Suicide ideators and attempters with schizophrenia – The role of 5-HTTLPR, rs25531, and 5-HTT VNTR Intron 2 variants

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Abstract

Aim

To examine the role of 5-HTTLPR, rs25531 and 5-HTT VNTR Intron 2 variants in subjects with psychotic disorders manifesting suicide ideation and behaviour.

Methods

The study included 519 subsequently hospitalized subjects who were genotyped for 5-HTTLPR, rs25531 and 5-HTT VNTR In2 variants. Clinical assessments included structured psychiatric interview, sociodemographic characteristics, suicide ideation and behaviour (SIBQ), severity of psychopathology (PANSS) and depression (CDSS).

Results

Three subgroups were identified: suicide attempters (N = 161), suicide ideators (N = 174) and subjects who never reported suicide ideation or behaviour (comparative group, N = 184). Major findings: 1) Suicide attempters scored highest on the CDSS, while no differences between the three clinical subgroups were detected in the PANSS scores; 2) Suicide attempters were more frequently the carriers of LA allele, while subjects in the comparative group were more frequently the carriers of low expression 5-HTTLPR/5-HTT rs25531 haplotype SLG; 3) No difference was found between the three clinical groups in the 5-HTT VNTR In2 variants; 4) Subjects with 5-HTTLPR/5-HTT rs25531 intermediate expression haplotype (LALG, SLA) scored higher on the PANSS general psychopathology subscale; 5) There was no association between suicide attempt or ideation and 5-HTTLPR/In2 or 5-HTTLPR/rs25531/In2 haplotype distribution.

Conclusion

The suicide ideators, attempters and controls did not differ significantly in 5-HTTLPR or 5-HTT VNTR In 2 variants, but 5-HTTLPR/5-HTT rs25531 haplotype might be a useful genetic marker in distinguishing these three clinical groups.

Introduction

Suicide ideation affects majority of people with schizophrenia, a large proportion of whom eventually attempt and complete suicide (De Hert et al., 2001). Today suicide is the leading cause of premature death in schizophrenia with approximately 5% completing suicide (Inskip et al., 1998; Palmer et al., 2005).

Findings from the epidemiological genetic studies suggested a genetic origin to substantial familial susceptibility both to schizophrenia and suicide behaviour (Shih et al., 2004; Brent and Mann, 2005). Disturbances in serotonin (5-hydroxitryptamine, 5-HT) transmission are the most frequently reported neurobiological substrates of suicide and the gene coding for the serotonin transporter (5-HTT) (GenBank accession no. X70697) has been a well-explored candidate for genetic studies on suicide. The 5-HTT promoter harbours a functional 43 bp insertion/deletion polymorphism (5-HTTLPR), which yields a short and a long allele. The S allele is associated with a nearly 50% reduction of basal 5-HTT activity in vitro (Heils et al., 1996) and reduced in vivo 5-HTT binding in Caucasians (Praschak-Rieder et al., 2007). Other polymorphisms have been found in the proximity of the Ins/Del locus such as rs25531, rs25532, rs2020933. The rs25531, a polymorphism nearest to the 5-HTTLPR, results in an A to G substitution and has been shown to modulate the effect of 5-HTTLPR on transcription efficacy. The rs25531 polymorphism is located immediately outside of the 5-HTTLPR segment, so they can be considered as two independent polymorphisms (Bonvicini et al., 2010.). The G allele of rs25531 is in phase with the 5-HTTLPR long allele and mitigates transcriptional efficacy more than does the 5-HTTLPR short allele. Therefore, the modulation of the 5-HTTLPR by rs25531 results in haplotypes with high (LA) or low (LG, SA or SG) transcriptional efficacy (Hu et al., 2006; Martin et al., 2007). A variable number tandem repeats (VNTR) polymorphism within intron 2 (5-HTT VNTR In2) contains 9, 10 (“s”, short allele) or 12 copies (“l”, long allele) of the 16 or 17-base pair repeats (Ogilvie and Harmar, 1997). Although intron parts of a gene are not transcribed, both common repeats “s” and “l” alleles are purported to increase its transcription, with “l” allele having stronger enhancer-like properties than “s” allele (MacKenzie and Quinn, 1999).

A systematic review of twelve studies with biallelic S/L genotyping demonstrated a higher frequency of the low activity S allele in mood disorders and with suicidal behaviour (Anguelova et al., 2003). Only one study examined the role of 5-HTTLPR/rs25531 haplotype and 5-HTT VNTR Intron 2 variants in suicide attempters with schizophrenia (De Luca et al., 2006). De Luca and colleagues genotyped 290 Caucasian subjects with schizophrenia and among these patients, 92 had a history of suicide attempt. No association with history of suicide attempt was found in the 5-HTTLPR haplotype, but they found significant association with the intron 2 VNTR polymorphism, as well as association between suicide attempt and haplotype distribution.

The aim of this study is to examine the role of 5-HTTLPR, rs25531, and 5-HTT VNTR Intron 2 variants in subjects with psychotic disorders who are manifesting suicide ideation and attempts, or none of these phenomena.

Section snippets

Patients and methods

The study included 519 subsequently hospitalized patients who met the following criteria: (a) an ICD-10 diagnosis of psychotic disorder (ICD-10, 1990) and (b) age ≥18 years. They were recruited over the three years period (from 2007 to 2010) from the Department of Psychiatry, University Hospital Center Zagreb. The study protocol was approved by the institutional ethical committee and all participants gave written informed consents.

Differences in general characteristics

The descriptive statistics for the entire sample (column All) and for each of the three clinical subgroups are shown in Table 1. The Kruskal–Wallis H test showed that subjects differed statistically significantly with regard to age. The post-hoc Mann–Whitney U test showed that suicide ideators were significantly younger than the comparative group (p = 0.001), whereas attempters did not differ in age from the comparative group nor from the ideators. The percentage of women differed between the

Discussion

Our findings indicate that suicide ideators and attempters with psychotic disorders can be distinguished from the comparative group of subjects with psychotic disorders who do not express suicide ideation, nor have ever attempted suicide, on both clinical and biological level.

The three clinical groups did not differ significantly in 5-HTTLPR – biallelic variant, however, looking at the 5-HTTLPR/rs25531 haplotype offers an entirely different perspective on the matter. Suicide attempters were

Role of funding source

The study was funded by the Ministry of Science, Education and Sports, Republic of Croatia.

Contributors

Bozina Nada was involved in writing the protocol, genotyping, and critically revised the manuscript.

Nikolina Jovanovic was involved writing the protocol, genotyping, data collection, data analyses and writing the first draft of the paper.

Anja Podlešek performed statistical analysis and critically revised the manuscript.

Martina Rojnic Kuzman was involved in statistical analysis and critically revised the manuscript.

Marija Kudumija Slijepcevic was involved in data collection and critically

Conflict of interest

The authors have no conflict of interest in regard to the publication of this paper.

Acknowledgements

We wish to thank Professor Ljubomir Hotujac for his support in the organization of the study, and Mrs. Zrinka Mirković for very fruitful collaborating and much appreciated help.

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