Schizophrenia is a debilitating mental health condition affecting the lives of many South Africans. The origins of the heterogeneity in the presentation of the illness remain uncertain.
This cross-sectional study performed a retrospective data analysis to determine the usefulness of digit ratio as an endophenotype in a South African schizophrenia population.
A large genetic study in a South African schizophrenia population recruited patients from services in the Western and Eastern Cape.
Complete clinical histories were captured for participants, including sets of images of the face and extremities. Software was utilised to measure the lengths of participants’ digits from said images and digit ratios (2D:4D) were calculated. Descriptive analyses were performed on the ratios and statistical differences in digit ratio means were calculated between groups characterised by sex, age of onset and the presence vs absence of positive symptoms. Linear modelling was utilised to assess for correlates between 2D:4D and positive and negative symptom severity using scores obtained from the Positive and Negative Syndrome Scale (PANSS) and Scale for the Assessment of Negative Symptoms (SANS).
2D:4D in male participants did not significantly differ from female participants as in healthy populations. 2D:4D did not significantly correlate with the severity of positive or negative symptoms and 2D:4D means between groups did not significantly relate to age of onset.
2D:4D appears to be a possible endophenotype in schizophrenia in this population. 2D:4D, however, may not be as readily identifiable as certain minor physical anomalies and neurological soft signs significantly associated with schizophrenia in this population.
The lifetime prevalence of mental disorders in South Africans is estimated at 30.8%.
Endophenotypes are defined as measurable factors – unobserved by the unaided eye – that occur intermediately along a path with clinical disease and a distal genotype at either end.
The ratio of the lengths of the second to fourth fingers is commonly referred to as 2D:4D or ‘digit ratio’. Links between digit ratio and in utero testosterone exposure, body-composition, alcohol dependency, risk-taking, moral judgement, psychopathy and sexual orientation have previously been researched.
Differences in digit ratio, specifically between males and females, have been widely described and are likely thought to be because of the action of androgens during the perinatal period according to Ventura et al.
Authors have previously investigated associations between digit ratio and specific symptoms of schizophrenia. Bolu et al. found that right and left 2D:4D ratios were oppositely affected in a Turkish Caucasian male population with schizophrenia.
Cerebral lateralisation is considered a normal developmental phenomenon where the left and right cerebral hemispheres develop in an asymmetrical fashion. Neural structures fulfilling specific functions ‘lateralise’ to either the left or right cerebral hemisphere and have been found to do so more significantly in males, who are normally exposed to higher levels of prenatal testosterone.
Venkatasubramanian et al. investigated the connection between abnormal cerebral lateralisation and schizophrenia by comparing 2D:4D of affected participants exhibiting Schneiderian first rank symptoms (FRS) with that of the affected participants who did not as well as healthy controls with digit ratio having been shown to be an indicator of cerebral lateralisation and the presence of FRS being thought to occur in aberrant lateralisation.
These FRSs are listed as auditory hallucinations, thought broadcasting (believing others can hear your thoughts), thought insertion (believing thoughts are being inserted into your mind without your control or consent), thought withdrawal (believing thoughts are being removed from your mind) and delusions.
More recently, Paipa et al. suggested a protective effect of higher in utero exposure of females to oestrogen (high 2D:4D) and males to testosterone (low 2D:4D) from developing negative symptoms, but a predisposing effect of said exposures to developing affective symptoms, such as depression in schizophrenia.
In a Chinese population with schizophrenia, 2D:4D ratios in both male and female participants were found to be significantly higher than in matched controls. A significant difference in right-sided 2D:4D between male patients and controls was found as opposed to a difference in both left and right-sided 2D:4D between female patients and controls. The authors partially interpreted the sex difference as a manifestation of the effect of testosterone on cerebral lateralisation as cited by Qian et al.
Our study attempts a unique analysis within a genetically homogenous South African population and attempts to expand on local data whilst further establishing universality of findings in a global context.
The aim of this cross-sectional study is to determine the utility of digit ratio as an endophenotype in a South African schizophrenia population by performing a retrospective data analysis. It is the wish of the researchers that this study benefits the ongoing search for clarity regarding the nature and development of schizophrenia.
The population investigated for the retrospective analysis was derived from a large study by Niehaus et al.
Gathered information included a standardised set of digital images of the faces, hands and feet of participants. These data and images of participants’ hands were utilised for
Image measuring software was used to accurately measure – in length − the second (2D) and fourth (4D) digits on the palmar aspects of both hands of participants from the most proximal basal creases where fingers join the hands to the very tips. The application ‘ImageJ’ allowed the measurer to place fine points at the bases and tips of fingers on the images and then reported the distance in pixels. An added zoom function aided in greater accuracy regarding point placement for measurement. The distance values of 2D and 4D of participants were captured and 2D:4D ratios were calculated from tabulated measurements. 2D:4D thus = distance 2D/distance 4D and was tabulated electronically as the resultant number.
Digit ratios were captured along with clinical parameters, that is, the presence versus the absence of positive symptoms as well as symptom severity, sex and age of onset. Descriptive analyses were performed comparing 2D:4D between groups using Statistical Product and Service Solutions (SPSS) 26.0 statistical software.
General linear modelling was used to test differences in the digit ratio means between groups and test for significant correlations between 2D:4D and symptomatology.
For the assessment of severity, symptom scores of participants were captured for positive and negative symptoms. These scores were calculated as a composite of the positive symptoms on the Positive and Negative Syndrome Scale (PANSS)
Age of onset of disease was defined as the age at which the diagnosis of schizophrenia was made in participants. Age of onset of disease in the population ranged from 13 to 51 years (mean = 23.75 years, SD = 6.96). Mean 2D:4D of an earlier onset group of 13–20 years (SD = 2.851) was compared to the uncapped range.
Lastly, 2D:4D means of male and female participants were compared.
Ethical approval to conduct the study was obtained from the Health and Undergraduate Research Ethics Committee of the University of Stellenbosch (reference #U19/07/030).
The main finding of the analyses performed is that 2D:4D of male participants did not significantly differ from that of female participants (
Mean 2D:4D of male and female participants.
R/L | Sex | Mean | Standard deviation | |
---|---|---|---|---|
L2D:4D | female | 32 | 0.9753 | 0.05113 |
male | 152 | 0.9659 | 0.05021 | |
R2D:4D | female | 32 | 0.9909 | 0.05778 |
male | 152 | 0.9767 | 0.05668 |
2D:4D means in participants were not found to differ significantly between individuals displaying only negative symptoms and those displaying positive and negative symptoms. 2D:4D did not correlate significantly with described symptom scores. This finding was repeated upon separate analysis of male and female 2D:4D characterised by symptomatology (
Positive and negative symptom scores and their digit ratio correlates.
Symptom domains | Correlates | R2D:4D ratio | L2D:4D ratio |
---|---|---|---|
Negative symptoms (SANS scores) (Mean = 9.494) | Pearson correlation | 0.040 | 0.095 |
Sig. (2-tailed) | 0.592 | 0.201 | |
183 | 183 | ||
Positive symptoms (Composite of positive symptoms in the PANSS) (Mean = 2.730) | Pearson correlation | −0.014 | −0.035 |
Sig. (2-tailed) | 0.859 | 0.657 | |
167 | 167 |
SANS, scale for the assessment of negative symptoms; PANSS, positive and negative syndrome scale.
Note: No significant relationship between digit ratio and age of disease onset was demonstrable.
This study explored the potential use of 2D:4D as an endophenotype in a South African schizophrenia population. The lack of difference found between mean 2D:4D of male and female participants and consequent loss of normal sexual dimorphism is a significant finding as differences in 2D:4D between healthy males and females are well described.
These differences are believed to arise from differences in exposure of in utero sex hormone,
Considering 2D:4D as an endophenotype in the light of the above finding, it is uncertain how closely 2D:4D relates to the genetics underpinning schizophrenia as opposed to being more representative of the sexual development of individuals with schizophrenia, which in turn may add nuance to their presentation.
Regarding the relationship between 2D:4D and clinical parameters in schizophrenia, previous studies have focused mainly on comparison between patients and healthy individuals and consequently consisted of smaller patient samples.
This study attempts to further establish universality of findings and better delineate the heterogeneity of the schizophrenia spectrum by making comparisons within a larger South African schizophrenia patient population.
Of interest to our analysis was whether symptom severity or predominance could be an indicator of further genetically underpinned heterogeneity within the clinical schizophrenia spectrum and whether or not digit ratio could be an indicator of this. For this purpose, patient-patient comparisons were done. Our analyses were not suggestive of such a relationship.
It is possible that genes underpinning clinical heterogeneity are not closely related to 2D:4D as a phenotypical characteristic; besides the clinical heterogeneity in schizophrenia is influenced by an array of other factors – genetics being one – or a combination of the above. This in turn would render 2D:4D an inadequately specific marker of said heterogeneity. It is also possible that pharmacological treatment may have a confounding effect on observations over and above the factors mentioned.
Regarding the age of onset, a relatively young mean was found in our population at roughly 23 years. Here, a disproportionate number of patients who were diagnosed at a younger age could skew the analysis. This may be a reason for not having replicated the 2D:4D or age of onset relationship of Qian et al.
As a physical attribute or measurement thereof, 2D:4D shows considerable variability within both healthy and patient populations.
A robustly sized, population-specific group of healthy individuals was not available for the retrospective analysis and investigating healthy individuals in this population remains an opportunity for expansion upon our current findings.
Furthermore, the use of images may have resulted in a slightly greater error margin than direct observation of physical characteristics. The standardised method of imaging, accurate measuring software and larger sample size were deemed adequate to acceptably offset such an error.
Sexual dimorphism in 2D:4D is well described.
2D:4D ultimately shows promise as an endophenotype in schizophrenia considering its association with the condition across multiple populations and our finding in further support thereof. 2D:4D may, however, be less readily identifiable than other minor physical anomalies
The analysis provides further data for comparison with a robust sample size of healthy individuals in this population for further expansion on its findings.
Special thanks to the Departments of Psychiatry and Health and Undergraduate Research of Stellenbosch University for making this research possible.
The authors have declared that no competing interests exist.
All authors contributed equally to this work.
This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
The data that support the findings of this study are available from the corresponding author, W.D.B.N., upon reasonable request.
The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors.