MYO18B, a protein with as yet unknown functions in the brain. As areas of the parietal cortex, in particular the intraparietal
sulcus (IPS), are involved in numerical processing in humans, we investigated whether rs133885 was associated with IPS
morphology using structural magnetic resonance imaging data from 79 neuropsychiatrically healthy adults. Carriers of the
MYO18B risk-genotype displayed a significantly lower depth of the right IPS. This validates the identified association between
rs133885 and mathematical disability at the level of a specific intermediate phenotype.
Translational Psychiatry (2013) 3, e229; doi:10.1038/tp.2012.148; published online 19 February 2013
Mathematical ability is a quantitative phenotype for which
substantial heritability estimates have been reported.1–3Only
onegenome-wideassociation study (GWAS) ofmathematical
performance has been performed to date.4This study
involved individuals from the general population but failed to
detect any genome-wide significant association. This may
have been due to the contribution of multiple genes with
low effect sizes, epistasis, gene–environment interactions or
technical aspects of the applied pooling method.5Research
has shown that among children with dyslexia, which is a
the prevalence of deficits in mathematical abilities is higher
than in the general population.7,8We hypothesized that
if distinct cognitive processes underlying mathematical
disability are preferentially affected in individuals with
heterogeneity, and thus increase statistical power for the
identification of risk genes.
Although differing brain areas have been implicated in the
performance of mathematic-related tasks across studies,9
several lines of evidence suggest that the intraparietal sulcus
(IPS) has a pivotal role in the representation of numeros-
ity.10,11The IPS, in particular its right horizontal segment, is
robustly activated during the active processing of num-
bers,12,13and studies of healthy individuals have revealed
that this is independent of their exact notation.12,14–18Specific
IPS responses to non-symbolic numerical processing have
been demonstrated in 4-year-old children with remarkable
preservation of this response pattern into adulthood.19
Abnormalities in IPS structure or function have also been
detected in other disorders affecting mathematical skills, such
as dyscalculia.20–23Structural magnetic resonance imaging
(MRI) has pointed out lower gray matter volume in the right
IPS and bilateral cingulofrontal areas in 9-year olds with
developmental dyscalculia22and lower gray matter volume in
more widespread posterior brain regions in a similar age
1Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany;2Institute of Human Genetics, University of Bonn, Bonn, Germany;3Max Planck
Institute of Psychiatry, Munich, Germany;4Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital Munich, Munich, Germany;
5Department of Psychology, University of Salzburg, Salzburg, Austria;6Institute of Human Genetics, Helmholtz Zentrum Mu ¨nchen—German Research Center for
Environmental Health,Neuherberg, Germany;7Department ofChildandAdolescent Psychiatry andPsychotherapy, UniversityHospital Wu ¨rzburg, Wu ¨rzburg, Germany;
8King’s College London, MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, London, UK and9Department of Psychology, University of
Graz, Graz, Austria
Correspondence: Dr D Czamara, Statistical Genetics Group, Max Planck Institute of Psychiatry, Kraepelinstr. 2–10, Munich D-80804, Germany.
10Current address: Department of Psychology, University of York, York, UK.
11These authors contributed equally to this work.
Keywords: dyscalculia; dyslexia; genomic imaging; mathematics; quantitative trait; sulcal morphology
Received 25 October 2011; revised 26 November 2012; accepted 2 Decemeber 2012
Citation: Transl Psychiatry (2013) 3, e229; doi:10.1038/tp.2012.148
& 2013 Macmillan Publishers Limited All rights reserved 2158-3188/13
Turner syndrome in adults, which is associated with specific
deficits in numerical processing and visuo-spatial functions,
exhibited lower depth of the right IPS with trend length and
The aim of this study was to identify genetic variants
contributing to mathematical ability (addition, multiplication
and numerosity judgements (NJs)). We applied a quantitative
trait design, and used genome-wide data of German children
with dyslexia. We then followed-up the most significant
findings in different independent samples. Finally, a structural
MRI study was performed to validate our genetic findings at
the level of an intermediate phenotype.
Materials and methods
The study was approved by the respective ethics committees,
and written informed consent was obtained from all probands
or their legal representatives. All association tests were
performed using quantitative arithmetic data. Numbers
presented in this section refer to sample sizes before
statistical quality control. The behavioral test batteries
(Supplementary Tables 1, 2) are presented online.
Individuals with dyslexia
German sample. The German sample comprised 386 chil-
dren who were subdivided into: (i) initial GWAS (n¼200,
discovery sample); and (ii) first replication sample (n¼186,
replication-1). The children were recruited at the Universities
of Marburg and Wu ¨rzburg in Germany. A diagnosis of dyslexia
was assigned when the result of an age appropriate spelling
test was at least 1 s.d. lower than expected on the basis of
intelligence quotient measurements.26In each individual, two
mathematical abilities were tested (Supplementary Methods),
among others.27Briefly, arithmetic abilities were assessed
using addition and multiplication tasks. The two scores were
then combined, and the mean was calculated as a measure of
mathematical calculation phenotype (mathematical calcula-
tion, MC). A second task addressed NJ. For NJ, subjects were
asked to make judgements on the number of objects or dots
presented. In a previous study, a principal component analysis
revealed that MC and NJ contributed to a common ‘basic
mathematical ability factor’ (BMAF).27
recalculated for the present data, and was used as a third
This factor was
German–Austrian replication-2 sample. A total of 206
German (Munich) and 118 Austrian (Salzburg) children were
recruited within the context of the NeuroDys consortium. A
diagnosis of dyslexia was assigned if reading performance
was 0.75 s.d. below that expected on the basis of age and
intelligence quotient. Mathematical ability was assessed by
MC and NJ. For the genetic association analysis, MC and NJ
were Z-standardized, and the mean of both phenotypes was
used as a combined measure (BMAF).
process and test batteries used for the 214 controls from
controlsample. The ascertainment
Munich and the 207 controls from Austria were analogous to
those used for the German–Austrian replication-2 sample. To
be included as a control, the child was required to have a
reading performance of 0.85 s.d. above the age norm.
NJ) were analogous to those used for the German–Austrian
Twin Early Development Study (TEDS) sample. This sample
constituted a population-based sample. Children were
recruited as previously described,28and each performed
tests of reading, spelling and mathematical ability at the ages
of 7, 9 and 10 years. The mathematics-related phenotypes
were assessed by: (i) using and applying mathematics
(including addition and subtraction tasks); (ii) number tasks
(including NJ and counting); and (iii) the perception of
shapes, space and measures. All data were ascertained
according to an ordinal scale. To generate a quantitative
phenotype, standardized scores were summed and re-stan-
dardized. Given the genetic continuity of quantitative traits,2
an average of this score across the three age groups was
used. In the present analyses, 1081 unrelated individuals
with measurements at all three time points were randomly
chosen (one from each twin pair). This sample comprised
356 individuals who had been included in the previous study
by Docherty et al.4However, as rs133885 was not one of the
individually genotyped markers used in that study, this sample
can be considered an independent replication sample.
Genotyping. The genome-wide data were retrieved from a
previous GWAS on dyslexia that had been conducted
using the Illumina HumanHap300k BeadChips (Illumina,
San Diego, CA, USA). In the replication studies, single-
nucleotide polymorphisms (SNPs) for the single-marker and
haplotype analyses were genotyped using the Sequenom
MassARRAY iPlex Gold system (Sequenom, San Diego,
CA,USA) and the SpectroTYPER software v3.1 (Sequenom).
Statistical analysis. For the GWAS data, analysis of all
autosomal SNPs was performed using analysis of variance,
the WG-Permer software (http://www.wg-permer.org/), and
R,29as previously described.30Genome-wide significance
(Po7.2?10?08).31The quality parameters used in the
replication samples and the GWAS sample were identical.
Quantitative association analyses of the replication and
combined samples were also conducted with R (using the
glm option in the R-library stats). The covariates were:
(i) sample origin (replication-2); and (ii) sample origin,
spelling and word reading (combined samples).
Haplotypic effects were first tested in the genome-wide
data, using a sliding window approach for up to five SNPs
(including rs133885). Nominal significant haplotypes were re-
analyzed in the replication-1 sample. Haplotypic P-values and
linkage disequilibrium measures were calculated using
PLINK.32Power analysis was performed post hoc, using the
Genetics Power Calculator33and the settings ‘no dominance’,
‘singletons with no parental genotypes’ and a genotypic
frequency of 0.317 (corresponding to the GG genotype in
CEU HapMap-individuals). Effect sizes were estimated using
MYO18B associated with mathematical ability
KU Ludwig et al
the R2-goodness-of-fit measure and two settings: (i) the R2for
each subsample; and (ii) the weighted average of R2across
both dyslexia- and non-affected samples, respectively
(Supplementary Table 3).
Sequencing analysis. Sequencing of the first four exons of
MYO18Blongwas performed exon-wise, in 35 children
(replication-1 sample), according to standard procedures.
Briefly, PCR products were purified using Agencourt AMPure
(Beckman Coulter, Krefeld, Germany) and sequenced in
both directions. Sequencing products were purified by
Agencourt CleanSEQ (Beckman Coulter, Krefeld, Germany)
and run on an ABI Capillary Sequencer (3130XL, Applied
Biosystems, Darmstadt, Germany). Data were analyzed
using ChromasLite 2.0 (http://technelysium.com.au/). Detected
variants were followed-up in the entire discovery sample.
Primer sequences and protocols are available on request.
Expression analysis. Expression analysis for MYO18B was
performed using N-terminal primers for MYO18Blong, and
primers for the core region of MYO18B (overlapping in
MYO18Blongand MYO18Bshort). Primers for glyceraldehyde
3-phosphate dehydrogenase were used as housekeeping
customary multiple tissue complementary DNA panels (Human
MTC-panel Human I (Lot-Nr.7080213); and Fetal (Lot-Nr.
7060067, all Clontech/Takara Bioscience, Saint-Germain-en-
Laye, France)). PCR products were assessed on a 1%
agarose gel. MYO18B identity was confirmed by sequencing.
Primer sequences and protocols are available on request.
were obtained from
Structural MRI analysis. A structural MRI study was
performed to measure sulcal depth in the IPS. This involved
automated sulcus allocation and a feature extraction pipe-
line. Voxel-based morphometry (VBM) was used to explore
genotype-dependent differences in regional gray matter
volume. The genotypic and imaging data were retrieved
from an independent genetic study34of 100 neuropsychia-
trically healthy adult subjects. All details of subject charac-
teristics, MRI sequence parameters, image postprocessing
steps and the software used for sulcus morphology analysis
and VBM are provided online (Supplementary Methods,
Supplementary Table 4). Briefly, sulcus morphology analysis
was directed to the bilateral IPS that contains the horizontal
segment (subsequently referred to as IPSmain). The bilateral
central sulcus was chosen as a control structure. The average
sulcus depth and the total sulcus volume of all classified sulci in
each hemisphere were calculated for later use as covariates.
Statistical analysis was performed using analysis of covariance,
and the covariates age, gender, and the average sulcus depth
or the total sulcus volume. Post hoc, the sulcus measures area
surface and length were analyzed for the right IPSmainonly to
complete the morphometric characterization. After optimal
intersubject co-registration, whole-brain VBM was performed
in the same sample using the conservative cluster-based
statistical inference method.
Initial GWAS. A Q–Q plot for the BMAF analysis is shown in
Figure 1 (for MC and NJ, see Supplementary Figure 1). No
significant deviation was observed. One SNP (rs133885)
reached genome-wide significance with BMAF, and two
SNPs (rs1399428 and rs4837521) attained this level with NJ,
based on Po7.2?10?08(Table 1, Figure 2, Supplementary
Figure 2). None of these three markers showed significant
association with dyslexia.
Replication in dyslexia samples. In the replication-1 sample,
association between rs133885 and BMAF was confirmed
(P¼0.0049), but replication failed for the two other SNPs
(Table 1). In the combined German sample, the association
for rs133885 was strongest in the dominant/recessive model,
with carriers ofthers133885
weaker performance in mathematical tasks than AA/AG
carriers (P¼8.81?10?10, carrier-A model, Supplementary
Figure 3). Calculation of the fraction of BMAF variance that
was accounted for by rs133885 yielded an estimated effect
size of 9.4%. Haplotype analyses did not improve P-values
for the association with BMAF, compared with rs133885
alone (Supplementary Table 5).
Genotyping rs133885 in the dyslexia replication-2 sample
revealed a significant BMAF association (P¼0.0446). Com-
bining all cases resulted in a P-value of 7.71?10?10. At least
a trend toward association was found for MC and NJ, but
neither of these two measures was solely responsible for the
association (SupplementaryTable6).Assomeofthe dyslexia
cases showed very low values for BMAF, an inverse rank-
based transformation was performed to achieve a more
normal distribution. Thereafter, the P-value remained gen-
Table 7). The overall effect size for the association between
(BMAF).Q–Q plot of the GWAS of 200 German dyslexia patients: the distribution of
expected (under the null-hypothesis) and observed w2values for the genotypic
model are depicted. Adherence to the diagonal, which is almost perfect in the lower
parts of the distribution, indicates no inflation of the statistics.
Quantile–Quantile (Q–Q) plot for the basic mathematical ability factor
MYO18B associated with mathematical ability
KU Ludwig et al
rs133885 and BMAF in samples with dyslexia was 4.87%
Replication independent of dyslexia. Genotyping rs133885
in the population-based TEDS sample revealed a significant
P-value of 0.048 (Table 2). As the phenotypes ‘numbers’ and
‘using and applying mathematics’ are the most comparable
to BMAF, we recalculated the association for TEDS after
removing the phenotype ‘shapes, space, and measures’. The
Table 8). The rs133885 association in the German–Austrian
control sample was in the same direction, although it did not
reach significance (P¼0.486, Table 2).
Sequencing analysis. The SNP rs133885 maps to the
MIM607295). Two distinct MYO18B protein isoforms have
been identified: MYO18Blong(2567 amino acids, SwissProt
accession number Q8IUG5-1); and MYO18Bshort(2080
amino acids, Q8IUG5-2). The p.E44G substitution mediated
by rs133885 is located in the N-terminus specific to
MYO18Blong. Sequencing of this N-terminal region revealed
the presence of three common variants, two of which
(rs61734946 and rs13058434) were non-synonymous. In
the discovery sample, rs61734946 was strongly associated
with mathematical abilities, but this effect was driven by
rs133885 (Supplementary Table 9). The SNP rs13058434
(p.P177L) showed nominally significant association with
BMAF in the subgroup of children who were not-at-risk
according to rs133885 genotype.
Expression analysis. Glyceraldehyde 3-phosphate dehy-
drogenase expression was found in all analyzed tissues and
stages. MYO18Blongwas expressed in all tissues except
brain and adult lung, and strong expression was found in
skeletal muscle and heart. The core part of MYO18B was
abundant in all tissues, including adult brain. However, this
expression was not observed in the developing fetal brain
(Supplementary Figure 4).
Structural MRI analysis. The results of the sulcus analysis
on 79 individuals are shown in Figure 3. In carriers of the
rs133885 GG-genotype, a lower average depth of the
IPSmain (mean±s.d. 23.18±2.62 versus 24.70±2.05mm;
F1,74¼11.74, P¼0.001) was observed after adjustment for
age, gender and average right-hemispheric sulcus depth.
Similar results were obtained for right IPS sulcus volume
(1665±535 versus 1900±425mm3; F1,74¼4.69, P¼0.033;
see Supplementary Results for surface area and sulcus
length). In the left hemisphere, genotype effects were in the
same direction, with a trend level for IPS depth (24.79±2.15
versus 25.41±2.14mm; F1,74¼3.69, P¼0.059); but non-
significant for sulcus volume (P¼0.167). No genotype effect
was found for the depth or volume of the central sulcus in
either hemisphere (P40.4; Figure 3).
Association results of the GWAS of 200 German dyslexia patients for the genotypic
model. Genomic position along the 22 autosomes is represented on the x axis;
?log10(P-value) is represented on the y axis. SNPs with a nominal P-value below
wide significance (Po7.2?10?08).
Table 1 SNPs with genome-wide significance (Po7.2?10–08) in the GWAS sample
P-values German sampleb
rs1399428 (NJ)9120 660 568 NAgenotypic
rs4837521 (NJ)9120 654 461NA
rs133885 (BMAF)22 26 159 289 MYO18B
Abbreviations: BMAF, basic mathematical ability factor; GWAS, genome-wide association study; het., heterozygous; hom., homozygous; NA, not assigned; NJ,
numerosity judgement; SNP, single-nucleotide polymorphism.
aGenetic models with a P-value o10?05for the specific phenotype (discovery-sample).bP-values in bold if genome-wide significant (discovery-sample), or Po0.05
(replication-1 sample).cRisk alleles not identical between discovery and replication-1 sample.
MYO18B associated with mathematical ability
KU Ludwig et al
Table 2 Association analyses for rs133885 in dyslexia, control and population-based samples
Genotypes AA/AGGenotype GGP-valueb
All case samplesd
All control/ population
Abbreviations: BMAF, basic mathematical ability factor, as defined in the respective samples; N, number of observations; TEDS, Twin Early Development Study.
aAfter quality control. No deviation from Hardy–Weinberg was observed for any of the samples. Demographic details of the samples are presented as Supplementary
Material online.bOne-sided, except for the German discovery and combined samples (carrier-A model). Sample origin was used as a covariate in replication-2.
cMeasures based on R2-goodness-of-fit coefficient. Inthe presenceof covariates, effect size wasbased onthe difference between theR2-coefficient inthe full model,
reading as covariates.
representative cases are shown. Note inter-individual variance of IPS geometry. Structural measurements were made for the depth (b) and volume (c) of the hypothesized
sulcusanda controlsulcus(centralsulcus).AnalysisofcovariancecomparingA-allelecarrierswith non-A-allelecarrierswasperformedfor bothmeasures,andwascorrected
for age,gender,andhemisphere averagesfor sulcaldepth andvolume,respectively.Bars showestimatedmeans and1 s.e.m. *Po0.05;**Po0.0063(Bonferroni-corrected
Morphological analysis of the intraparietal sulcus (IPS). (a) Automated assignment was performed for right IPS segmentations and central sulcus. Three
MYO18B associated with mathematical ability
KU Ludwig et al
The effect on the depth of the right IPSmain withstood
correction for multiple testing (Pcorrected¼0.008). Regional
specificity was emphasized by an explorative analysis of all
extracted sulci, which yielded no stronger association than
that obtained for IPSmain (Supplementary Results). VBM
analysis revealed no significant genotype effect on regional
gray- or white matter volume (Supplementary Results).
In this study, we systematically investigated genetic
variants contributing to mathematical abilities. Genome-
wide data were retrieved from a GWAS of dyslexia, in view
of previous reports that the prevalence of mathematical
deficits is higher in dyslexia compared with the general
population.7,8Phenotypic data on mathematical performance
were available for all children, thus enabling a quantitative
Although three variants were genome-wide significant, only
rs133885 was successfully replicated. The other two SNPs
rs4837521) and showed genome-wide significance with NJ.
They are around 6.1kb apart and share high LD (r2¼0.71,
D0¼0.88), indicating that they reflect the same effect.
Unexpectedly, however, we failed to replicate this association
in the replication-1 sample, which may be due to a number of
reasons. First, children included in the GWAS were more
severely affected with dyslexia compared with children in the
replication-1 sample. It is therefore possible that the genetic
effect of the 9q33.1 locus on mathematical ability is triggered
by the severity of spelling impairment. A second possible
explanation is that the two markers appeared among the top
quantitative trait analyzed.
It also has to be mentioned that it is highly possible that
genetic components mainly defining NJ or MC may exist. By
restricting our replication study to the three top hits, we
might have missed other possible causal variants. Further
experiments are therefore warranted to dissect the contribu-
tion of the 9q33.1 locus and of other yet unknown loci to
rs133885 was replicated with an estimated effect size of
9.4% in the German sample. Although this might be an
data, the observation of 3.6% in the replication-1 sample
independently supports a strong contribution of rs133885 in
individuals with spelling disorder. The difference in effect
sizes, however, may also be attributable to the different
degrees of dyslexia severity in the samples. Results of a
stratification analysis in the German sample support this
hypothesis, as an increasing effect size was observed with
increasing degree of spelling disorder (Supplementary
Table 10). An even lower effect size was observed in the
replication-2 sample. Although this may have resulted from
simple power issues, this observation might also reflect
potential differing underlying core deficits in children with
spelling disorder (initial, replication-1), and those with a
disorder in reading (replication-2).
Although different phenotypic measures were used for the
assessment of the complex construct of mathematical
abilities, a consistent pattern of findings emerged from our
MCs and NJ. Our measures of mathematical abilities
(accuracy and fluency of mental addition and multiplication)
that are typically experienced by dyslexic individuals and the
genetic association might reflect these particular problems.
However, this is not the case for the very simple task of
number comparison. It has been claimed that arithmetical
abilities are built on an inherited core knowledge system that
can be assessed by such simple tasks35–37suggesting
that our findings are a direct indication for the genetic basis
of this numerical core knowledge, rather than mathematical
ability as such.
The aforementioned results suggest that rs133885 con-
tributes to mathematical performance in children with dys-
lexia, and that a more pronounced effect is found in those with
spelling disorder. On the basis of this, we investigated
whether rs133885 was associated with mathematical perfor-
mance independent of weak reading or spelling disabilities.
Although we observed a nominally significant association in
the population-based sample, no statistically significant
association was observed in children with superior reading
performance (unfortunately, no sample showing superior
spelling performance was available). However, the observa-
tion of a trend in the hypothesized direction suggests that an
effect of rs133885 might be detected in larger samples
(Supplementary Table 3). We also attempted a subgroup
analysis of the TEDS, involving only those individuals with a
weak performance in both the mathematical and the reading–
spelling tasks. However, only a few individuals met these
criteria, and so this analysis could not be completed (data not
shown). In total, our results give rise to the hypothesis that the
association between rs133885 and mathematical abilities is
enhanced in dyslexic individuals. One possible explanation
therefore might be the lack of compensatory mechanisms in
dyslexic individuals, which render the genetic effect more
pronounced at phenotypic level and, thus, more likely to be
detected in smaller samples.
The associated variant rs133885 encodes an amino-acid
within MYO18Blong(p.E44G). MYO18B belongs to the family
of unconventional myosins,38and has been implicated
in carcinogenesis39,40and the composition of myofibrillar
structures.41The functionally relevant position of rs133885
suggests that the variant is causative, and this was supported
by the results of the haplotype analyses. Based on recent
evidence suggesting the presence of important actin-binding
sites within the MYO18B N-terminus42,43(Supplementary
sequence alterations of the N-terminus might also affect
mathematical performance. Although no novel variants were
detected, the independent association of a second common
non-synonymous variant p.P177L suggests that additional
N-terminal alterations within MYO18Blongmay contribute to
The functional consequences of rs133885 are difficult to
predict at the time of writing. The expression of both MYO18B
with the reported function of MYO18B in myocardial struc-
tures.41Although substantial MYO18Bshort-expression was
and heart is consistent
MYO18B associated with mathematical ability
KU Ludwig et al
observed in the adult brain, no evidence was obtained for
MYO18B-expression in the developing fetal brain. However,
as the fetal customary complementary DNA panel comprised
tissues from 20 to 30 weeks old fetuses, the relevant
developmental time point might have been missed. If
MYO18B is expressed at other developmental time points,
this might explain the failure to detect MYO18B expression in
the fetal samples. Interestingly, one previous study demon-
strated a contribution of MYO18B to cognitive pheno-
types.44,45In one of the largest GWAS case–control studies
of schizophrenia performed to date,45a variant located in the
first exon of MYO18Blongwas among the most strongly
associated SNPs (rs5761163). Analysis of this variant in our
GWAS datarevealed an
(P¼0.00546), although this effect disappeared when the
analysis was conditioned on rs133885 (P¼0.19).
On the functional level, the sulcus analysis of the IPS
demonstrated that carriers of the associated rs133885
GG-genotype showed a lower average depth of the right
IPSmain. The identification of this intermediate phenotype is
well concordant with the fact that basic features of gyrogen-
esis andsulcal morphology
The lack of differences in gray matter and white matter
volume as measured by VBM is divergent from previously
reported VBM comparisons between dyscalculic subjects and
respective age-matched healthy controls. In 9-year-old
children with developmental dyscalculia, Rotzer et al.22found
reduced gray matter volume in the right IPS andcingulofrontal
areas and Rykhlevskaia et al.,24in the same age class, found
reduced gray matter volume in more widespread occipital,
cerebellar and posterior parietal regions. Isaacs et al.23
revealed increased gray matter density, a measure sensitive
to mesoscopic gyral differences, in the left parietal lobe in
dyscalculic adolescents with a history of preterm birth.
Several points may underlie the divergence between
these results and our result: mainly, these reports studied
subjects with a clinical manifestation of dyscalculia whereas
the variance of the continuous behavioral phenotype
explained by the genotype in this study ranged below 10%.
This suggests that also at the brain level lower genotype-
dependent effects may be expected compared with altera-
tions in subjects that have impairments classifiable as
dyscalculia. Although we have directed our analysis to the
IPS based on converging evidence for this area being key to
the representation of numerosity, formally, our MRI analysis
was explorative as no generally accepted structural or
functional imaging endophenotypes of arithmetic abilities
(or dyscalculia) have been defined yet. Recent GWAS
imaging studies, however, point out, that even for validated
imaging endophenotypes such as hippocampal volume, the
strongest detectable genetic univariate effects are not
necessarily stronger than typical associations with a neurop-
sychiatric phenotype.48A second reason for not detecting
VBMassociations may lie in the age discrepancy between our
MRI sample and previous VBM reports of dyscalculia. This
latter assumption is strengthened by the close analogies
between our results and the report of Molko et al.25who
performed a multimodal study on adult Turner syndrome
patients with dyscalculia, finding right-emphasized IPS
structural differences in the sulcal analyses but only marginal
gray matter alterations. Presumably, among the structural
techniques, sulcus measurements could be more sensitive
to gyral folding differences than VBM, which is not a
surface-based technique yet, except for Molko et al.,25no
combined sulcus/VBM analyses have been reported to allow
for in-depth cross-correlation of these techniques.
Although involvement of the IPS in numerical processing
has been well established,10recent evidence suggests that
other brain areas are also involved,9depending on task
specificities such as the type of calculation (accurate versus
approximate) and type of number representation (symbolic
versus non-symbolic). To determine whether our findings
were specific to the IPS, we expanded our sulcal analysis to
58 sulci from each hemisphere. In the right hemisphere, one
structure (superior temporal sulcus) showed nominal signifi-
cance. In the left hemisphere, six additional sulci showed
nominal significance with no particular regional specificity for
the IPS. Despite the lack of behavioral data to demonstrate a
direct association between sulcus measures and arithmetic
abilities in this same study, MRI findings support the
hypothesis of a specific association between rs133885 and
variability in the structure of the right IPS, with weaker
left-hemispheric associations possibly related to the symbolic
representation of numbers in the original arithmetic tests.9
Although there is evidence from functional studies that non-
symbolic numerical processing is represented in the IPS as
early as at age 4 with continuity into adulthood,19a direct
extrapolation of our structural results to young age is
hampered by limited knowledge on the trajectories of the
here studied sulcus measures over the life span in humans.
Hence, although the here reported sulcal variations represent
a plausible first neural correlate, further structural cortex
measures and functional MRI activation studies on younger
samples with genetic and phenotypic characterization are
essential to understand which dimensions of arithmetic
operations are impacted by rs133885.
In summary,this study identified a non-synonymous variant
in MYO18B as the first genome-wide significant marker to
contribute to human mathematical ability. Our data provide
evidence that weak spelling ability might be a modifying factor
for the strength of the observed association with rs133885.
population, albeit with a smaller effect size. At the level of an
between rs133885 and structural variability of the IPS, which
is a key structure in terms of numerical processing. We found
that healthy carriers of the MYO18B risk-genotype exhibited
reduced depth of the right IPS, thus implicating MYO18B in
cognitive processes. Future studies should elucidate how
genetic variation in this gene exactly relates to human
Conflict of interest
The authors declare no conflict of interest.
Acknowledgements. We thank the children and their families for
participating in the study. GSK, BMM and MMN were supported by the Deutsche
Forschungsgemeinschaft, and received funding from the EU, within the context of
MYO18B associated with mathematical ability
KU Ludwig et al
the Sixth Framework Program LifeScienceHealth project ‘Dyslexia genes and
neurobiological pathways’ (Neurodys, 018696). MMN received support for this work
from the Alfried Krupp von Bohlen und Halbach-Stiftung, JS was supported by a
NIH/DFG Research Career Transition Award. TEDS is funded by the UK Medical
Research Council (G500079). We are grateful to Anna Olyinyk for her support with
the image quality controlof the MRI sample,and Denis Rivierefor his support in the
employment of the BrainVisa(BV)/Anatomist software.
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MYO18B associated with mathematical ability
KU Ludwig et al