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EFHC2 SNP rs7055196 is not associated with fear recognition in 45 X Turner syndrome.

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American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 147B:507 –509 (2008)
Brief Research Communication
EFHC2 SNP rs7055196 Is Not Associated
With Fear Recognition in 45,X Turner Syndrome
Andrew R. Zinn,1* Harvey Kushner,2 and Judith L. Ross3
Department of Internal Medicine and McDermott Center for Human Growth and Development,
University of Texas Southwestern Medical Center, Dallas, Texas
Biomedical Computer Research Institute, Philadelphia, Pennsylvania
Department of Pediatrics, Thomas Jefferson University, Philadelphia, Pennsylvania
The neurocognitive phenotype of Turner syndrome
(TS) includes deficits in social cognitive skills
such as recognition of the facial affect expressing
fear. A TS social cognition locus was previously
mapped to a 5 megabase interval of Xp11.3-p11.4 by
Good et al. [2003]. A recent study by these same
workers found evidence for association of a SNP
in the EFHC2 gene, rs7055196, within this interval
with fear recognition in 45,X TS. As EFHC2 was not
a biological candidate gene for this phenotype a
priori, we sought to replicate their finding in an
independent cohort of 45,X TS subjects, using
the same instrument to measure facial affect fear
recognition. In contrast to the previous results,
we find no evidence of an association between
rs7055196 genotype and fear recognition. Other
variations in EFHC2 and other candidate genes
should be tested for association with social cognition in 45,X TS.
ß 2007 Wiley-Liss, Inc.
Turner syndrome; affect recognition; EFHC2
Please cite this article as follows: Zinn AR, Kushner H,
Ross JL. 2008. EFHC2 SNP rs7055196 Is Not Associated
With Fear Recognition in 45,X Turner Syndrome. Am
J Med Genet Part B 147B:507–509.
Turner syndrome (TS; 45,X, monosomy X) in adolescents
and adults is associated with deficits in the recognition of faces
and the identification of a ‘‘fearful’’ facial expression [Romans
et al., 1998; Ross et al., 2002, 2004; Lawrence et al., 2003],
which may be related to impaired social function and increased
risk of autism [Skuse 2005]. Skuse and co-workers mapped a
locus for TS social cognitive ability to a 5 megabase (Mb) critical
region of the X chromosome short arm, Xp11.3-p11.4, by
deletion mapping [Good et al., 2003]. Women with overlapping
This article contains supplementary material, which may
be viewed at the American Journal of Medical Genetics
website at
Grant sponsor: NIH; Grant numbers: NS42777, NS35554.
*Correspondence to: Andrew R. Zinn, 5323 Harry Hines
Boulevard, Dallas, TX 75390-8591.
Received 16 March 2007; Accepted 20 August 2007
DOI 10.1002/ajmg.b.30625
ß 2007 Wiley-Liss, Inc.
partial X chromosome deletions that included this region had a
social cognitive phenotype similar to that of 45,X women. Six
genes within this region were considered as candidates for the
social cognitive phenotype on the basis of escape from X
inactivation and reported brain expression: MAOA, MAOB,
NDP, DDX53, UTX, and USP9X [Jones et al., 1996; Lahn and
Page, 1997; Carrel et al., 1999; Hartzer et al., 1999; Jansson
et al., 2005]. These workers further investigated MAOB, which
encodes an isoform of monoamine oxidase isoform B, and
showed that MAOB platelet enzyme activity was reduced in
45,X TS versus 46,XX controls, consistent with the gene
escaping X inactivation [Good et al., 2003]. They hypothesized
that MAOB modulates central serotonergic activity, thereby
influencing amygdala cortical functional connectivity. However, in a subsequent study they found no association between
MAOB enzymatic activity and sociocognitive mentalizing
skills (attributing mental states to animated objects) that are
deficient in 45,X TS [Lawrence et al., 2007].
As an adjunct to human studies, the 39,X (XO) mouse has
been investigated as an animal model for TS cognitive
phenotypes. Isles et al. [2004] reported that 39,X mice show
increased fear reactivity and an altered pattern of GABAA
subunit expression in brain. Their data implicated haploinsufficiency of a gene outside of the mouse pseudoautosomal
region as the cause of the fear reactivity difference. There are
presently only four nonpseudoautosomal mouse genes known
to escape inactivation: Utx, Dbx, Jarid1c, and Eif2s3 [Isles
et al., 2004]. UTX and DDX3X, the human orthologs of Utx and
Dbx, respectively, are situated within the 5 Mb Xp11.3-p11.4
critical region for TS sociocognitive deficits [Good et al., 2003].
UTX is ubiquitously expressed and encodes a protein of
unknown function [Greenfield et al., 1998]. DDX3X encodes a
predicted RNA helicase that is most highly expressed in
hematopoietic cells [Chung et al., 1995]. There are also human
orthologs of the other two candidate mouse genes elsewhere on
Xp. JARID1C encodes a protein involved in transcriptional
regulation and chromatin remodeling [Jensen et al., 2005].
Mutations in human JARID1C have been shown to cause
X-linked mental retardation [Jensen et al., 2005; Santos et al.,
2006]. EIF2S3 encodes the gamma subunit of eukaryotic
translation initiation factor 2, a ubiquitious housekeeping
protein [Ehrmann et al., 1998]. Although mouse Eif2s3 mRNA
level is gene dosage-sensitive, the level of Eif2s3 protein is the
same in brains of XO, XX, and XY mice [Xu et al., 2006].
Recently, Skuse and co-workers performed a SNP association analysis of the 5 Mb critical region using 242 SNPs, an
initial sample of 93 adults with 45,X TS, and a replication
sample of 77 subjects with 45,X TS recruited in the United
Kingdom [Weiss et al., 2007]. They found no significant
association with any of the six a priori candidate cognitive
genes listed above. Instead, they found that EFHC2, another
gene within this region, was a quantitative trait locus (QTL) for
fear recognition in 45,X TS. Two SNPs less than 20 kb apart
within EFHC2, rs7887763, and rs7055196, were associated
Zinn et al.
with fear recognition (P ¼ 0.022). Because these SNPs were in
perfect linkage disequilibrium, only rs7055196 was further
analyzed. Although the frequency of the minor, risk allele for
the most strongly associated EFHC2 SNP, rs7055196, was only
0.088, it accounted for over 13% of the variance in facial
affect fear recognition. EFHC2 is a novel gene expressed in
brain and elsewhere predicted to contain a calcium-binding
domain and other conserved domains of unknown function.
The rs7055196 SNP was in linkage disequilibrium with nearby
SNPs, including a Ser430Tyr coding SNP, but because the
association was somewhat weaker for these other SNPs, Weiss
et al. [2007] proposed that noncoding or untyped variation in
EFHC2 is responsible for the observed association. No functional data were reported regarding variation in EFHC2
alleles, for example, expression differences.
We genotyped SNP rs7055196 in 97 predominantly Caucasian
subjects with 45,X TS, age >11 years, for whom we had fear
recognition data. Our subjects were recruited from pediatric
and adult endocrinology clinics in the United States. We used
the same instrument to measure facial affect recognition
[Ekman and Friesen 1976] as Weiss et al. [2007]. The test was
administered according to the standard protocol provided with
the test instructions. Photographs showing six frequently
expressed emotions (happiness, sadness, fear, anger, disgust,
and surprise) are shown for 10 sec. The answer sheet provides a
choice of six emotions. The subject is asked to select the one word
on the answer sheet which best describes the emotion expressed
in the photograph. The results are scored according to the percent
correct for each emotion. Nontransformed data were analyzed
using SAS 8.2 (Cary, NC). We treated the phenotype as a
continuous variable rather than an arbitrary dichotomous
selection in order to maximize the statistical power to detect a
genotype effect. Using the Genetic Power Calculator [Purcell
et al., 2003] with QTL variance 0.13, minor (risk) allele frequency
0.088, sample size 97, and alpha ¼ 0.05, our power to detect an
association was 96% if rs7055196 is in complete linkage
disequilibrium with the causal EFHC2 variation (D0 ¼ 1) and
83% if D0 ¼ 0.8 (Table 1). We had 80% power to detect an effect
size of 8% of the total QTL variance if D0 ¼ 1 and 12% if D0 ¼ 0.8.
We used a pre-designed Applied Biosystems (ABI) TaqMan1
allelic discrimination (AD) assay (ABI Part Number 4351379,
Assay ID: C__29047262_10) according to the manufacturer’s
Eighty-six subjects had the common A allele, and 11 had
the minor G allele, giving a minor allele frequency (MAF) of
0.113, not significantly different from that of 0.088 reported by
Weiss et al. [2007] (P ¼ 0.53, Fisher’s exact test). The mean
TABLE I. Power Calculations
Total QTL
Power, MAF ¼ 0.088,
D0 ¼ 1
Power, MAF ¼ 0.088,
D0 ¼ 0.8
MAF, minor allele frequency.
Fig. 1. Mean Facial Affect Fear Recognition score (% correct) of 45,X TS
subjects according to rs7055196 genotype. Data shown are mean þ SD.
Facial Affect Fear Recognition scores (percent recognition) for
our 45,X subjects who carried the different rs7055196 alleles
showed no significant difference: 49.8 26.5 (n ¼ 86) versus
46.2 26.1 (n ¼ 11), P ¼ 0.67, t-test (Fig. 1).
The study by Weiss et al. [2007] included only adult
women with TS, whereas our study population included both
adults and adolescents. However, this cognitive phenotype
has been shown to be present and stable in TS females across
a wide age range [Ross et al., 1995, 2002; Romans et al., 1998].
To test whether age differences could explain the lack
of association in our study, we performed ANCOVA with
rs7055196 genotype and age as covariates. The overall R
squared was only 0.005613. The overall F-ratio with age and
SNP genotype was 0.17 (overall P-value 0.7675). The P-value
for SNP genotype was 0.6846, and the P-value for age was
0.5535. The measure of skewness was 0.054 and the measure
of kurtosis was 1.04, so neither affected the results. The
complete battery of nonparametric tests available in SAS
8.2 were also run, and none showed a significant difference in
mean facial affect recognition score between SNP genotype
groups (data not shown).
Our results do not support the contention that fear
recognition as measured by recognition of facial affect is
associated with genetic variation in EFHC2 SNP rs7055196, at
least not in a typical North American 45,X TS cohort. Possible
reasons for the lack of replication include differences in ethnic/
racial makeup, IQ, visuospatial ability, or behavioral status
of the study groups, but this information was not given in
the previous study. In addition, there could be differences in
overall facial processing ability, which we did not measure.
Given possible genetic differences in the populations, other
SNPs in EFHC2 should be tested for association with fear
recognition in 45,X TS, followed by SNPs in other genes in the
Xp11.4-p11.3 interval, and in candidate genes elsewhere on
the X chromosome such as JARID1C.
The authors thank Purita Ramos and the UT Southwestern
Human Genetic Variation core laboratory for genotyping. The
study was supported by NIH grants NS42777, NS32531 (JLR)
and NS35554 (ARZ).
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