Catechol-O-Methyltransferase Val158Met and brain-derived neurotrophic factor Val66Met gene polymorphisms in paraphilic sexual offenders.

BACKGROUND: Child sexual abuse (CSA) is an important problem worldwide. The reason of sex abuse is considered as multifactorial. Genetic contribution reported by recent studies is a significant evidence for this pathologic behavior. Catechol-O-Methyltransferase (COMT) is an enzyme in the metabolic inactivation of catecholamine and substances containing catecholamines such as dopamine, epinephrine, and norepinephrine. COMT polymorphism causes functional changes in COMT enzyme activity. Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor usually synthesized from central nervous system neurons. With the effect of BDNF, dopamine and serotonin play important roles on neurogenesis, survival, and synaptic plasticity. AIM: This study aims to examine COMT Val158Met (rs4680) and BDNF Val66Met (rs6265) polymorphisms in CSA. SETTINGS AND
DESIGN: This was a case-control study.
MATERIALS AND METHODS: Seventy paraphilic child sexual abuser patients and seventy age- and gender-matched healthy controls participated in this study. COMT Val158Met and BDNF Val66Met polymorphisms were genotyped by real-time polymerase chain reaction assay.
RESULTS: COMT Val158Met genotype frequencies were determined as GG 31.4%, GA 45.7%, and AA 22.9% in patients; GG 24.3%, GA 45.7%, and AA 8.6% in controls; and exhibited a positive relationship between the groups (P = 0.018). BDNF Val66Met genotype frequencies were determined as GG 77.1%, GA 21.4%, and AA 1.4% in patients; GG 65.7%, GA 31.4%, AA 2.9% in controls; and no significant relationship was observed between the groups (P = 0.317).
CONCLUSIONS: This research investigated COMT (Val158Met) and BDNF (Val66Met) in paraphilic child sexual offenders. A positive relationship was found for COMT gene; however, no significant relation was observed for BDNF gene between paraphilic sexual offenders and controls.

INTRODUCTION

Paraphilic disorders have been increased in recent years. Paraphilic disorders are significant problems both in Turkey and worldwide. In the Diagnostic and Statistical Manual of Mental Disorders 5th edition, paraphilic interests are called “any intense and persistent sexual interest other than sexual interest in genital stimulation or preparatory fondling with phenotypically normal physiologically mature, consenting human partners.”[1] Paraphilic interests are different from paraphilic disorders. Paraphilic disorders include pedophilic disorder, sexual sadism disorder, and sexual offendings.[2]

The incidence of paraphilic disorders is approximately 50% in sexual offenders, including pedophilic child sexual abuse (CSA) (40%), and an important part of them has several mental disorders.[23]

CSA which is an important public health problem influencing women and men in childhood time has 22.3% and 8.5% prevalence, respectively.[4] According to a study performed in 173 Turkish students, 51.4% of the students were found to be subjected to at least one type of physical, emotional, or sexual child abuse.[5] In another study performed in American population, it was reported that 8%–12% of American youth experienced at least one sexual assault in their lifetime.[6] Paraphilic sexual abuse can be prevented if the risk factors can be realized. There is so much theory and study about the causes of sexual assault to children. The researchers are investigating these factors as biological, psychological, and environmental related with the paraphilic CSA. In a study performed by Gaffney et al., CSA occurred more frequent in the families of pedophiles than in the families of nonpedophiles.[7]

There are some candidate genes having roles both in appearing normal sexual behaviors and in sexual behavior disorders. For instance, Miller et al. determined that there was a relationship between dopamine D2 and D1 receptor alleles and age of the first sexual intercourse in males.[8] According to another study, D4 receptor gene was more important than other dopamine alleles for the age of first sexual intercourse, genes, and social context.[9] They determined that these findings which signed dopaminergic receptors may play an important role in male sexual behaviors.[9] Alanko et al. studied the single nucleotide polymorphisms (SNPs) of hormonal genes – androgen, estrogen, and prolactin and corticotropin-releasing hormone and found nominally significant main effects on pedophilic sexual interest for these SNPs linked to these hormones. However, these associations did not remain significant after multiple testing.[10] The orientation of sexual behavior may be affected from environmental factors and also from genetic properties. Genetic influences on sexual behavior may be mediated by different mechanisms, such as testosterone levels, and dopaminergic and serotonergic systems. In a study, it has been found that genetic differences may be systematically associated with environmental exposure which was treated as the cause of sexual behavior (gene–environment correlation).[11]

It is known that catechol-O-methyl transferase (COMT) polymorphism is effective in schizophrenia, bipolar disorder, obsessive-compulsive disorder, hyperactivity, and diseases such as migraine, and also in the pathogenesis of aggressive and antisocial behavior. COMT has also a role in drug metabolism including catechol used for the treatment of many diseases such as asthma and Parkinson's disease.[12131415] The monoamines, epinephrine, norepinephrine, serotonin, and tyramine, may play a role in the pathophysiology of paraphilias. These neurotransmitters are neuromodulators having effects on memory, motivational behavior, appetite, and sexuality of people.[161718] Kafka claimed that, sexual effects of the pharmacological medications which influence the monoamines can have both facilitative and inhibitory impacts on sexual behavior.[18] One of the candidate genes, COMT having Val158Met polymorphism, has been implicated in the susceptibility of sexual abusers.[19] COMT is an enzyme which is responsible for the degradation of catecholamine and also metabolizes monoamine neurotransmitters in the central nervous system (CNS). This gene is located on chromosome 22q11. It is expressed in the prefrontal cortex (PFC) and hippocampus. In a study, COMT Val158Met polymorphism was studied in paraphilic sexual offenders in Poland society,[19] but they did not find a significant relationship between sex offenders and controls.

COMT Val158Met (rs4680) polymorphism results in the substitution of amino acid valine to methionine. This change affects dopamine regulation of PFC. The Met158Met (LL) genotype was associated with a 3–4 times reduced enzyme activity compared to Val158Val (HH) genotype, and the Val158Met (HL) genotype has an intermediate activity.[20]

Brain-derived neurotrophic factor (BDNF) is generally synthetized from the CNS neurons, and it serves as a neurotrophic factor playing an important role in the growth of serotoninergic neurons and nerve plasticity. It was also reported that it increases monoaminergic activity.[21] In the pro-domain of BDNF, a SNP was detected converting the 66th amino acid valine into methionine. This amino acid change affects dendritic impulse and synaptic localization of BDNF and disrupts its secretion. Short-term memory and BDNF activation were disrupted in the cases which have the Val66Met SNP.[22] BDNF is an important neurotrophin which may be secreted in response to neuronal activity. For the further implicating role of BDNF signaling in depression and anxiety, it has been shown that the reduction in hippocampal BDNF levels was correlated with stress-induced depressive behaviors.[2324] Beyond that, a study reported an association between BDNF and bipolar disorder.[25] It was hypothesized the COMT and BDNF may affect the orientation of the paraphilic CSA. With all this information, we aimed to analyze the relationship between child sex abusers with COMT and BDNF genes.

MATERIALS AND METHODS

Patients

This case–control study included a total of 140 Turkish individuals, 70 paraphilic sexual offenders (age: 30.46 ± 11.78) and 70 healthy male controls (age: 31.91 ± 12.19). The eligible patients were taken from Istanbul branch of Forensic Medical Council. The controls were consisted of randomly selected healthy controls who visited Cerrahpasa Medical Faculty Hospital for regular health screenings. Individuals were excluded if they had any neurological and psychiatric disorders and also any self-reported personal or familial psychiatric history or psychotropic medication history. They were age and sex matched. All of the participants were of Turkish origin. The information of ethnicity, age, and family history were determined by directly asking the participants. All patients provided informed consent before they took part in the study. The study was approved by the Local Ethics Committee of the Cerrahpasa Medical Faculty in Istanbul, Turkey.

Blood samples and DNA isolation

Venous blood samples were obtained from the patient and control groups and collected into EDTA tubes. Genomic DNA was extracted from whole blood using a commercial kit (Roche Diagnostics, Mannheim, Germany) according to the manufacturer's instructions.

Genotyping of gene variants

COMT Val158Met (rs4680) and BDNF Val66Met (rs6265) genotypes were determined by real-time polymerase chain reaction (RT-PCR). LightCycler 1.5® system was used to perform SNP genotyping using hybridization probes consisting of 3’-fluorescein and a 5’-LightCycler® Red labeled pair of oligonucleotide probes.[26]

Statistical analysis

The ages of patient and control groups were compared with Student's t-test. Data are expressed as mean ± standard deviation, frequency, and percentage. Chi-square test was used in allele frequency and genotype percentages of patients and controls. P <0.05 was considered as statistically significant. All statistical analyses were performed using the SPSS for Windows software (Version 21.0) (IBM Corp, Armonk, NY, USA).

RESULTS

The mean age of the patients in the CSA group was 30.46 ± 11.78 and control group was 31.91 ± 12.19. CSA group consists of 70 male patients and the control group was 70 healthy controls [Table 1].

Table 1

Demographic and clinical characteristics of patients and controls

Parameter	Patients	Controls	P
Age (years), mean±SD	30.46±11.78	31.91±12.19	0.493
Gender (male), n	70	70
Alcohol or drug use	15	10
Psychiatric disease	45	-

SD – Standard deviation

The distribution of the COMT Val158Met (rs4680) and BDNF (Val66Met) genotype and allele frequencies are shown in Tables 2 and 3, respectively. Statistically significant differences were observed in the genotype frequencies of COMT polymorphism between CSA patients and healthy controls (P = 0.018). There was no statistical difference in BDNF (Val66Met) polymorphism between patients and controls.

Table 2

Distribution of genotypes and allele frequencies of catechol-O-methyl transferase (Val158Met) in patients and controls

COMT (Val158Met)	GG	GA	AA	P	G allele frequency	A allele frequency	P
Patients, n (%)	22 (31.4)	32 (45.7)	16 (22.9)	0.018	0.54	0.46	0.54
Controls, n (%)	17 (24.3)	47 (67.1)	6 (8.6)		0.58	0.42

COMT – Catechol-O-methyl transferase

Table 3

Genotypes and allele frequencies of brain-derived neurotrophic factor (Val66Met) in patients and controls

BDNF (Val66Met)	GG	GA	AA	P	G allele frequency	A allele frequency	P
Patients, n (%)	54 (77.1)	15 (21.4)	1 (1.4)	0.317	0.88	0.12	0.13
Controls, n (%)	46 (65.7)	22 (31.4)	2 (2.9)		0.81	0.19

BDNF – Brain-derived neurotrophic factor

The distribution of the COMT rs4680 and BDNF Val66Met genotype of the patients having personality disorder, schizophrenia, bipolar disorder, and mental retardation are shown in Tables 4 and 5, respectively. The number of patients according to the clinical distribution is 2 having personality disorder, 12 having schizophrenia and other psychotic disorders, 4 having bipolar disorder, and 27 diagnosed with mental retardation.

Table 4

Catechol-O-methyl transferase Val158Met genotype distribution according to clinical diagnosis

COMT (Val158Met)	GG	GA	AA	P
Personality disorder, n (%)	0 (0.0)	1 (50.0)	1 (50.0)	0.235
Schizophrenia and other psychotic disorders, n (%)	7 (58.3)	3 (25.0)	2 (16.7)
Bipolar disorder, n (%)	0 (0.0)	3 (75.0)	1 (25.0)
Mental retardation, n (%)	7 (25.9)	11 (40.7)	9 (33.3)

COMT – Catechol-O-methyl transferase

Table 5

Brain-derived neurotrophic factor genotype distribution according to clinical diagnosis

BDNF (Val66Met)	GG	GA	AA	P
Personality disorder, n (%)	2 (100.0)	0 (0.0)	0 (0.0)	0.797
Schizophrenia and other psychotic disorders, n (%)	9 (75.0)	3 (25.0)	0 (0.0)
Bipolar disorder, n (%)	4 (100.0)	0 (0.0)	0 (0.0)
Mental retardation, n (%)	23 (85.2)	3 (11.1)	1 (3.7)

BDNF – Brain-derived neurotrophic factor

There was no relationship between COMT rs4680 and BDNF Val66Met and the clinical diagnosis of the patients (P > 0.05). These results may be obtained because of the small sample size.

DISCUSSION

The genetic studies about the paraphilic child sexual offenders in the world are not frequent according to the literature research.[1019] However, it is an important problem for all countries.[22728] We analyzed two different genetic polymorphisms which are significant in the psychiatric diseases in 70 child sexual male offenders and 70 healthy controls. We chose COMT and BDNF genes because of their roles in the behavioral control, aggressiveness, addiction, and drug use. The number of patients diagnosed with psychiatric diseases was in high frequency in our study [Table 1]. According to the clinical distribution of 70 paraphilic CSA patients, 2 of them had personality disorder, 12 patients had schizophrenia and other psychotic disorders, 4 of them had bipolar disorder, and 27 were diagnosed with mental retardation.

The study of Dunsieth et al. made a research on 113 male sexual offenders and found that 84 (74%) of the patients had paraphilia and 66 (58%) of them had a mood disorder (40 [35%] bipolar disorder and 27 [24%] depressive disorder).[2] The study of Dunsieth et al. supported our results.

Several studies have shown that COMT and BDNF polymorphisms were more common in psychiatric patient groups compared to the general population.[1223242526] In our previous study performed in panic disorder patients, we found an important association in COMT Met/Met genotype in patients according to controls.[26] In the study of Šberg et al., it is found that depressed patients had higher frequency of COMT Met/Met (LL) genotype.[29] In a study made in Turkish violent offenders with mental retardation, no relationship in COMT Val158Met polymorphism was found between patients and controls.[30] Some studies suggested that COMT Met allele was related with mania symptoms.[31]

In the study of Bordolato et al., it was found that although there was no direct relationship between COMT Val158Met and the mania, the severity of the manic symptoms was highly correlated with the COMT enzyme activity. The results of our study show that COMT gene has an important relationship with sexual offenders, but the BDNF gene does not support our hypothesis. The present results are not agreed with Jakubczyk et al.'s study which did not find a significant association between COMT polymorphism and CSA.[19]

Our study found an important relationship in COMT variants between CSA patients and controls. We found that COMT LL genotype was significantly associated with sexual offenders. COMT polymorphism results in the substitution of amino acid valine to methionine in the enzyme. This change affects dopamine regulation of PFC. The Met158Met genotype is associated with a 3–4 times reduced enzyme activity compared to Val158Val genotype, and Val158Met genotype has an intermediate activity. Low COMT activity causes high dopamine levels and thus produces excessive dopamine levels. Our study confirms this relationship between low COMT activity excessive dopamine levels, disrupting cognitive information processing, and generating symptoms of anxiety in the paraphilic CSA patients. According to a study, it was found that increasing dopamine levels of male rats by giving L-DOPA causes hypersexuality in male rats.[32] Thus, there may be other factors contributing to this discrepancy in other work[19] such as sample size and the inclusion criteria used in the sample selection process.

These results may be attributable to the multigenetic nature of paraphilic CSA. BDNF has been studied in diseases related with the behavior. BDNF expresses BDNF in the brain. Neurotrophic factors play an important role in the formation of neuronal plasticity and neuronal networks.[33] BDNF is an important factor; some studies show that acute stress induces a decreased BDNF expression in the brain hippocampus.[21] BDNF Val66Met polymorphism lowers BDNF expression in Met allele; carriers of the Met/Met allele show more aggressive behavior than Val/Val carriers.[34]

We did not observe significant differences in the genotype distribution of BDNF subtypes. We observed no relationship between BDNF Val66Met and paraphilic CSA. Our study is supported by other studies in the literature.[19] In the study of Jakubczyk et al., no relationship was found in BDNF Val66Met polymorphism between 97 paraphilic sexual offenders and 76 controls.[19]

According to our findings, COMT Val158Met polymorphism may be related with CSA in male patients, but no relationship was found with the BDNF Val66Met polymorphism in the same patients.

There are some limitations in our study; sizes of individual genetic variants were so small. Therefore, it is likely that interactions among genes, hormones, and environmental factors are involved in the sexual interest in the population.

CONCLUSION

Thus, COMT AA (Met) variant can be associated with paraphilic sexual offenders.

Financial support and sponsorship

This study was supported by the Scientific Research Projects Coordination Unit of Istanbul University-Cerrahpasa, Project number: 54609.

This study was presented at the 15th National Medical Biology and Genetics Congress, 26–29 October 2017 Mugla, Turkey.

Conflicts of interest

There are no conflicts of interest.