Interaction between SLC6A4 promoter variants and childhood trauma on the age at onset of bipolar disorders.

L. Stertz,F. Mathieu,F. Kapczinski,C. Henry,S. Jamain,A. Henrion,F. Bellivier,M. Lajnef,A.A. Dargél,J. P. Kahn,B. Etain,M. Leboyer,S. Gard

doi:10.1038/srep16301

Abstract

Age at onset (AAO) of bipolar disorders (BD) could be influenced both by a repeat length polymorphism (5HTTLPR) in the promoter region of the serotonin transporter gene (SLC6A4) and exposure to childhood trauma. We assessed 308 euthymic patients with BD for the AAO of their first mood episode and childhood trauma. Patients were genotyped for the 5HTTLPR (long/short variant) and the rs25531. Genotypes were classified on functional significance (LL, LS, SS). A sample of 126 Brazilian euthymic patients with BD was used for replication. In the French sample, the correlation between AAO and trauma score was observed only among ‘SS’ homozygotes (p = 0.002) but not among ‘L’ allele carriers. A history of at least one trauma decreased the AAO only in ‘SS’ homozygotes (p = 0.001). These results remained significant after correction using FDR. Regression models suggested an interaction between emotional neglect and ‘SS’ genotype on the AAO (p = 0.009) and no further interaction with other trauma subtypes. Partial replication was obtained in the Brazilian sample, showing an interaction between emotional abuse and ‘LS’ genotype on the AAO (p = 0.02). In conclusion, an effect of childhood trauma on AAO of BD was observed only in patients who carry a specific stress responsiveness-related SLC6A4 promoter genotype.

Highlights

Of a subgroup of Bipolar disorder (BD) patients with a high familial risk that is coupled to increased comorbid medical and psychiatric disorders and poor prognosis[1,2,3]
The methodological quality of the reviewed studies has been relatively poor, primarily due to small sample sizes and a lack of standardized assessment of BD diagnosis and childhood trauma. To overcome these methodological difficulties, we recently studied the influence of childhood trauma, using the Childhood Trauma Questionnaire (CTQ), on the clinical expression of BD in a large sample of 587 BD patients from France and Norway[13]
On the basis of such data, this study investigated the interaction between SLC6A4 promoter variants and CTQ on the age at onset (AAO) of BD

Summary

Introduction

Of a subgroup of BD patients with a high familial risk that is coupled to increased comorbid medical and psychiatric disorders and poor prognosis[1,2,3]. Several studies have shown AAO to be a heritable clinical characteristics in families affected by BD1,7,8, one study failed to replicate these findings[9] This intrafamilial resemblance suggests that AAO is determined by common familial factors of genetic and/ or environmental origins. The methodological quality of the reviewed studies has been relatively poor, primarily due to small sample sizes and a lack of standardized assessment of BD diagnosis and childhood trauma. To overcome these methodological difficulties, we recently studied the influence of childhood trauma, using the Childhood Trauma Questionnaire (CTQ), on the clinical expression of BD in a large sample of 587 BD patients from France and Norway[13]. On the basis of such data, this study investigated the interaction between SLC6A4 promoter variants and CTQ (total score and subtypes of abuses and neglects) on the AAO of BD

Methods

Results

Discussion

Conclusion