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Clinical Anatomy 00:0000 (2015)

ORIGINAL COMMUNICATION

The Ratios of 2nd to 4th Digit May be a Predictor


of Schizophrenia in Male Patients
ABDULLAH BOLU,1 TANER OZNUR,2* SEDAT DEVELI,3 MURAT GULSUN,2
EMRE AYDEMIR,2 MUSTAFA ALPER,2 AND MEHMET TOYGAR4
1

Aircrews Health Research and Training Center, Department of Psychiatry, Eskisehir, Turkey
2
Gulhane Military Medical Faculty, Department of Psychiatry, Ankara, Turkey
3
Gulhane Military Medical Faculty, Department of Anatomy, Ankara, Turkey
4
Gulhane Military Medical Faculty, Department of Forensic Medicine, Ankara, Turkey

The production of androgens (mostly testosterone) during the early fetal stage is
essential for the differentiation of the male brain. Some authors have suggested a
relationship between androgen exposure during the prenatal period and schizophrenia. These two separate relationships suggest that digit length ratios are associated with schizophrenia in males. The study was performed in a university
hospital between October 2012 and May 2013. One hundred and three male
patients diagnosed with schizophrenia according to DSM-IV using SCID-I, and 100
matched healthy males, were admitted to the study. Scale for the Assessment of
Positive Symptoms (SAPS), Scale for the Assessment of Negative Symptoms
(SANS) and Brief Psychiatric Rating Scale (BPRS) were used to assess schizophrenia symptoms. The second digit (2D) and fourth digit (4D) asymmetry index (AI),
and the right- and left-hand 2D:4D ratios were calculated. All parametric data in
the groups were compared using an independent t-test. The predictive power of
the AI was estimated by receiver operating characteristics analysis. The 2D:4D AI
was statistically signicantly lower in the patient group than the healthy control
comparison group. There were signicant differences between the schizophrenia
and the control groups in respect of left 2D:4D and right 2D:4D. There was no correlation between AI, left, or right 2D:4D, BPRS, or SAPS in the schizophrenia
group. However, there was a negative correlation between left 2nd digit (L2D):4D
and the SANS score. Our ndings support the view that the 2D:4D AI can be used
as a moderate indicator of schizophrenia. Even more simply, the right or left
2D:4D can be used as an indicator. L2D:4D could indicate the severity of negative
symptoms. Clin. Anat. 00:000000, 2015. VC 2015 Wiley Periodicals, Inc.
Key words: schizophrenia; digit ratio (2D:4D); asymmetry index

INTRODUCTION
Schizophrenia is a progressive, chronic, complex
brain disease with a multifactorial etiology leading to
social incapacity. It is a cause of disability worldwide.
There is accumulating evidence that schizophrenia is
produced by abnormalities in the brain resulting from
factors such as developmental impairment (Arato et al.,
2004; Compton and Walker, 2009; Libin et al., 2014). It
has been suggested that testosterone inhibits the
growth of certain areas of the left hemisphere and facilitates development of the corresponding areas in the
right hemisphere (Geschwind and Behan, 1982).

C
V

2015 Wiley Periodicals, Inc.

Abbreviations used: AI, asymmetry index; BPRS, Brief Psychiatric Rating Scale; L4D, left 4th digit; L2D, left 2nd digit;
R4D, right 4th digit; R2D, right 2nd digit; SANS, Scale for
the Assessment of Negative Symptoms; SAPS, Scale for the
Assessment of Positive Symptoms
*Correspondence to: Taner Oznur, Department of Psychiatry,
Gulhane Military Medical Faculty, Etlik, Ankara 06018, Turkey.
E-mail: drtaneroznur@gmail.com
Received 14 October 2014; Revised 27 January 2015; Accepted
28 January 2015
Published online in Wiley Online Library (wileyonlinelibrary.com).
DOI: 10.1002/ca.22527

Bolu et al.

Fig. 1.

The measurement of 2nd and 4th digit.

The production of testicular hormones (mostly testosterone) during the early fetal stage, around the third
month, is essential for the differentiation of the male
brain. Prenatal testosterone exposure could be considered a negative prognostic factor for schizophrenia.
Perhaps in relation to the situation, male patients seem
more prone to a poor prognosis in a neurodegenerative
subtype of schizophrenia than female patients (Castle
and Murray, 1991; Salem and Kring, 1998). It is difcult to evaluate prenatal estrogen:testosterone ratios
directly in humans for ethical reasons.
According to one hypothesis (Manning and Bundred,
2000), the ratio (2D:4D) of index nger length (second
digit, or 2D) to ring nger length (fourth digit, or 4D)
can be used as a marker and predictor for a variety of
disorders associated with a disturbed testosterone:es-

Fig. 2. Comparison of 2D: 4D and assymetry indexes


between SCH and control groups. [Color gure can be
viewed in the online issue, which is available at wileyonlinelibrary.com.]

trogen balance. THe measurement of digit ratio asymmetry has attracted interest, especially as it has been
shown that 2D:4D reects the asymmetry of the limbic
system, particularly the hippocampus (Kallai et al.,
2005). A previous study revealed a higher right 2nd
digit (R2D):4D in male schizophrenia patients than
healthy male controls (Collinson et al., 2010).
In this study, we compared the ratio of 2D (2nd
digit) to 4D (4th digit) among schizophrenia patients
and healthy control subjects. Another aim was to evaluate the relationship between this ratio and schizophrenia. The hypothesis of the study was as follows:
The ratio of 2D to 4D is higher in schizophrenia
patients than controls. If the hypothesis is correct,
then this ratio can be used as a predictor of
schizophrenia.

TABLE 1. The Comparison of Height, Age, and Finger Length Measurements of Schizophrenia and
Healthy Control Group
Schizophrenia group
(n 5 103)
Height (m)
Age
R2D (mm)
L2D (mm)
R4D (mm)
L4D (mm)
R2D/4D
L2D/4D
2D:4D AI
SANS
SAPS
BPRS

Control group (n 5 100)

Mean

SD

Mean

SD

Comparison
t-, P-values

1.755
22.728
73.952
73.730
76.176
76.139
0.972
0.969
20.001
41.39
48.87
42.49

0.060
3.612
4.047
3.971
4.411
4.490
0.037
0.039
0.014
9.83
7.76
5.82

1.768
21.98
70.677
72.821
73.708
72.635
0.959
1.004
0.022

0.055
2.707
3.969
4.215
4.136
4.458
0.036
0.042
0.023

1.566, 0.119
1.184, 0.097
5.821, 0.001
1.582, 0.115
5.560, 0.001
4.109, 0.001
2.385, 0.018
6.029, 0.001
8.723, 0.001

Abbreviations: R2D, right 2nd digit; R4D, right 4th digit; L2D, left 2nd digit; L4D, left 4th digit.

Digit Ratio and Schizophrenia

TABLE 2. The Correlations Between SANS, SAPS, BPRS Scores, and Finger Length Measurements

Right 2D
Right 4D
Right 2D:4D
Left 2D
Left 4D
Left 2D:4D
2D:4D AI

SANS
(r-, P-values)

SAPS
(r-, P-values)

BPRS
(r, P-values)

20.200*, 0.043
20.231*, 0.019
0.129, 0.195
20.172, 0.082
0.059, 0.552
20.243*, 0.013
0.087, 0.381

20.100, 0.314
0.054, 0.588
20.065, 0.516
20.151, 0.127
20.059, 0.554
20.121, 0.225
20.080, 0.419

20.186, 0.060
20.122, 0.219
20.083, 0.407
20.167, 0.091
20.159, 0.110
0.012, 0.908
0.121, 0.223

Abbreviations: SANS, Scale for the Assessment of Negative Symptoms; SAPS, Scale for the Assessment of Positive
Symptoms; BPRS, Brief Psychiatric Rating Scale; R2D, right 2nd digit; R4D, right 4th digit; L2D, left 2nd digit; L4D,
left 4th digit.

PATIENTS AND METHODS


Participants
The participants were 103 male Turkish patients
(age, 22.7 6 3.6 years, mean 6 SD) diagnosed with
schizophrenia according to DSM-IV criteria and hospitalized in our clinic, and 100 matched healthy male
Turkish controls. The control group was selected from
hospital staff members with similar sociodemographic
features who had been judged psychiatrically normal
during regular periodic health controls. Only Caucasian men from the Turkish population were included in
the study, the homogeneity being intended to eradicate confounding factors arising from anthropological
differences. The study was performed between October 2012 and May 2013.

Ethical Approval
This study was approved by the local ethics committee. The required permissions to examine the
patient les were provided by the management of the
institution. The study was designed on the basis of
the principles of the Helsinki Declaration.

Psychiatric Diagnosis
We used the Structured Clinical Interview for DSMIV axis I disorders (SCID-I) criteria, a validated and
reliable semi-structured method for establishing the
major DSM-IV Axis I for diagnosing psychiatric disorders (First et al., 1996).

Scales
The Scale for the Assessment of Positive Symptoms
(SAPS), Scale for the Assessment of Negative Symptoms (SANS), and Brief Psychiatric Rating Scale
(BPRS) were used to assess schizophrenia symptoms.
The SAPS was developed by Andreasen to measure
the level, distribution, and change of severity of positive symptoms of schizophrenia (Andreasen, 1990).
The validityreliability of the Turkish version was studied by Erkoc
et al. (1991a, b).
The SANS was developed by Andreasen to measure
the level, distribution, and change of severity of nega-

tive symptoms of schizophrenia (Andreasen, 1990).


The validityreliability of the Turkish version was studied by Erkoc
et al. (1991a, b).
The BPRS was developed by Lukoff et al. (1993)
and was translated into Turkish by Soykan (1989).1 It
measures the severity of psychotic symptoms and
some depressive mood symptoms in schizophrenia
and other psychotic disorders.

Finger Length Measurements


The measurements were taken from the palmar
side of the hand according to anatomical position with
a digital caliper (Mitutoyo Digimatic) (Fig. 1).
The 2nd and 4th digits were measured from the
basal crease to the tip of the nger. Each nger was
measured three times with a ruler and the arithmetic mean of these measurements was used for statistical analysis. Discrimination between these
measurements was no higher than 0.02 mm. Discrimination among repeated measurements was no
higher than 0.1 mm. The digit lengths (2D and 4D)
were measured from the proximal nger crease to
the tip using a digital vernier caliper with an accuracy of 0.01 mm. The rater (RA) was blind to the
study hypothesis at the time of measurement. There
was good inter-rater reliability (assessed by two
raters, RA and GV, on 10 participants), with an intraclass correlation coefcient of 0.9 for both right and
left 2D:4D. The 2D:4D asymmetry index (AI) was
calculated according to the following formula,
reported by Venkatasubramanian (2011):
2D : 4D AsymmetryIndex

L2D : 4D2R2D : 4D
(1)
L2D : 4D1R2D : 4D

These ratios were compared between the schizophrenia and the healthy control groups.

Statistics
SPSS for Windows version 16.0 was used for statistical analysis. Descriptive analyses are presented as
1

Institutional differences, and case typicality as related to


diagnosis system severity, prognosis and treatment (Unpublished). Middle East Technical University, Ankara (Masters
thesis).

Bolu et al.
case for the left 2D (t 5 1.582, P 5 0.115). Both left
4th digit (L4D) (t 5 5.56, P < 0.001) and right 4th digit
(R4D) (t 5 4.109, P < 0.001) were longer in the schizophrenia group than the control group. The left 2nd
digit (L2D):4D ratio was higher in the schizophrenia
group (t 5 6.029, P < 0.001) but the R2D:4D ratio was
lower (t 5 2.385, P 5 0.018) (Table 1) (Fig. 2).
There was no correlation between the nger length
measurements and the BPRS or SAPS scores (P > 0.05),
but there was a negative correlation between the SANS
score and right 2D length (r 5 20.200*, P 5 0.043) in
the schizophrenia group. There was also a negative correlation between the SANS score and the right 4D length
(r 5 20.231*, P 5 0.019) and the left 2D:4D ratio
(r 5 20.243*, P 5 0.013) (Table 2).
The use of AI values for predicting schizophrenia
was evaluated using ROC curve analysis. The AUC was
0.801 (range, 0.7390.863) (Fig. 3). Multiple cut-off
values were determined from the AI. When the AI was
0.084, the sensitivity was 80%, specicity 74%, positive predictive value 75%, and negative predictive
value 79%. The sensitivity, specicity, and positive and
negative predictive values are listed in Table 3.

Fig. 3. ROC curve analysis that using AI values in


predicting presence of schizophrenia. [Color gure can be
viewed in the online issue, which is available at wileyonlinelibrary.com.]

means and standard deviations. Normal distribution of


data was conrmed by the KolmogorovSmirnov test.
Parametric data were compared between the groups
by an independent t-test. The correlation coefcients
and their signicance were calculated using the Pearson test.
The potential value of AIs for predicting schizophrenia was assessed by receiver operating characteristics
(ROC) curve analysis. When a signicant cut-off value
was observed, the sensitivity, specicity, and positive
and negative predictive values were recorded. The
threshold for statistical signicance was set at
P < 0.05.

RESULTS
The 2D:4D AI (t 5 8.723, P < 0.001) was lower in
the schizophrenia group than the control group. There
was no difference between the schizophrenia and the
healthy control groups in respect of height (t 5 1.566,
P 5 0.119) or age (t 5 1.184, P 5 0.238). The right 2D
was longer in the schizophrenia group than the control
group (t 5 5.821, P < 0.001) but the opposite was the

DISCUSSION
Our aim in this study was to investigate whether
2D:4D and the 2D:4D AI can be used as a predictor of
schizophrenia in the Turkish population. We found that
the R2D:4D ratios were statistically signicantly higher
in the schizophrenia patients than the control group,
but L2D:4D ratios were signicantly lower in the patient
group. A number of studies have indicated that some
phenotypic differences could be the predictors for certain diseases or syndromes. For example, the relationship between phenotype and schizophrenia has been
studied (Rosa et al., 2002; Arato et al., 2004; Huang
et al., 2010). Some authors believe that a disturbed
testosterone:estrogen hormone balance can be used
as a marker and predictor for it (Manning and Bundred,
2000). The relationship between gonad differentiation
and the formation of ngers and toes led to the conjecture that patterns of digit and toe morphology correlate
with gonad function in the fetus and adult (Manning
et al., 1998). Some authors have proposed that the
2D:4D ratio indicates potentially critical prenatal exposure to androgens (Muller et al., 2013).
We found the right-hand 2D:4D ratio to be signicantly higher and the left-hand ratio signicantly
lower in the schizophrenia group than the healthy
control group. The R2D:4D ratio nding was

TABLE 3. Sensitivity, Specicity, Positive, and Negative Predictive Values Obtained from ROC Analysis
That was Made by Using AI Values in Predicting the Presence of Schizophrenia
Cut-off
values of AI
0.084
0.012
0.015
0.002
20.001
20.010

Sensitivity (%)

Specicity (%)

Positive
predictive values (%)

Negative
predictive values (%)

80
85
91
59
48
27

74
65
55
80
85
94

75
71
67
75
76
82

79
81
86
66
62
56

Digit Ratio and Schizophrenia


consistent with Collinsons study (Collinson et al.,
2010). It has been reported that testosterone exposure affects central areas such as 2nd and 4th nger
growth and inuences cerebral lateralization (Geschwind and Behan, 1982; Honekopp et al., 2007).
According to some authors, testosterone inhibits the
growth of certain areas in the left hemisphere and
facilitates the development of the corresponding
areas in the right hemisphere (Geschwind and Behan,
1982). Our ndings, which indicate that the left- and
right-hand 2D:4D ratios are opposites, suggest that
testosterone affects nger ratios differently as it acts
in different ways on the left and right hemispheres of
the brain. However, we have insufcient data at present to explain the observations clearly (higher
R2D:4D ratio and lower L2D:4D ratios in schizophrenics than controls).
We also measured 2D:4D asymmetry, an index
consisting of left and right 2D and 4D to correct these
results, and we found that the 2D:4D AI was signicantly lower in the schizophrenia group than the control group. These ndings support cerebral
lateralization theories of schizophrenia (Venkatasubramanian et al., 2011). As in our ndings, other
authors have found the mean 2D:4D AI to be signicantly lower in male schizophrenia patients than
healthy male controls (Venkatasubramanian et al.,
2011). In addition, in contrast to the study of Collinson
et al. (2010), we found a relationship between the levels of negative symptoms in schizophrenia and
L2D:4D (P < 0.05). No similar relationship between
positive symptoms and BPRS scores with L2D:4D and
neurodevelopmental defects has been reported to be
in the foreground in schizophrenia with negative
symptoms (Arango et al., 2000; Galderisi et al., 2002;
Tiryaki et al., 2003). Therefore, a relationship can be
supposed between neurodevelopmental impairment
and L2D:4D in schizophrenia with negative symptoms.
However, to explain these ndings, we believe that to
explain a relationship between neurodevelopmental
impairment in schizophrenia and L2D:4D, biological
research including imaging methods is required.
AI ROC analysis showed moderate discriminatory
power and hence the AI has potential use as a diagnostic test for schizophrenia (Fig. 3 and Table 3).
When the cut-off point for the AI was set at 0.084,
the highest levels for schizophrenia were sensitivity
(80%) and specicity (74%).
The absence of brain imaging methods and a small
sample size are limitations of this study. In addition,
although excluding schizophrenic women is a limitation, it is also a strong aspect of the study because it
helped to ensure sample homogeneity.

CONCLUSIONS
In conclusion, the 2D:4D ratio and the 2D:4D AI
are easy-to-determine markers of prenatal androgen
exposure that have been evoked in numerous studies
of adult diseases and disorders including schizophrenia and autism. Our ndings support the view that the
2D:4D ratio, especially the 2D:4D AI, can also be
used as an indicator of schizophrenia.

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