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Digit ratio (2D:4D) in a Chinese population with schizophrenia
Early Human Development 98 (2016) 45–48
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Digit ratio (2D:4D) in a Chinese population with schizophrenia☆ Wenli Qian, Zhenghao Huo, Hong Lu ⁎, Youjing Sheng, Zhi Geng, Zhanbing Ma Ningxia Medical University, Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education/ Key Laboratory of Reproduction and Genetics/ Department of Medical Genetic and Cell Biology, Yinchuan 750004, PR China
a r t i c l e
i n f o
Article history: Received 15 March 2016 Received in revised form 14 May 2016 Accepted 24 May 2016 Keywords: 2D:4D Digit ratio Gonadal hormone Schizophrenia
a b s t r a c t Background: Prenatal gonadal hormones may play a major role in pathogenesis of schizophrenia. It has been reported that second to fourth digit ratio (2D:4D) was influenced by the levels of exposure to prenatal testosterone and estrogen. So, 2D:4D may help to predict the disease susceptibility to schizophrenia. Aims: The aim of this study was to investigate the relationship between the digit ratio (2D:4D) and schizophrenia in Chinese population. Methods: We recruited 178 schizophrenics (males: 76; females: 102) and 365 controls (males: 218; females: 147) in this study. Photocopies of both hands were collected and left hand, right hand, mean hand and left minus right hand (DL-R) 2D:4D were analyzed. Results: The right and mean hand 2D:4D ratios were significantly higher in schizophrenics compared to that of controls in both males and females. The left hand 2D:4D ratio in female schizophrenics was also significantly higher than in controls. Compared to controls, the DL-R 2D:4D in male schizophrenics was obviously higher. There was a weakly (but not significantly) negative correlation between the mean hand 2D:4D ratio and the age of onset. Conclusions: The 2D:4D ratio may correlate with the schizophrenia in Chinese population, and it may be an indicator of schizophrenia. © 2016 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Schizophrenia is known as a neurodevelopmental disorder. Though the origin of this disease is not well-understood, researchers have found sex differences in the age of onset, epidemiology, neural mechanisms and clinical manifestations of schizophrenia. In past decades, it has been reported that the onset of schizophrenia is correlated with perturbations in the fetal central nervous system during early development [1]. Differences in prenatal gonadal hormones have been suggested to be a reasonable explanation for the pathogenesis of schizophrenia [2]. Sex hormones, including testosterone and estrogen, are vital during brain development due to their permanent organizational effects during fetal cortical development and transient effects on neural activation after birth. In human fetuses, weeks 8–24 of gestation are an extraordinarily sensitive period due to permanent organizational events occurring in the developing cortex; at this time, there is also a peak in testosterone levels [3]. After birth, gonadal hormones can alternatively enhance neural changes later in life [4]. In Arnold's report [5], gonadal ☆ Funding: This study was supported by grants from National Natural Science Foundation of China (Grant No. 31460272; 30960154; 31360257). ⁎ Corresponding author at: Department of Medical Genetics and Cell Biology, Ningxia Medical University, 1160 Shengli Street, Yinchuan Ningxia, 750004, PR China. Tel.: +86 9516980110. E-mail address: [email protected] (H. Lu).
http://dx.doi.org/10.1016/j.earlhumdev.2016.05.003 0378-3782/© 2016 Elsevier Ireland Ltd. All rights reserved.
androgen, especially testosterone, played a crucial role in modulating nerve cell migration, synaptogenesis and dendritification. Further researches have demonstrated that the altered laterality in schizophrenia was due to disrupted prenatal testosterone (PT) [6] or absence of the protective effects of prenatal estrogen (PE) [7]. Several reports have suggested that schizophrenics, particularly males, have reduced strength of hand preference [8], lessened left hemisphere capacity and decreased representation of language [9], which are all consistent with altered prenatal gonadal hormone levels and altered laterality in schizophrenia. Although controversial, it has been hypothesized that unbalanced exposure to sex steroids is related to numerous diseases in adulthood, such as some cancers, fertility, heart disease and schizophrenia [10–14]. In recent years, digit ratios, especially the ratio of second finger length to fourth finger length (2D:4D), have received considerable attention as new anatomical indicators that can reflect the level of exposure to PT and PE. Manning and colleagues [15] have suggested that digit ratios are developed early in pregnancy and are maintained in later fetal periods and after birth and that digit ratios may indicate variations in circulating prenatal gonadal hormones, with lower 2D:4D representing relatively higher PT and lower PE. Subsequently, some authors have reported similar results to Manning's. Furthermore, several lines of evidence, especially recent evidence from a mouse model, suggest that prenatal hormone exposure or sensitivity to testosterone and
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W. Qian et al. / Early Human Development 98 (2016) 45–48
estrogen influenced the 2D:4D ratio, with a higher ratio of testosterone relative to estrogen correlated with a lower 2D:4D ratio [16]. To date, there have been a number of studies investigating the relationship between 2D:4D ratio and central nervous system diseases, including autism, schizophrenia, and others; however, not all of the results are consistent. Manning et al. [17] reported that the 2D:4D ratio was significantly lower in children with autism or autism spectrum disorders compared to matched control children. Later, the investigation conducted by Arato et al. [18] revealed that schizophrenics had a more “feminine” phenotype, with higher relative length of 2D compared to 4D in both males and females. Walder et al. [19] investigated the 2D:4D ratio in Caucasian adolescents with schizotypal personality disorder and found that male patients had higher 2D:4D ratio than the controls. On the contrary, Daly et al. [20] found no effect in a non-clinical population considered at high risk for schizophrenia. Gooding et al. [21] indicated that neither negative schizotypy nor positive schizotypy was associated with altered digit ratio. Venkatasubramanian et al. [22] found that female schizophrenia patients had lower 2D:4D ratios than controls but reported no difference in males. Recently, Collinson et al. [14] studied the digit ratio of schizophrenic inpatients and outpatients compared with controls and observed higher 2D:4D ratios in male schizophrenics. We conducted an investigation of the 2D:4D ratio in schizophrenia patients from the Ningxia region, China to determine whether 2D:4D ratio could be regarded as an indicator to identify schizophrenia during early development. 2. Subjects and methods 2.1. Study site and subjects In our study, we collected 76 male (age: 17–59 years, mean age ± S.D. = 32.50 ± 10.62) and 102 female schizophrenia patients (age: 15–62 years, mean age ± S.D. = 34.80 ± 10.05) during 2014 to 2015. At the same time, we recruited 218 males (age: 17–60 years, mean age ± S.D. = 32.05 ± 8.40) and 147 females (age: 17–63 years, mean age ± S.D. = 36.10 ± 10.38) as the control groups. All the participants were from Yinchuan city, the Ningxia region, China. The controls were exhibited healthy physical and mental states. The patients were all diagnosed with schizophrenia in term of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) [23]. The subjects with finger fractures or abnormal defects were excluded. 2.2. Ethical statements This study was approved by the Ningxia Medical University Committee for the Protection of Human Subjects, and all the participants had informed written consent before the experiment. 2.3. Measurement of digit ratios All subjects had their left and right hand palms photographed with keeping the camera perpendicular to the palms side in the same height. When taking photos, the participants were required to spread their fingers and hand palms. The Adobe Photoshop Software was used to
analyze the photos. Index finger and ring finger of both hands were measured twice from the tip of the finger towards the middle point of the most proximal crease to the palm to get more exact measurement [24]. Then we calculated the ratios of digit lengths between index finger and ring finger, and regarded the average digit ratio value of two measurements as the final result of each indicator. In addition, the mean hand 2D:4D ratio showed the average value of left hand 2D:4D and right hand 2D:4D, the left minus right hand 2D:4D (DL-R 2D:4D) was calculated based on the formula: the DL-R 2D:4D = left hand 2D:4D right hand 2D:4D. 2.4. Statistical analysis Data analysis were conducted with SPSS 19.0 software and expressed as mean ± standard deviation (S.D.). Comparison of the variables between groups was carried out by using independent sample ttest. The Pearson correlation coefficient test was done to discover the correlation between 2D:4D digit ratios and age of onset in schizophrenia. The p-value b 0.05 was regarded as having a significant difference. 3. Results 3.1. Mean values and distribution of 2D:4D ratio There was no significant difference between each individual's first and second measurements of each digit length (p N 0.05). In both males and females, no significant difference was found in 2D:4D ratio between the right and left hands neither in controls nor in schizophrenic patients respectively (p N 0.05). The range of 2D:4D ratio for controls was similar to the patients (Tables 1–2). No significant sex difference was found in 2D:4D ratio among the control subjects (p N 0.05). The patients have significantly higher 2D:4D ratios in the right and mean hands compared to that of controls in both males (right hand: t = − 4.11, p = 0.000; mean hand: t = − 3.29, p = 0.001) (Table 1) and females (right hand: t = − 3.59, p = 0.000; mean hand: t = − 4.92, p = 0.000) (Table 2). In males, there was no significant difference in left hand 2D:4D ratio between two groups (t = − 1.52, p = 0.13) (Table 1); while in females, the patients had significantly higher left hand 2D:4D ratios than controls (t = − 4.74, p = 0.000) (Table 2). About the DL-R 2D:4D, there was a significantly difference between two groups in males (t = 2.39, p = 0.02) (Table 1), but not in females (t = −0.43, p = 0.67) (Table 2). 3.2. Correlations between age/age of onset and 2D:4D ratio in controls and patients In Table 3, it showed the correlation between the age of onset in schizophrenics (present age in controls) and 2D:4D digit ratios respectively. We did not found any significant correlation between age (in controls) or age of onset (in patients) and 2D:4D ratio both in males and females (all p N 0.05). However, there was a weakly negative correlation trend between the age of onset and the mean hand 2D:4D in male schizophrenics (r = −0.211, p = 0.067) (Fig. 1).
Table 1 Mean values and ranges of 2D:4D ratio in both patients and controls in males. Controls (N = 218)
Left hand 2D:4D Right hand 2D:4D Mean hand 2D:4D DL-R 2D:4D
Schizophrenics (N = 76)
Mean (S.D.)
Range
Mean (S.D.)
Range
0.950 (0.035) 0.948 (0.037) 0.949 (0.032) 0.002 (0.032)
0.837–1.057 0.812–1.045 0.843–1.033 −0.070–0.109
0.957 (0.034) 0.968 (0.037)⁎⁎ 0.963 (0.028)⁎⁎ −0.011 (0.044)⁎
0.895–1.064 0.876–1.076 0.909–1.033 −0.127–0.113
⁎ p b 0.05 (difference of 2D:4D between controls and schizophrenics). ⁎⁎ p b 0.01 (difference of 2D:4D between controls and schizophrenics).
W. Qian et al. / Early Human Development 98 (2016) 45–48
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Table 2 Mean values and ranges of 2D:4D ratio in both patients and controls in females. Controls (N = 147)
Left hand 2D:4D Right hand 2D:4D Mean hand 2D:4D DL-R 2D:4D
Schizophrenics (N = 102)
Mean (S.D.)
Range
Mean (S.D.)
Range
0.956 (0.035) 0.955 (0.040) 0.956 (0.032) 0.001 (0.041)
0.869–1.088 0.839–1.042 0.872–1.035 −0.113–0.118
0.978 (0.037)⁎ 0.975 (0.046)⁎ 0.976 (0.034)⁎ 0.003 (0.047)
0.884–1.061 0.880–1.120 0.896–1.054 −0.132–0.142
⁎ p b 0.01 (difference of 2D:4D between controls and schizophrenics).
4. Discussion During the past several decades, although controversial, the relationship between 2D:4D ratio and patients with schizophrenia has been investigated in several ethnic groups [14,18–22]. This study was undertaken to examine the digit ratio (2D:4D) in schizophrenia patients from the Ningxia region, China. The present evidence showed that the right and mean hand 2D:4D ratios were significantly higher in schizophrenics compared to that of controls in both males and females. The left hand 2D:4D ratio in female schizophrenics was also significantly higher than in controls, but no difference was observed in males. Compared to controls, the DL-R 2D:4D in male schizophrenics was obviously higher. There was a weakly (but not significantly) negative correlation between the mean hand 2D:4D ratio and age of onset in male schizophrenics. Our results indicating increased 2D:4D digit ratios in schizophrenic patients were in agreement with studies conducted by Arato et al. [18] and Collinson et al. [14]. Previous studies have shown that PE is positively related to 2D:4D ratio, while PT is inversely related to 2D:4D ratio. Therefore, our results predict that patients with schizophrenia may have had higher PE or lower PT exposure during fetal development compared to controls. Higher levels of PE or relatively lower PT levels may be responsible for the higher 2D:4D ratio (so-called “feminine pattern”) in the schizophrenic patient group. Additionally, PT and PE are thought to regulate the expression of HOX gene which is vital to both brain formation and the digit development [25,26]. A disturbance in hormone levels may lead to the abnormal expression of HOX gene, which may result in the subsequent abnormal development of the brain and digit ratio. According to the information mentioned above, we propose that exposure to higher levels of PE or lower PT during fetal development may result in increases in both 2D:4D ratio and the risk of developing schizophrenia in adulthood. It is significant that 2D:4D has been shown to be negative correlated with testosterone/estrogen ratios from amniotic fluid [27]. Furthermore, there is increasing evidence that prenatal hormone (PT/PE) increases the risk of schizophrenia later in life [28]. Thus, our results could be interpreted that the greater exposure to testosterone before birth provides some protection from later developing schizophrenia. This finding also predicts that 2D:4D digit ratio may be an indicator of schizophrenia. In our study, we did not observe differences in the left hand 2D:4D ratio between male patients and controls. Only in females did we observe that both right and left hand 2D:4D ratios in patients was significantly higher than in controls. The result for the male group was consistent
with studies conducted by Bolu et al. [29] and Walder et al. [19], but it was slightly different from the results of Arato et al. [18]. The reason behind these differences may be that our method of measuring 2D:4D ratio differed from that of Arato et al. [18], who measured the relative distance from the tip of the index and ring finger to the third digit. At the same time, differences in patient ethnicity and sample size between the two studies may also contribute to the different results. In addition, it has been reported that the exposure level of PT can affect central activities and cerebral lateralization [30]. Geschwind et al. [31] thought testosterone might inhibit the growth of certain areas in the left hemisphere and adversely promote the development of the right hemisphere. Thus, we would predict that the influence of PT/PE on the left and right hand in male and female schizophrenia patients would be different. The DR-L 2D:4D or the DL-R 2D:4D are indicators that may reveal 2D:4D asymmetry between the left and right hands. Previous evidence has suggested that both the right hand 2D:4D and the DR-L 2D:4D were inversely correlated to prenatal exposure and sensitivity to testosterone. Several reports have also proposed that DR-L 2D:4D had a more obvious association with the exposure or sensitivity to prenatal estrogen than the right hand 2D:4D ratio [32]. In our study, we observed that the DL-R 2D:4D of male schizophrenics was significantly lower than that of controls, which is similar to what has been reported in previous studies. But we did not find any significant difference between the DL-R 2D:4D of female schizophrenia patients and controls which may indicate that the DL-R 2D:4D may has a more obvious association with PT exposure or sensitivity in men. According to our results and previous studies, we propose that the 2D:4D asymmetry between the left and right hands is more pronounced in male schizophrenics and may reflect differences in the effects of testosterone on the development of the left and right cerebral hemispheres from another side. We cannot fully explain why this difference was not observed in females, further investigation is needed. But we point out that, in addition to our findings, several other studies have suggested that the logical explanation for this difference between males and females may lie in the impact of sex hormones on HOX gene expression, which can influence brain development during pregnancy. As early as 2011, Muller et al. [33] found a weak inverse association between 2D:4D ratio and early onset prostate cancer risk. Subsequently, they conducted a study between 2D:4D and breast cancer risk and concluded that digit ratio measures might be associated with breast cancer risk and age of disease onset [10]. Recently, an exploratory analysis conducted by Stolten et al. [11] also showed a relationship between alternative digit ratio and diagnosis age in prostate cancer. All aforementioned studies suggested to us that digit ratio may also be related to the age of
Table 3 Correlations between the age/age of onset and 2D:4D ratio in both controls and schizophrenia patients (r, p). Male
Age (years) Left hand 2D:4D Right hand 2D:4D Mean hand 2D:4D DL-R 2D:4D
Female
Schizophrenics (N = 76)
Controls (N = 218)
Schizophrenics (N = 102)
Controls (N = 147)
32.50 ± 10.62 −0.169 (0.145) −0.163 (0.158) −0.211 (0.067) 0.005 (0.967)
32.05 ± 8.40 0.003 (0.963) 0.081 (0.232) 0.048 (0.477) −0.090 (0.186)
34.80 ± 10.05 −0.015 (0.877) −0.032 (0.750) −0.030 (0.768) 0.019 (0.850)
36.10 ± 10.38 −0.062 (0.456) −0.002 (0.978) −0.036 (0.666) −0.083 (0.343)
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W. Qian et al. / Early Human Development 98 (2016) 45–48
Fig. 1. Correlations between the mean hand 2D:4D ratio and the age/age of onset in male controls and male patients (because 2D:4D does not appreciably change with age, the absence of a relationship between age and digit ratios in male controls is the expected results).
onset or diagnosis age in schizophrenia. Therefore, to further investigate the correlation between age of onset in schizophrenic patients and their 2D:4D digit ratio, we conducted a thorough analysis. Unfortunately, no significant correlation was found between 2D:4D digit ratio and age of onset in our study. However, compared to other indicators, we found a weakly trend in which the mean hand 2D:4D ratio showed a negative correlation with age of onset in male schizophrenics. Although it was nonsignificant, the finding still suggests that the mean hand 2D:4D ratio may indeed act as an indicator for early clinical diagnosis and treatment for potential schizophrenia patients, where higher mean hand 2D:4D ratio correlates with an earlier age of onset. For this is the first study investigating 2D:4D digit ratio and age of onset in schizophrenic patients, further research with large sample size and different populations is needed. In conclusion, our data support the view that schizophrenia patients have a “feminine” pattern 2D:4D digit ratio, which may be an indicator of schizophrenia; however, given the complicated pathogenesis of schizophrenia and the fact that some mechanisms are still not clearly understood, further research is needed to characterize the correlation between 2D:4D ratio and schizophrenia. Author contributions Conceived and designed the experiments: HL; performed the experiments: HL, ZHH; analyzed the data: WLQ, YJS, ZG, ZBM; wrote the paper: HL, WLQ. Conflict of interest statement The authors have declared that no competing interests exist. Acknowledgments This study was supported by grants from National Natural Science Foundation of China (Grant Nos. 31460272; 30960154; 31360257). Reference [1] J. Schiffman, E. Walker, M. Ekstrom, F. Schulsinger, H. Sorensen, S. Mednick, Childhood videotaped social and neuromotor precursors of schizophrenia: a prospective investigation, Am. J. Psychiatry 161 (2004) 2021–2027. [2] J.S. Brown Jr., Association of increased prenatal estrogen with risk factors for schizophrenia, Schizophr. Bull. 37 (2011) 946–949.
[3] D.F. Swaab, Sexual differentiation of the brain and behavior, Best Pract. Res. Clin. Endocrinol. Metab. 21 (2007) 431–444. [4] H. Phoenix, Organizing action of prenatally administered testosterone propionate on the tissues mediating mating behavior in the female guinea pig, Horm. Behav. 55 (2009) 566. [5] A.P. Arnold, The organizational–activational hypothesis as the foundation for a unified theory of sexual differentiation of all mammalian tissues, Horm. Behav. 55 (2009) 570–578. [6] A. Mendrek, Reversal of normal cerebral sexual dimorphism in schizophrenia: evidence and speculations, Med. Hypotheses 69 (2007) 896–902. [7] M. Procopio, R.J. Davies, P. Marriott, The hormonal environment in utero as a potential aetiological agent for schizophrenia, Eur. Arch. Psychiatry Clin. Neurosci. 256 (2006) 77–81. [8] S. Dane, S. Yildirim, E. Ozan, N. Aydin, E. Oral, N. 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Peng, et al., The ratio of second to fourth digit length (2D:4D) and coronary artery disease in a Han Chinese population, Int. J. Med. Sci. 10 (2013) 1584–1588. [14] S.L. Collinson, M. Lim, J.H. Chaw, S. Verma, K. Sim, A. Rapisarda, et al., Increased ratio of 2nd to 4th digit (2D:4D) in schizophrenia, Psychiatry Res. 176 (2010) 8–12. [15] J.T. Manning, D. Scutt, J. Wilson, D.I. Lewis-Jones, The ratio of 2nd to 4th digit length: a predictor of sperm numbers and concentrations of testosterone, luteinizing hormone and estrogen, Hum. Reprod. 13 (1998) 3000–3004. [16] A. Talarovičová, L. Kršková, J. Blažeková, Testosterone enhancement during pregnancy influences the 2D:4D ratio and open field motor activity of rat siblings in adulthood, Horm. Behav. 55 (2009) 235–239. [17] J.T. Manning, S. Baron-Cohen, S. Wheelwright, G. Sanders, The 2nd to 4th digit ratio and autism, Dev. Med. Child Neurol. 43 (2001) 160–164. [18] M. Arato, E. Frecska, C. Beck, M. An, H. 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Early Human Development journal homepage: www.elsevier.com/locate/earlhumdev
Digit ratio (2D:4D) in a Chinese population with schizophrenia☆ Wenli Qian, Zhenghao Huo, Hong Lu ⁎, Youjing Sheng, Zhi Geng, Zhanbing Ma Ningxia Medical University, Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education/ Key Laboratory of Reproduction and Genetics/ Department of Medical Genetic and Cell Biology, Yinchuan 750004, PR China
a r t i c l e
i n f o
Article history: Received 15 March 2016 Received in revised form 14 May 2016 Accepted 24 May 2016 Keywords: 2D:4D Digit ratio Gonadal hormone Schizophrenia
a b s t r a c t Background: Prenatal gonadal hormones may play a major role in pathogenesis of schizophrenia. It has been reported that second to fourth digit ratio (2D:4D) was influenced by the levels of exposure to prenatal testosterone and estrogen. So, 2D:4D may help to predict the disease susceptibility to schizophrenia. Aims: The aim of this study was to investigate the relationship between the digit ratio (2D:4D) and schizophrenia in Chinese population. Methods: We recruited 178 schizophrenics (males: 76; females: 102) and 365 controls (males: 218; females: 147) in this study. Photocopies of both hands were collected and left hand, right hand, mean hand and left minus right hand (DL-R) 2D:4D were analyzed. Results: The right and mean hand 2D:4D ratios were significantly higher in schizophrenics compared to that of controls in both males and females. The left hand 2D:4D ratio in female schizophrenics was also significantly higher than in controls. Compared to controls, the DL-R 2D:4D in male schizophrenics was obviously higher. There was a weakly (but not significantly) negative correlation between the mean hand 2D:4D ratio and the age of onset. Conclusions: The 2D:4D ratio may correlate with the schizophrenia in Chinese population, and it may be an indicator of schizophrenia. © 2016 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Schizophrenia is known as a neurodevelopmental disorder. Though the origin of this disease is not well-understood, researchers have found sex differences in the age of onset, epidemiology, neural mechanisms and clinical manifestations of schizophrenia. In past decades, it has been reported that the onset of schizophrenia is correlated with perturbations in the fetal central nervous system during early development [1]. Differences in prenatal gonadal hormones have been suggested to be a reasonable explanation for the pathogenesis of schizophrenia [2]. Sex hormones, including testosterone and estrogen, are vital during brain development due to their permanent organizational effects during fetal cortical development and transient effects on neural activation after birth. In human fetuses, weeks 8–24 of gestation are an extraordinarily sensitive period due to permanent organizational events occurring in the developing cortex; at this time, there is also a peak in testosterone levels [3]. After birth, gonadal hormones can alternatively enhance neural changes later in life [4]. In Arnold's report [5], gonadal ☆ Funding: This study was supported by grants from National Natural Science Foundation of China (Grant No. 31460272; 30960154; 31360257). ⁎ Corresponding author at: Department of Medical Genetics and Cell Biology, Ningxia Medical University, 1160 Shengli Street, Yinchuan Ningxia, 750004, PR China. Tel.: +86 9516980110. E-mail address: [email protected] (H. Lu).
http://dx.doi.org/10.1016/j.earlhumdev.2016.05.003 0378-3782/© 2016 Elsevier Ireland Ltd. All rights reserved.
androgen, especially testosterone, played a crucial role in modulating nerve cell migration, synaptogenesis and dendritification. Further researches have demonstrated that the altered laterality in schizophrenia was due to disrupted prenatal testosterone (PT) [6] or absence of the protective effects of prenatal estrogen (PE) [7]. Several reports have suggested that schizophrenics, particularly males, have reduced strength of hand preference [8], lessened left hemisphere capacity and decreased representation of language [9], which are all consistent with altered prenatal gonadal hormone levels and altered laterality in schizophrenia. Although controversial, it has been hypothesized that unbalanced exposure to sex steroids is related to numerous diseases in adulthood, such as some cancers, fertility, heart disease and schizophrenia [10–14]. In recent years, digit ratios, especially the ratio of second finger length to fourth finger length (2D:4D), have received considerable attention as new anatomical indicators that can reflect the level of exposure to PT and PE. Manning and colleagues [15] have suggested that digit ratios are developed early in pregnancy and are maintained in later fetal periods and after birth and that digit ratios may indicate variations in circulating prenatal gonadal hormones, with lower 2D:4D representing relatively higher PT and lower PE. Subsequently, some authors have reported similar results to Manning's. Furthermore, several lines of evidence, especially recent evidence from a mouse model, suggest that prenatal hormone exposure or sensitivity to testosterone and
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estrogen influenced the 2D:4D ratio, with a higher ratio of testosterone relative to estrogen correlated with a lower 2D:4D ratio [16]. To date, there have been a number of studies investigating the relationship between 2D:4D ratio and central nervous system diseases, including autism, schizophrenia, and others; however, not all of the results are consistent. Manning et al. [17] reported that the 2D:4D ratio was significantly lower in children with autism or autism spectrum disorders compared to matched control children. Later, the investigation conducted by Arato et al. [18] revealed that schizophrenics had a more “feminine” phenotype, with higher relative length of 2D compared to 4D in both males and females. Walder et al. [19] investigated the 2D:4D ratio in Caucasian adolescents with schizotypal personality disorder and found that male patients had higher 2D:4D ratio than the controls. On the contrary, Daly et al. [20] found no effect in a non-clinical population considered at high risk for schizophrenia. Gooding et al. [21] indicated that neither negative schizotypy nor positive schizotypy was associated with altered digit ratio. Venkatasubramanian et al. [22] found that female schizophrenia patients had lower 2D:4D ratios than controls but reported no difference in males. Recently, Collinson et al. [14] studied the digit ratio of schizophrenic inpatients and outpatients compared with controls and observed higher 2D:4D ratios in male schizophrenics. We conducted an investigation of the 2D:4D ratio in schizophrenia patients from the Ningxia region, China to determine whether 2D:4D ratio could be regarded as an indicator to identify schizophrenia during early development. 2. Subjects and methods 2.1. Study site and subjects In our study, we collected 76 male (age: 17–59 years, mean age ± S.D. = 32.50 ± 10.62) and 102 female schizophrenia patients (age: 15–62 years, mean age ± S.D. = 34.80 ± 10.05) during 2014 to 2015. At the same time, we recruited 218 males (age: 17–60 years, mean age ± S.D. = 32.05 ± 8.40) and 147 females (age: 17–63 years, mean age ± S.D. = 36.10 ± 10.38) as the control groups. All the participants were from Yinchuan city, the Ningxia region, China. The controls were exhibited healthy physical and mental states. The patients were all diagnosed with schizophrenia in term of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) [23]. The subjects with finger fractures or abnormal defects were excluded. 2.2. Ethical statements This study was approved by the Ningxia Medical University Committee for the Protection of Human Subjects, and all the participants had informed written consent before the experiment. 2.3. Measurement of digit ratios All subjects had their left and right hand palms photographed with keeping the camera perpendicular to the palms side in the same height. When taking photos, the participants were required to spread their fingers and hand palms. The Adobe Photoshop Software was used to
analyze the photos. Index finger and ring finger of both hands were measured twice from the tip of the finger towards the middle point of the most proximal crease to the palm to get more exact measurement [24]. Then we calculated the ratios of digit lengths between index finger and ring finger, and regarded the average digit ratio value of two measurements as the final result of each indicator. In addition, the mean hand 2D:4D ratio showed the average value of left hand 2D:4D and right hand 2D:4D, the left minus right hand 2D:4D (DL-R 2D:4D) was calculated based on the formula: the DL-R 2D:4D = left hand 2D:4D right hand 2D:4D. 2.4. Statistical analysis Data analysis were conducted with SPSS 19.0 software and expressed as mean ± standard deviation (S.D.). Comparison of the variables between groups was carried out by using independent sample ttest. The Pearson correlation coefficient test was done to discover the correlation between 2D:4D digit ratios and age of onset in schizophrenia. The p-value b 0.05 was regarded as having a significant difference. 3. Results 3.1. Mean values and distribution of 2D:4D ratio There was no significant difference between each individual's first and second measurements of each digit length (p N 0.05). In both males and females, no significant difference was found in 2D:4D ratio between the right and left hands neither in controls nor in schizophrenic patients respectively (p N 0.05). The range of 2D:4D ratio for controls was similar to the patients (Tables 1–2). No significant sex difference was found in 2D:4D ratio among the control subjects (p N 0.05). The patients have significantly higher 2D:4D ratios in the right and mean hands compared to that of controls in both males (right hand: t = − 4.11, p = 0.000; mean hand: t = − 3.29, p = 0.001) (Table 1) and females (right hand: t = − 3.59, p = 0.000; mean hand: t = − 4.92, p = 0.000) (Table 2). In males, there was no significant difference in left hand 2D:4D ratio between two groups (t = − 1.52, p = 0.13) (Table 1); while in females, the patients had significantly higher left hand 2D:4D ratios than controls (t = − 4.74, p = 0.000) (Table 2). About the DL-R 2D:4D, there was a significantly difference between two groups in males (t = 2.39, p = 0.02) (Table 1), but not in females (t = −0.43, p = 0.67) (Table 2). 3.2. Correlations between age/age of onset and 2D:4D ratio in controls and patients In Table 3, it showed the correlation between the age of onset in schizophrenics (present age in controls) and 2D:4D digit ratios respectively. We did not found any significant correlation between age (in controls) or age of onset (in patients) and 2D:4D ratio both in males and females (all p N 0.05). However, there was a weakly negative correlation trend between the age of onset and the mean hand 2D:4D in male schizophrenics (r = −0.211, p = 0.067) (Fig. 1).
Table 1 Mean values and ranges of 2D:4D ratio in both patients and controls in males. Controls (N = 218)
Left hand 2D:4D Right hand 2D:4D Mean hand 2D:4D DL-R 2D:4D
Schizophrenics (N = 76)
Mean (S.D.)
Range
Mean (S.D.)
Range
0.950 (0.035) 0.948 (0.037) 0.949 (0.032) 0.002 (0.032)
0.837–1.057 0.812–1.045 0.843–1.033 −0.070–0.109
0.957 (0.034) 0.968 (0.037)⁎⁎ 0.963 (0.028)⁎⁎ −0.011 (0.044)⁎
0.895–1.064 0.876–1.076 0.909–1.033 −0.127–0.113
⁎ p b 0.05 (difference of 2D:4D between controls and schizophrenics). ⁎⁎ p b 0.01 (difference of 2D:4D between controls and schizophrenics).
W. Qian et al. / Early Human Development 98 (2016) 45–48
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Table 2 Mean values and ranges of 2D:4D ratio in both patients and controls in females. Controls (N = 147)
Left hand 2D:4D Right hand 2D:4D Mean hand 2D:4D DL-R 2D:4D
Schizophrenics (N = 102)
Mean (S.D.)
Range
Mean (S.D.)
Range
0.956 (0.035) 0.955 (0.040) 0.956 (0.032) 0.001 (0.041)
0.869–1.088 0.839–1.042 0.872–1.035 −0.113–0.118
0.978 (0.037)⁎ 0.975 (0.046)⁎ 0.976 (0.034)⁎ 0.003 (0.047)
0.884–1.061 0.880–1.120 0.896–1.054 −0.132–0.142
⁎ p b 0.01 (difference of 2D:4D between controls and schizophrenics).
4. Discussion During the past several decades, although controversial, the relationship between 2D:4D ratio and patients with schizophrenia has been investigated in several ethnic groups [14,18–22]. This study was undertaken to examine the digit ratio (2D:4D) in schizophrenia patients from the Ningxia region, China. The present evidence showed that the right and mean hand 2D:4D ratios were significantly higher in schizophrenics compared to that of controls in both males and females. The left hand 2D:4D ratio in female schizophrenics was also significantly higher than in controls, but no difference was observed in males. Compared to controls, the DL-R 2D:4D in male schizophrenics was obviously higher. There was a weakly (but not significantly) negative correlation between the mean hand 2D:4D ratio and age of onset in male schizophrenics. Our results indicating increased 2D:4D digit ratios in schizophrenic patients were in agreement with studies conducted by Arato et al. [18] and Collinson et al. [14]. Previous studies have shown that PE is positively related to 2D:4D ratio, while PT is inversely related to 2D:4D ratio. Therefore, our results predict that patients with schizophrenia may have had higher PE or lower PT exposure during fetal development compared to controls. Higher levels of PE or relatively lower PT levels may be responsible for the higher 2D:4D ratio (so-called “feminine pattern”) in the schizophrenic patient group. Additionally, PT and PE are thought to regulate the expression of HOX gene which is vital to both brain formation and the digit development [25,26]. A disturbance in hormone levels may lead to the abnormal expression of HOX gene, which may result in the subsequent abnormal development of the brain and digit ratio. According to the information mentioned above, we propose that exposure to higher levels of PE or lower PT during fetal development may result in increases in both 2D:4D ratio and the risk of developing schizophrenia in adulthood. It is significant that 2D:4D has been shown to be negative correlated with testosterone/estrogen ratios from amniotic fluid [27]. Furthermore, there is increasing evidence that prenatal hormone (PT/PE) increases the risk of schizophrenia later in life [28]. Thus, our results could be interpreted that the greater exposure to testosterone before birth provides some protection from later developing schizophrenia. This finding also predicts that 2D:4D digit ratio may be an indicator of schizophrenia. In our study, we did not observe differences in the left hand 2D:4D ratio between male patients and controls. Only in females did we observe that both right and left hand 2D:4D ratios in patients was significantly higher than in controls. The result for the male group was consistent
with studies conducted by Bolu et al. [29] and Walder et al. [19], but it was slightly different from the results of Arato et al. [18]. The reason behind these differences may be that our method of measuring 2D:4D ratio differed from that of Arato et al. [18], who measured the relative distance from the tip of the index and ring finger to the third digit. At the same time, differences in patient ethnicity and sample size between the two studies may also contribute to the different results. In addition, it has been reported that the exposure level of PT can affect central activities and cerebral lateralization [30]. Geschwind et al. [31] thought testosterone might inhibit the growth of certain areas in the left hemisphere and adversely promote the development of the right hemisphere. Thus, we would predict that the influence of PT/PE on the left and right hand in male and female schizophrenia patients would be different. The DR-L 2D:4D or the DL-R 2D:4D are indicators that may reveal 2D:4D asymmetry between the left and right hands. Previous evidence has suggested that both the right hand 2D:4D and the DR-L 2D:4D were inversely correlated to prenatal exposure and sensitivity to testosterone. Several reports have also proposed that DR-L 2D:4D had a more obvious association with the exposure or sensitivity to prenatal estrogen than the right hand 2D:4D ratio [32]. In our study, we observed that the DL-R 2D:4D of male schizophrenics was significantly lower than that of controls, which is similar to what has been reported in previous studies. But we did not find any significant difference between the DL-R 2D:4D of female schizophrenia patients and controls which may indicate that the DL-R 2D:4D may has a more obvious association with PT exposure or sensitivity in men. According to our results and previous studies, we propose that the 2D:4D asymmetry between the left and right hands is more pronounced in male schizophrenics and may reflect differences in the effects of testosterone on the development of the left and right cerebral hemispheres from another side. We cannot fully explain why this difference was not observed in females, further investigation is needed. But we point out that, in addition to our findings, several other studies have suggested that the logical explanation for this difference between males and females may lie in the impact of sex hormones on HOX gene expression, which can influence brain development during pregnancy. As early as 2011, Muller et al. [33] found a weak inverse association between 2D:4D ratio and early onset prostate cancer risk. Subsequently, they conducted a study between 2D:4D and breast cancer risk and concluded that digit ratio measures might be associated with breast cancer risk and age of disease onset [10]. Recently, an exploratory analysis conducted by Stolten et al. [11] also showed a relationship between alternative digit ratio and diagnosis age in prostate cancer. All aforementioned studies suggested to us that digit ratio may also be related to the age of
Table 3 Correlations between the age/age of onset and 2D:4D ratio in both controls and schizophrenia patients (r, p). Male
Age (years) Left hand 2D:4D Right hand 2D:4D Mean hand 2D:4D DL-R 2D:4D
Female
Schizophrenics (N = 76)
Controls (N = 218)
Schizophrenics (N = 102)
Controls (N = 147)
32.50 ± 10.62 −0.169 (0.145) −0.163 (0.158) −0.211 (0.067) 0.005 (0.967)
32.05 ± 8.40 0.003 (0.963) 0.081 (0.232) 0.048 (0.477) −0.090 (0.186)
34.80 ± 10.05 −0.015 (0.877) −0.032 (0.750) −0.030 (0.768) 0.019 (0.850)
36.10 ± 10.38 −0.062 (0.456) −0.002 (0.978) −0.036 (0.666) −0.083 (0.343)
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Fig. 1. Correlations between the mean hand 2D:4D ratio and the age/age of onset in male controls and male patients (because 2D:4D does not appreciably change with age, the absence of a relationship between age and digit ratios in male controls is the expected results).
onset or diagnosis age in schizophrenia. Therefore, to further investigate the correlation between age of onset in schizophrenic patients and their 2D:4D digit ratio, we conducted a thorough analysis. Unfortunately, no significant correlation was found between 2D:4D digit ratio and age of onset in our study. However, compared to other indicators, we found a weakly trend in which the mean hand 2D:4D ratio showed a negative correlation with age of onset in male schizophrenics. Although it was nonsignificant, the finding still suggests that the mean hand 2D:4D ratio may indeed act as an indicator for early clinical diagnosis and treatment for potential schizophrenia patients, where higher mean hand 2D:4D ratio correlates with an earlier age of onset. For this is the first study investigating 2D:4D digit ratio and age of onset in schizophrenic patients, further research with large sample size and different populations is needed. In conclusion, our data support the view that schizophrenia patients have a “feminine” pattern 2D:4D digit ratio, which may be an indicator of schizophrenia; however, given the complicated pathogenesis of schizophrenia and the fact that some mechanisms are still not clearly understood, further research is needed to characterize the correlation between 2D:4D ratio and schizophrenia. Author contributions Conceived and designed the experiments: HL; performed the experiments: HL, ZHH; analyzed the data: WLQ, YJS, ZG, ZBM; wrote the paper: HL, WLQ. Conflict of interest statement The authors have declared that no competing interests exist. Acknowledgments This study was supported by grants from National Natural Science Foundation of China (Grant Nos. 31460272; 30960154; 31360257). Reference [1] J. Schiffman, E. Walker, M. Ekstrom, F. Schulsinger, H. Sorensen, S. Mednick, Childhood videotaped social and neuromotor precursors of schizophrenia: a prospective investigation, Am. J. Psychiatry 161 (2004) 2021–2027. [2] J.S. Brown Jr., Association of increased prenatal estrogen with risk factors for schizophrenia, Schizophr. Bull. 37 (2011) 946–949.
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