Asian Journal of Psychiatry 9 (2014) 67–72

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The 2D:4D ratio of the hand and schizotypal personality traits in schizophrenia patients and healthy control persons Yi-Kang Zhu a, Chun-Bo Li a,**, Jin Jin a, Ji-Jun Wang a, Bernd Lachmann b, Rayna Sariyska b, Christian Montag b,c,* a

Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Wan Ping Nan Road 600, 200030 Shanghai, China Department of Psychology, University of Bonn, Kaiser-Karl-Ring 9, 53111 Bonn, Germany c Center for Economics and Neuroscience, University of Bonn, Germany b

A R T I C L E I N F O

A B S T R A C T

Article history: Received 6 August 2013 Received in revised form 6 January 2014 Accepted 19 January 2014

Prenatal estrogen/testosterone exposure is known to be involved in early brain development. In this context, the ratio of the index finger to ring finger length (2D:4D) has been put forward as an indicator of the intrauterine sex hormonal level. A previous study by Collinson et al. (2010) examined 2D:4D ratios in Asian patients with schizophrenia and found an increased 2D:4D pattern in male patients compared to male healthy controls. In the current study, we tried to replicate the result of this study on the 2D:4D ratio in schizophrenia patients and controls in a Chinese sample. Moreover, we investigated the link between 2D:4D ratios and schizotypal personality traits in the participants of the study. No significant difference between cases and controls in 2D:4D ratios for both hands could be observed. However, a positive association between right 2D:4D ratio and schizotypal personality traits was found in healthy controls (both in the male and female subsamples) suggesting that a high 2D:4D ratio could represent a vulnerability factor for schizophrenia in healthy males and females. Same results were observed for the digit ratio of the left hand and the SPQ in the healthy total and healthy female subsample. Therefore, the inclusion of personality measures to study the link between the digit ratio and schizophrenia might help to provide insights in a potential continuum from healthy to schizophrenic behavior. ß 2014 Elsevier B.V. All rights reserved.

Keywords: Schizophrenia Digit ratio Personality SPQ

1. Introduction Schizophrenia represents a heavy burden for the patients afflicted and causes great costs for society (Knapp et al., 2004). Therefore, research to better understand schizophrenia represents an important endeavor. As schizophrenia cannot be explained by a single factor, but can be best described as a multi-factorial caused disorder including the influence of both genetics and environment (Cannon et al., 2003; Polan et al., 2007; Tsuang, 2000; Tsuang et al., 2001), diverse approaches are used to investigate the biological underpinnings of schizophrenia.

* Corresponding author at: Department of Psychology, University of Bonn, KaiserKarl-Ring 9, 53111 Bonn, Germany. Tel.: +49 228 73 4309; fax: +49 228 73 62331. ** Corresponding author at: Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Wan Ping Nan Road 600, 200030 Shanghai, China. Tel.: +86 21 64387250 3243; fax: +86 21 64387986. E-mail addresses: [email protected] (C.-B. Li), [email protected] (C. Montag). 1876-2018/$ – see front matter ß 2014 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ajp.2014.01.005

It has been proposed that neurodevelopmental insults during gestation are associated with the pathogenesis of schizophrenia (Markham, 2012; Mednick et al., 1988; Moldin and Gottesman, 1997). This hints toward antenatal factors being involved in the development of this psychopathological disorder. In this context, mounting evidence indicates a reduction or reversal of hemispheric lateralization, either functional or anatomical, in schizophrenia (Angrilli et al., 2009; Bhojraj et al., 2009; Bleich-Cohen et al., 2009; Crow, 2010; Crow et al., 1996; Mohr et al., 2001; Oertel et al., 2010; Sheng et al., 2013). On a hormonal level, androgen theories suggest that hemispheric lateralization occurs early in development in response to prenatal estrogen/testosterone exposure (Grimshaw et al., 1995; Witelson and Nowakowski, 1991). However, it is difficult to measure directly the prenatal estrogen/testosterone concentrations in humans because of ethical problems. The ratio of index finger to ring finger length (2D:4D) is a sexually dimorphic anatomic feature determined by the thirteenth week of pregnancy (Manning, 2009). It remains relatively stable throughout adult stage, and has been put forward as an indicator of intrauterine sex hormonal levels (Brown et al., 2002; Manning et al., 1998;

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McIntyre et al., 2005). A low 2D:4D ratio indicates a more ‘male’ hand mirroring a stronger influence of prenatal testosterone on the bodily (brain) development while gestation. The strong line of evidence from a large number of studies showing a link between individual differences in the 2D:4D ratio and prenatal testosterone levels, but not the level of testosterone or other sexual hormones in adulthood has been summarized in a seminal work by Honekopp et al., 2007. Supporting these observations, numerous studies have demonstrated that males tend to display lower values of 2D:4D ratio than females (Daly et al., 2008; Manning, 2009; Walder et al., 2006; Yang et al., 2009). Some of the variations in behavioral tendencies and personality have been reported to be associated with 2D:4D ratio (the pattern of early exposure to sex hormones). For example, autistic features such as deficits in communication and social interactions were thought to be related to a low 2D:4D ratio in children with autism (Bejerot et al., 2012; De Bruin et al., 2009; Manning et al., 2001; Milne et al., 2006). A recent study by Leow and Davis (2012) provided evidence that 2D:4D ratio predicts adult face perception skills. Moreover, it was reported that a more masculinized (low) 2D:4D ratio was correlated with attention-deficit/hyperactivity disorder (ADHD) symptoms (Martel, 2009), but there was also an inconsistent finding (Lemiere et al., 2010). Low 2D:4D ratio was also found to be linked to physical aggression (Bailey and Hurd, 2005; Benderlioglu and Nelson, 2004; van der Meij et al., 2012) and alcohol dependence (Kornhuber et al., 2011). Recently, a study by Wacker et al. (2013) demonstrated a link between impulsive sensation seeking and a low 2D:4D ratio in males. Older studies by Fink et al. (2004) and Lippa (2006) revealed inconsistent findings with respect to the Big Five of Personality. In particular, the study by Lippa (2006) is noteworthy because of its large sample size (>1000 participants) reporting a weak negative correlation between the 2D:4D ratio and extraversion as well as agreeableness and a weak positive correlation between 2D:4D ratio and openness to experience. In schizophrenia research, findings involving 2D:4D ratio and asymmetry have not always been consistent. Collinson et al. (2010) examined the 2D:4D ratio in Asian patients with schizophrenia and found less masculinized (increased) 2D:4D pattern in male patients compared to male controls but not in females, which was partly consistent with the previous finding of Arato et al. (2004), who observed more ‘female’ hands in both male and female schizophrenia patients (although they did not calculate the 2D:4D ratio but subtracted the length of 2D 4D). On the contrary, another study by Venkatasubramanian et al. (2011) showed a significantly lower 2D:4D ratio in female patients with schizophrenia compared to female healthy controls, which was consistent in parts with the result reported by Procopio et al. (2006), who found a difference between the second digit when comparing females with schizophrenia and female healthy controls, but also did not calculate ratios. Venkatasubramanian et al. (2011) further analyzed the 2D:4D asymmetry index (see method section 2.3.) and found that mean 2D:4D asymmetry index was lower in male patients with schizophrenia than male healthy controls. Daly et al. (2008) investigated 2D:4D ratio in individuals at risk for schizophrenia and found no significant difference between risk and control groups. Walder et al. (2006) examined the 2D:4D ratio in adolescents with schizotypal personality disorder (SPD) and demonstrated that the typical sex difference in the 2D:4D ratio could only be observed in healthy controls (with males showing lower 2D:4D ratios), but not in patients with SPD. Gooding et al. (2010) examined two groups of participants at risk for schizophrenia (positive and negative schizotypy) and a control group and found an overall lower left digit ratio in males than females, but no group differences in the digit ratio for both hands. In sum, the 2D:4D represents an interesting approach to study schizophrenia. Nevertheless, several inconsistencies exist, which can be explained

by the varying sample sizes, different ethnicities investigated (e.g. Manning et al. (2007) showed that ethnic differences might exist with respect to the 2D:4D ratio), and – perhaps most important – different approaches have been used to measure the finger length: here, studies range from the investigation of only fingers over the subtraction of the 2D 4D to the use of the digit ratio and the inclusion of only one or both hands. All results relevant for the link between schizophrenia and 2D:4D are summarized in detail in Table 1. To the best of our knowledge, no study has examined the link between individual differences in the 2D:4D digit ratio and schizotypal personality traits in schizophrenia and healthy controls until now – thereby going beyond classic case control designs. Our aims of the present study were: (1) to replicate the study of 2D:4D ratio and schizophrenia in a Chinese sample (compare the study of Collinson et al. (2010)); (2) to investigate the association between 2D:4D ratio and schizotypal personality traits in schizophrenia patients and healthy controls. Given the initial findings by Collinson et al. (2010) investigating in large parts a Chinese sample, we set up the hypothesis that male schizophrenia patients are associated with a higher 2D:4D ratio compared to male control persons. With respect to a potential link between schizotypal personality traits and the 2D:4D ratio in both schizophrenia patients and healthy controls, we hypothesized that more ‘female’ hands would be associated with higher scores on a questionnaire measuring schizotypal personality traits particularly in males. 2. Method 2.1. Participants A total of 102 Chinese participants (51 schizophrenia patients and 51 healthy controls) were enrolled in the study. The schizophrenia patients were inpatients recruited from Shanghai Mental Health Center, Shanghai, China, with the following inclusion criteria: age between 18 and 45; a diagnosis of schizophrenia based on the Structured Clinical Interview for DSM (SCID) Patient Edition for DSM-IV (First et al., 1997). Control participants were college students and staff at Shanghai Jiao Tong University School of Medicine, Shanghai, China. One schizophrenia patient reported to be left handed and two control persons reported to be left handed. The rest of the sample stated to be right handed. Inclusion criteria for the control group were: age between 18 and 45; no Axis I or Axis II diagnosis by using the Structured Clinical Interview for DSM-IV (First et al., 1997, 1999), and no history of Axis I disorders in their first-degree relatives. Participants with a history of broken fingers were excluded. The study was approved by the local institutional ethics board (Institutional Review Board of Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine), and written informed consent was obtained from all participants prior to inclusion. 2.2. Personality measures Each participant completed a short questionnaire, including the information of age, sex and education, and a 22-item scale of the Schizotypal Personality Questionnaire-Brief Form (SPD-B) (Raine and Benishay, 1995). The SPQ-B measures the personality traits of ‘‘Cognitive–Perceptual Schizotypy’’ (8 items), ‘‘Interpersonal Schizotypy’’ (8 items) and ‘‘Disorganization’’ (6 items) with yes/no format. Each ‘‘yes’’ response counts as one point, with total scores (adding up the numbers of the subscales) ranging from 0 to 22. The SPQ-B total score showed strong internal consistency (Cronbach’s a = .871) in the current sample (consisting of both schizophrenia patients and controls). The coefficient a value for each subscale of

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Table 1 Findings of previous schizophrenia-2D:4D studies in alphabetical order. Author

Sample

Age

Gender

Results

Arato et al. (2004)

Study from Hungary, USA, Canada – no information on the ethnicity

Schizophrenia: males (41.4  11.3), females (40.4  11.1); healthy control persons: males (38.3  11.0), females (37.6  10.1)

80 male and 80 female schizophrenia patients compared with 80 male and 80 female healthy control patients

Collinson et al. (2010)

Mixed group of Asian participants (mostly Chinese participants)

Daly et al. (2008)

English speaking undergraduates from USA

33 male and 31 female schizophrenia patients compared with 33 male and 31 female healthy control patients 49 male and 57 female persons at risk for schizophrenia compared with 137 male and 93 female healthy controls

Gooding et al. (2010)

Participants from the United Kingdom

Schizophrenia: males (27.6  5.1), females (33.5  10.1); healthy control persons: males (26.1  8.1), females (28.8  8.1) Persons at risk: males (19.24  1.49), females (19.28  1.44); healthy control persons: males (19.01  0.89), females (19.13  1.42) Control group (19.01  1.40), Social Anhedonia group (19.48  2.51), Perceptual abberation and magical ideations group (19.18  2.19)

Both male and female schizophrenia patients showed a lower 2D minus 4D length (no ratio was calculated, here) compared to the male and female control group (both the left and right hand) Males schizophrenia patients showed a more female 2D:4D ratio compared to healthy male controls (right hand)

Procopio et (2006)

Participants from the United Kingdom

Age between 18 and 65

Venkatasubramanian et al. (2011)

Study from India

Patient group (29.40  7.3), healthy controls (31.1  8.2)

41 male and 8 female schizophrenia patients were compared with 37 male and 38 female healthy controls

Walder et al. (2006)

Mixed sample of participants (mostly White Caucasians but also African and Asian Amercians)

Patient group (14.09  1.69), healthy controls (14.20  1.94)

22 male and 12 female patients with schizotypal personality disorder (SPD) compared with 27 male and 17 female healthy controls

al.

SPQ-B was .774, .747 and .698, respectively. The Chinese version of the Schizotypal Personality Questionnaire has been already used in a sample of college students, and the test–retest reliability after 4 weeks was .84, here (Li et al., 2010). Three cases omitted the assessment of the SPQ-B scale, therefore, the data of 98 participants were included in the analysis. 2.3. Assessment of digit ratios We scanned the right and left hands of all participants with a Canon LiDE 110 scanner. The hand scans were then processed using Gimp 2.8.2 Snow on a MacBook with the operating system Lion x64. The finger lengths were measured by drawing a line from the top of each finger to the middle of the lowest crease of the finger. Two raters independently measured the lengths of the index (2D) and ring fingers (4D) for both hands of each participant. Afterwards the interrater reliabilities in form of correlations were built (index finger left hand .94, ring finger left hand .93, index finger right hand .97, ring finger right hand .98). As the correlations between the measurements of the two raters were high, means for the index and ring fingers of both measures by the independent raters were calculated. The digit ratios were then computed by dividing the (mean) length of the index finger by the (mean) length of the ring finger for each participant and hand. The 2D:4D asymmetry index was computed according to the following formula (as reported in Venkatasubramanian et al. (2011)): 2D:4D Asymmetry Index = (Left 2D:4D Right 2D:4D)/(Left 2D:4D + Right 2D:4D).

46 male and 33 female Social Anhedonia participants, 56 male and 30 female Perceptual aberration– magical Ideation participants, and 48 male and 69 female control participants 35 male and 25 female schizophrenia patients compared with 27 male and 32 female healthy controls

No differences in the 2D:4D ratio.

There was no significant difference between the three groups on the digit ratio.

Female schizophrenia patients were associated with a shorter 2D compared to the healthy female controls (right hand; no 2D:4D ratio was calculated). Note that the height of the participants was taken into account in this study. Female schizophrenia patients showed a lower 2D:4D ratio compared to healthy female controls (left hand). Moreover male schizophrenia patients showed a lower 2D:4D asymmetry index than healthy male controls No significant sex differences of 2D:4D ratio in SPD patients (left and right hand). The typical significant sex difference occurred in healthy control persons (right hand). Moreover a trend towards a higher 2D:4D ratio could be observed in male Caucasian SPD patients compared to control persons (right hand).

2.4. Statistical analyses The statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS; SPSS Inc., Chicago, IL, USA) version 16.0 for Windows. First, one-sample Kolmogorov–Smirnov (KS) tests were used to test the normal distribution of the variables SPQ-B/subscales (non-normally distributed) and 2D:4D ratio (normally distributed) for the total sample. Second, the KS-test showed that in the schizophrenia group only the SPQ-subscale ‘‘Cognitive–Perceptual’’ of the mentioned variables was not normally distributed. Third, the KS-test showed for the control group that the 2D:4D ratios were normally distributed, but the SPQ-scores were not. These informations were taken into account in the statistical analyses (as explained in the following). Chi-square analyses were conducted to assess potential differences in the sex distribution between patients and control persons. Mann–Whitney-U-Test was employed to assess for group differences in age (non-normal distributed data), education level (ranked data) and SPQ scores (non-normal distributed data). Univariate analyses of variance (ANOVAs) were conducted to assess interaction effects of the independent variables sex by group (patients/healthy controls) on the dependent variable 2D:4D ratio and 2D:4D asymmetry index (both normally distributed). Further independent t-tests were employed to test for significant differences of 2D:4D ratio and 2D:4D asymmetry index between males and females in both schizophrenia patients and healthy control persons. For the case-control comparison the level of significance was set to p < .05 (two tailed).

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Table 2 Demographic characteristics and personality measures of the study sample. Variable (mean  S.D.)

Patient group (n = 51)

Control group (n = 51)

Age (years) Gender (M/F), n Education, mean rank SPQ-B score Cognitive–Perceptual Interpersonal Disorganization

26.49  6.74 24/27 34.82 9.31  4.93 3.00  2.31 3.94  2.28 2.29  1.54

24.98  2.94 23/28 68.18 3.78  3.52 1.02  1.42 2.18  1.89 0.59  1.17

Z/x2 0.58 0.04 5.84 5.47 4.63 3.76 5.73

p 0.56 0.84 0.000* 0.000* 0.000* 0.000* 0.000*

S.D., standard deviation; M, male; F, female; SPQ-B, Schizotypal Personality Questionnaire-Brief Form. * p < 0.05 significant two-sided testing.

Spearman’s and Pearson’s correlation tests were conducted to test for correlations between finger digit measures and SPQ scores, depending on the (non) normal distribution of the data. Given the sometimes large differences between Spearman and Pearson correlation outcomes in the following analyses, we included information on both Pearson’s and Spearman’s correlations for the main correlations between SPQ scores and 2D:4D measures. With respect to multiple testing in the context of the SPQsubscales (three subscales) we adjusted the alpha = .05 to be reached for significance to alpha = .016 dividing .05 by three tests for three subscales. As left-handedness could be observed in n = 3 of the total sample, we decided to conduct the main statistical analyses as described below also without these three participants. 3. Results 3.1. Statistical analyses comparing sociodemographic variables/ personality between cases and controls Table 2 shows the demographic characteristics and personality measures of patient and control groups. There were no significant differences between schizophrenia patients and healthy controls in age (U = 1214.5, p > .05) and sex (x2 = .04, df = 1, p = .84). Education level was ranked from 1 to 7 (1 = Primary school, 2 = Junior high school, 3 = Senior middle school, 4 = University student, 5 = Bachelor degree, 6 = Master degree, 7 = Doctor degree). Patients had less education than control group (U = 450, p < .05). For SPQ-B scale, schizophrenia patients scored significantly higher than healthy controls on the total scale and all the three subscales (total scale: U = 445, p < .05; Cognitive-Perceptual: U = 598.5, p < .05; Interpersonal: U = 710.5, p < .05; Disorganization: U = 444.5, p < .05). 3.2. Comparison of the 2D:4D ratio between cases and controls Table 3 shows the finger digit measures of the patient and the control group. Univariate ANOVA for left 2D:4D showed no main effect of group (F(1, 98) = 0.413, p = .52) or interaction effect between sex and group (F(1, 98) = 0.998, p = .32). Instead, a

significant main effect of sex was found (F(1, 98) = 5.915, p = .02). Then, independent t-tests were further conducted and revealed that males had significantly lower 2D:4D ratios for the left hand than females in the control group (t = 2.17, df = 49, p = .04), but not in the schizophrenia group (t = 1.17, df = 49, p = .25). Therefore, the typical statistical sex difference in the digit ratio could only be observed in healthy participants. Univariate ANOVA for the right 2D:4D ratio was not significant for sex (F(1, 98) = 3.394, p = .07, trend level significance), group (F(1, 98) = .271, p = .60), or sex  group interaction (F(1, 98) = .018, p = .89). Univariate ANOVAs for 2D:4D asymmetry index were likewise not significant for sex (F(1, 98) = .362, p = .55), group (F(1, 98) = .007, p = .93), or sex  group interaction (F(1, 98) = 1.967, p = .16). 3.3. Correlations between SPQ-B scores and 2D:4D ratio in schizophrenia patients and healthy controls Among schizophrenia patients, no significant result could be observed between left/right 2D:4D and the SPQ-B scores considering Pearson’s correlations. A Spearman correlation for the not normally distributed variable ‘‘Cognitive–Perceptual’’ and 2D:4D ratios yielded no significant result either. Among healthy controls, a significant positive association between right 2D:4D and SPQ-B total score (rho = .44, p = .001; compare to r = .33, p = .02 using Pearson’s correlation) was found across male (rho = .52, p = .01, compare to r = .39, p = .07 using Pearson’s correlation) and female (rho = .41, p = .03, compare to r = .39, p = .04 using Pearson’s correlation) groups. Additional analyses revealed positive correlations between right 2D:4D and the subscale Cognitive–Perceptual (rho = .43, p = .002, compare to r = .34, p = .01 using Pearson’s correlation) and between right 2D:4D and the subscale Interpersonal (rho = .34, p = .02, compare to r = .30, p = .03 using Pearson’s correlations) for the complete healthy sample. No association could be observed between Disintegration and 2D:4D in the healthy sample. In healthy females the association between right 2D:4D and Cognitive–Perceptual was also visible (rho = .46, p = .02, compare to r = .37, p = .05 using Pearson’s correlation). The other two subscales were not significantly correlated with the 2D:4D marker of the right hand in females. In healthy males the correlations between right 2D:4D and the subscale Cognitive–Perceptual (rho = .44, p = .04, compare to r = .41, p = .05 using Pearson’s correlation) and between right 2D:4D and the subscale Interpersonal (rho = .46, p = .03, compare to r = .39, p = .07 using Pearson’s correlation) were significant. For the 2D:4D ratio of the left hand similar significant results appeared in the control sample. Here, the total SPQ scale correlated positively with the 2D:4D ratio (rho = .33, p = .02; compare to r = .23, p = .10). In addition, the healthy female subsample showed a positive correlation between the left 2D:4D ratio and the total SPQ scale (rho = .46, p = .01, compare to r = .38, p = .04) and a same association between the left 2D:4D and the Cognitive-Perceptual subscale (rho = .38, p = .049, compare to r = .38, p = .05). In healthy males no significant association between the left 2D:4D and the SPQ appeared.

Table 3 Finger digit measures of patient and control groups. Variable (mean  S.D.)

2D:4D Left 2D:4D Right 2D:4D Asymmetry index S.D., standard deviation.

Patient group

Control group

Male (n = 24)

Female (n = 27)

0.96  0.032 0.96  0.032 0.002  0.012

0.973  0.026 0.974  0.033 0.001  0.012

Male (n = 23) 0.961  0.036 0.965  0.037 0.002  0.017

Female (n = 28) 0.984  0.038 0.977  0.038 0.004  0.014

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We mentioned in the statistical analyses section that we adjusted the p-value from .05 to be reached to .016 due to multiple testing for the subscale SPQ-analyses. Taking this into account in particular the association between the SPQ total scale and the right 2D:4D marker is noteworthy (rho = .44, p = .001). 3.4. Further analyses controlling the variable age Moreover, a negative correlation between SPQ-total and age appeared in the control sample (rho = .38, p < .01, compare to r = .38, p < .01 using Pearson’s correlation). The same was also observed for the Cognitive–Perceptual subscale (rho = .40, p < .01, compare to r = .34, p = .01 using Pearson’s correlation) and Disorganization subscale (rho = .47, p < .01, compare to r = .31, p < .03 using Pearson’s correlation). Therefore, we also computed a partial correlation between right 2D:4D and SPQ-B total score controlling for age. The results remained significant (r = .28, df = 48, p < .05). The same was true for the correlation between the right 2D:4D and the Cognitive–Perceptual subscale while controlling for age (r = .30, df = 48, p < .05). Please compare the partial correlations presented in this section to the Pearson’s correlation in the preceding section (and not to Spearman’s Rhos), because partial correlations as Pearson’s correlations also depend on normally distributed variables. A last note: The correlations between the left 2D:4D ratio and SPQ scores were not significant after controlling for age. 3.5. Left-handedness Three participants of the complete sample were left-handed. Therefore, we conducted the main analyses (case-control comparison of 2D:4D and the personality-2D:4D correlations for SPQ-B total in the healthy complete sample) also without the left-handed participants. The results did not change significantly. For the sake of brevity, we do not add these statistics in the present article. 4. Discussion The current study aimed to examine 2D:4D ratio as well as 2D:4D asymmetry in patients with schizophrenia relative to healthy controls, and to determine the link between finger digit measures and schizotypal personality traits. Our findings indicated that left 2D:4D ratio was significantly increased in females than males among healthy controls, but there was no such significant sex difference in patients with schizophrenia. This supports in parts the findings of Walder et al. (2006), who also could not find a significant difference in the 2D:4D ratio for the left and right hand between males and females with schizotypal personality disorder, but at least for the right hand in healthy males and females. The two groups did not differ in 2D:4D ratios for both hands and 2D:4D asymmetry index. Inconsistent with the previous findings from an Asian population provided by Collinson et al. (2010), we did not find significant differences between (male) schizophrenia patients and (male) healthy controls in 2D:4D ratio. Moreover, no significant difference in the 2D:4D asymmetry index could be observed. However, a positive association between right 2D:4D ratio and schizotypal personality traits was found in both healthy controls (across males and females), which in part supports a high (feminized) 2D:4D pattern in schizophrenia-spectrum disorders (Collinson et al., 2010; Voracek, 2008). The same effects could be observed for the 2D:4D of the left hand and SPQ in healthy controls and the healthy female subsample. Based on the present data, it is imaginable that a high 2D:4D ratio could represent a vulnerability factor for schizophrenia in healthy males and females. Same results were

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observed for the digit ratio of the left hand and the SPQ in the healthy total and healthy female subsample. Therefore, the inclusion of personality measures to study the link between the digit ratio and schizophrenia might help in the future to clarify some of the inconsistencies observed in the literature. Furthermore, the use of the SPQ-B might help to provide a researchcontinuum for schizophrenia-2D:4D research from healthy to psychopathological behavior. Although the role of testosterone for schizophrenia is not clear until now, a recent review by (Elias and Kumar, 2007, p. 2) summarized several studies on testosterone as follows in a rule of thumb: ‘‘. . . people suffering from schizophrenia exhibit significantly lower serum levels of oestradiol, oestrogen, testosterone and free testosterone and abnormalities in cortisol/DHEA ratio . . .’’. This summary is reflected in parts by our data in the subclinical area, because higher SPQ-B scores are associated with lower prenatal testosterone levels. Nevertheless, we state that it is at least problematic to derive ideas from studies investigating testosterone levels in the adult brain for an interpretation of the present results, because the impact of prenatal testosterone on the young developing brain cannot be compared to the influence of testosterone on the human brain in adulthood. A limitation of the study should be taken into account. Although all participants were recruited from the Chinese population as in the study from Collinson et al. (2010), the small sample size reduced the power for detecting diagnostic group and sex differences. In conclusion, the present study indicates that there were no significant differences between schizophrenia patients and healthy controls in 2D:4D ratio and 2D:4D asymmetry; nevertheless, a positive association between left and right 2D:4D ratio and schizotypal personality traits was found in healthy controls (across both sex groups with respect to the right hand). The relationships between the digit ratio and brain structural and functional asymmetry (using techniques such as fMRI) need to be investigated to explain the genesis of the link between 2D:4D and schizophrenia in upcoming studies. Two studies already followed this approach: Kallai et al. (2005) demonstrated that the 2D:4D marker was associated with asymmetry of the left hippocampus volume in females. Adding to this, Kalmady et al. (2013) recently showed a 2D:4D by sex effect on working memory in an fMRI experiment. Both studies are support for the idea that adding structural/functional brain imaging to investigate the role of 2D:4D for schizophrenia might reveal interesting new insights by providing information on individual differences in structure or activation of the brain.

Role of the funding source This work was supported by grants from Leading Project of Shanghai Municipal Health Bureau (XBR2011005) for CL and the National Natural Science Foundation of China (81171267) for JW.

Conflict of interest The authors declare that they have no conflicts of interest.

Contributors CM designed and planned the study. YZ and JJ contributed to the participants’ collection. BL, RS, YZ and CM performed the data analysis. YZ and CM drafted the manuscript. CL, JW, BL and RS reviewed the manuscript. All authors have read and approved the final manuscript.

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