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Clinical Anatomy 00:00–00 (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

Aircrew’s 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 significantly lower in the patient group than the healthy control
comparison group. There were significant 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 findings 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. 00:000–000, 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).

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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

Prenatal testosterone exposure could be considered a negative prognostic factor for schizophrenia. L2D. Another aim was to evaluate the relationship between this ratio and schizophrenia. 1998). THe measurement of digit ratio asymmetry has attracted interest. 2.411 4.385.635 0. then this ratio can be used as a predictor of schizophrenia. The production of testicular hormones (mostly testosterone) during the early fetal stage. 2005).119 1.037 0. . male patients seem more prone to a poor prognosis in a neurodegenerative subtype of schizophrenia than female patients (Castle and Murray.139 0.490 0.458 0. 2010).49 0.036 0.707 3. right 4th digit..821.215 4. or 2D) to ring finger length (fourth digit.] trogen balance.136 4. If the hypothesis is correct. 0. [Color figure can be viewed in the online issue. 0.039 0.001 – – – Abbreviations: R2D. or 4D) can be used as a marker and predictor for a variety of disorders associated with a disturbed testosterone:es- Fig.001 8.029. The Comparison of Height.969 4. 0.82 1. 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-.022 – – – 0.76 5.566. 0.060 3. we compared the ratio of 2D (2nd digit) to 4D (4th digit) among schizophrenia patients and healthy control subjects.971 4.755 22. right 2nd digit.014 9. particularly the hippocampus (Kallai et al. 0. The hypothesis of the study was as follows: The ratio of 2D to 4D is higher in schizophrenia patients than controls. 1. It is difficult to evaluate prenatal estrogen:testosterone ratios directly in humans for ethical reasons. 0.109. especially as it has been shown that 2D:4D reflects the asymmetry of the limbic system.184. Perhaps in relation to the situation.097 5..001 1.98 70.004 0.055 2.560. 2000). 0.952 73.39 48. A previous study revealed a higher right 2nd digit (R2D):4D in male schizophrenia patients than healthy male controls (Collinson et al. around the third month. 1991.115 5.612 4. Age. P-values 1.730 76.018 6.001 4.023 – – – 1. The measurement of 2nd and 4th digit. 0. Comparison of 2D: 4D and assymetry indexes between SCH and control groups. is essential for the differentiation of the male brain.176 76.708 72. R4D.959 1. Fig.042 0.001 41. Salem and Kring.87 42. the ratio (2D:4D) of index finger length (second digit. left 2nd digit. which is available at wileyonlinelibrary.582.83 7. L4D. In this study.969 20. 0. left 4th digit.972 0. TABLE 1.047 3.2 Bolu et al.723.677 72.001 2.728 73.com.768 21. According to one hypothesis (Manning and Bundred.821 73.

381 20. Ethical Approval This study was approved by the local ethics committee.908 0.407 20. 1990). L4D. The study was performed between October 2012 and May 2013. 0. b). The SAPS was developed by Andreasen to measure the level. left 4th digit.225 20. 0. The control group was selected from hospital staff members with similar sociodemographic features who had been judged psychiatrically normal during regular periodic health controls.091 20. distribution. BPRS. Scales The Scale for the Assessment of Positive Symptoms (SAPS). 0.159. 1). 0.082 0. The BPRS was developed by Lukoff et al. 0. 0.127 20.9 for both right and left 2D:4D. R4D.552 20. 0. Only Caucasian men from the Turkish population were included in the study. The study was designed on the basis of the principles of the Helsinki Declaration. 1990).419 20. with an intraclass correlation coefficient of 0.087.043 20.167. The 2nd and 4th digits were measured from the basal crease to the tip of the finger. and case typicality as related to diagnosis system severity. and change of severity of nega- tive symptoms of schizophrenia (Andreasen. Ankara (Master’s thesis).110 0.223 Abbreviations: SANS. RA and GV.122. P-values) BPRS (r. on 10 participants). 0. and Brief Psychiatric Rating Scale (BPRS) were used to assess schizophrenia symptoms. (1993) and was translated into Turkish by Soykan (1989). b). reported by Venkatasubramanian (2011): 2D : 4D AsymmetryIndex ¼ ðL2D : 4D2R2D : 4DÞ (1) ðL2D : 4D1R2D : 4DÞ These ratios were compared between the schizophrenia and the healthy control groups.013 0. right 2nd digit. 0.314 0. R2D. 1996). 0. .100. 0.6 years. BPRS Scores. right 4th digit. the homogeneity being intended to eradicate confounding factors arising from anthropological differences.172. 0. (1991a. 0. 0.516 20. 0.129. P-values) SAPS (r-.059. Descriptive analyses are presented as 1 Institutional differences. 0.054.243*. There was good inter-rater reliability (assessed by two raters..231*.01 mm.Digit Ratio and Schizophrenia 3 TABLE 2.02 mm. Statistics SPSS for Windows version 16. Discrimination among repeated measurements was no higher than 0.1 It measures the severity of psychotic symptoms and some depressive mood symptoms in schizophrenia and other psychotic disorders. The 2D:4D asymmetry index (AI) was calculated according to the following formula.065. Scale for the Assessment of Positive Symptoms. 0. and change of severity of positive symptoms of schizophrenia (Andreasen.1 mm. The Correlations Between SANS. SAPS.080. Each finger was measured three times with a ruler and the arithmetic mean of these measurements was used for statistical analysis.186.0 was used for statistical analysis. mean 6 SD) diagnosed with schizophrenia according to DSM-IV criteria and hospitalized in our clinic.121. The SANS was developed by Andreasen to measure the level.151. The required permissions to examine the patient files were provided by the management of the institution. (1991a. P-values) 20.200*. 0.588 20. SAPS.219 20. 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. 22. Discrimination between these measurements was no higher than 0. The digit lengths (2D and 4D) were measured from the proximal finger crease to the tip using a digital vernier caliper with an accuracy of 0. and Finger Length Measurements Right 2D Right 4D Right 2D:4D Left 2D Left 4D Left 2D:4D 2D:4D AI SANS (r-.7 6 3. 0. Psychiatric Diagnosis We used the Structured Clinical Interview for DSMIV axis I disorders (SCID-I) criteria. and 100 matched healthy male Turkish controls. prognosis and treatment (Unpublished). L2D.554 20.019 0. left 2nd digit.012. The validity–reliability of the Turkish version was studied by Erkoc ¸ et al. a validated and reliable semi-structured method for establishing the major DSM-IV Axis I for diagnosing psychiatric disorders (First et al. PATIENTS AND METHODS Participants The participants were 103 male Turkish patients (age.083. The rater (RA) was blind to the study hypothesis at the time of measurement. Scale for the Assessment of Negative Symptoms.121.060 20. Scale for the Assessment of Negative Symptoms (SANS). Middle East Technical University. The validity–reliability of the Turkish version was studied by Erkoc ¸ et al. Brief Psychiatric Rating Scale. 0. distribution.195 20. 0.059.

043) in the schizophrenia group.012 0. ROC curve analysis that using AI values in predicting presence of schizophrenia. For example. P 5 0. We found the right-hand 2D:4D ratio to be significantly higher and the left-hand ratio significantly lower in the schizophrenia group than the healthy control group.566.019) and the left 2D:4D ratio (r 5 20.001) were longer in the schizophrenia group than the control group..001 20. specificity.05. which is available at wileyonlinelibrary. The sensitivity.029. 2004. P 5 0. 3.119) or age (t 5 1.001) but the R2D:4D ratio was lower (t 5 2. There was no difference between the schizophrenia and the healthy control groups in respect of height (t 5 1. Huang et al.231*.801 (range. The threshold for statistical significance was set at P < 0. P 5 0. P 5 0.243*.385. but L2D:4D ratios were significantly lower in the patient group. P < 0.] means and standard deviations.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.582. Arato et al. P 5 0. The potential value of AIs for predicting schizophrenia was assessed by receiver operating characteristics (ROC) curve analysis. the sensitivity was 80%.56. P < 0. the sensitivity. and negative predictive value 79%. 2000). The use of AI values for predicting schizophrenia was evaluated using ROC curve analysis.001) and right 4th digit (R4D) (t 5 4. The AUC was 0. We found that the R2D:4D ratios were statistically significantly higher in the schizophrenia patients than the control group. 3).115).. RESULTS The 2D:4D AI (t 5 8.821. Parametric data were compared between the groups by an independent t-test. 1998). P 5 0.002 20. Some authors have proposed that the 2D:4D ratio indicates potentially critical prenatal exposure to androgens (Muller et al. Fig. specificity 74%.018) (Table 1) (Fig. Specificity.com. The right 2D was longer in the schizophrenia group than the control group (t 5 5. There was no correlation between the finger length measurements and the BPRS or SAPS scores (P > 0.010 Sensitivity (%) Specificity (%) 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 . When the AI was 0. The relationship between gonad differentiation and the formation of fingers 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. and positive and negative predictive values were recorded. When a significant cut-off value was observed. but there was a negative correlation between the SANS score and right 2D length (r 5 20. Positive.238). The correlation coefficients and their significance were calculated using the Pearson test. case for the left 2D (t 5 1. P < 0.. Some authors believe that a disturbed testosterone:estrogen hormone balance can be used as a marker and predictor for it (Manning and Bundred. [Color figure can be viewed in the online issue. specificity.4 Bolu et al. Sensitivity.013) (Table 2). A number of studies have indicated that some phenotypic differences could be the predictors for certain diseases or syndromes. the relationship between phenotype and schizophrenia has been studied (Rosa et al. P 5 0. 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.. The R2D:4D ratio finding was TABLE 3. 2013).200*.084. There was also a negative correlation between the SANS score and the right 4D length (r 5 20. 0.739–0. P < 0. Multiple cut-off values were determined from the AI.109. P < 0. Both left 4th digit (L4D) (t 5 5.184. The left 2nd digit (L2D):4D ratio was higher in the schizophrenia group (t 5 6. Normal distribution of data was confirmed by the Kolmogorov–Smirnov test. 2010).084 0. 2).. and positive and negative predictive values are listed in Table 3.015 0.05). 2002. positive predictive value 75%.863) (Fig.001) was lower in the schizophrenia group than the control group.723.

Therefore. 1996. Castle DJ. Significance of morphological features in schizophrenia of a chinese population. Mod Probl Pharmacopsychiatry 24:73–88. Hu TM. Libin L. 1991. €ver F. Brief Psychiatric Rating Scale (BPRS) Version 3. a relationship can be supposed between neurodevelopmental impairment and L2D:4D in schizophrenia with negative symptoms. Wilson J. Negatif semptomları  erlendirme o € lc  inin gu  i ve gec  i..084. 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. other authors have found the mean 2D:4D AI to be significantly lower in male schizophrenia patients than healthy male controls (Venkatasubramanian et al. Ivanov MB. The ratio of 2nd to 4th digit length: A new predictor of disease predisposition? Med Hypotheses 54: 855–857. Proc Natl Acad Sci USA 79:5097–5100. Wang HF. Neurological signs and the heterogeneity of schizophrenia. Yu YH. Arango C. Am J Psychiatry 159:983– 990. Pini S. 2004. When the cut-off point for the AI was set at 0. 1991a. Chen SF. € Erkoc ¸S ¸. Maj M.. Liu YR. Arkonac ¸ O. luteinizing hormone and oestrogen. Ataklı C. English DR. 2010. 2011). In addition. Vita A. suggest that testosterone affects finger ratios differently as it acts in different ways on the left and right hemispheres of the brain. Expended Version. 2014. Buchanan RW.  M. Ataklı C. Liebert A. Adam Psikiyatri Ve No First MB. Kiss H. Kuo SW. Psychiatry Res 176:8–12. Nemes J. Cassano GB. 2010). although excluding schizophrenic women is a limitation. Bartholdt L.. migraine. Second to fourth Ho digit length ratio (2D:4D) and adult sex hormone levels: New data and a meta-analytic review.. Galderisi S. 2007). Lukoff D. Walker EF. we found a relationship between the levels of negative symptoms in schizophrenia and L2D:4D (P < 0. Daneluzzo E. 2013. 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Methods for assessing positive and negative symptoms. The neurodevelopmental basis of sex differences in schizophrenia. and developmental learning disorder. Prog Neuropsychopharmacol Biol Psychiatry 28:191– 194.05). Hopper JL. to explain these findings.0. Kova  cs Kallai J. € nekopp J. In addition. and we found that the 2D:4D AI was significantly lower in the schizophrenia group than the control group. 2007. it is also a strong aspect of the study because it helped to ensure sample homogeneity. 2010. Manning JT. biological research including imaging methods is required. Increased ratio of 2nd to 4th digit (2D:4D) in schizophrenia. 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. 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. Compton MT. Du € venilirlig €¸ € nen deg ¸eg ¸erlilig su € rolojik Bilimler Dergisi 4:20–24. MRI-assessed volume of left and right hippocampi in females correlates with the relative length of the second and fourth fingers (the 2D:4D ratio). Manning JT. Williams JBW. in contrast to the study of Collinson et al. Left-handedness: Association with immune disease. 2009.Digit Ratio and Schizophrenia consistent with Collinson’s study (Collinson et al.. an index consisting of left and right 2D and 4D to correct these results. Manning JT. Galderisi et al. can also be used as an indicator of schizophrenia. and neuropsychological aspects of deficit schizophrenia: A multicenter study. It has been reported that testosterone exposure affects central areas such as 2nd and 4th finger growth and influences cerebral lateralization (Geschwind and Behan. Ann Hum Biol 40:201–204. Lifanova DE. Bundred PE. Murray RM. 1982). Lan TH. CONCLUSIONS In conclusion. neurological. Lim M. . The absence of brain imaging methods and a small sample size are limitations of this study. AI ROC analysis showed moderate discriminatory power and hence the AI has potential use as a diagnostic test for schizophrenia (Fig. Nuechhtriein KH. Beck C. Digit length pattern Arato in schizophrenia suggests disturbed prenatal hemispheric lateralization. we have insufficient data at present to explain the observations clearly (higher R2D:4D ratio and lower L2D:4D ratios in schizophrenics than controls). Vertuna J. 3 and Table 3). Scutt D. Chong SA. 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