1. ¹Psychiatry Section, Department of Clinical Neuroscience, Karolinska Institute and Hospital, Stockholm, Sweden
2. ²Center for Molecular Medicine, CMM L8:01, Karolinska Institute, Stockholm, Sweden
3. ³Psychotherapy Section, Department of Clinical Neuroscience, Karolinska Institute and Hospital, Stockholm, Sweden

Correspondence: G Zaboli, Department of Clinical Neuroscience, Karolinska Institute, Karolinska Hospital, CMM L8:01, 17 176 Stockholm, Sweden. Tel: +46 (8) 517 74 602; Fax: +46 (8) 517 76 180; E-mail: ghazal.zaboli@ki.se

Received 29 July 2005; Revised 16 November 2005; Accepted 18 January 2006; Published online 22 February 2006.

Abstract

Alterations in the serotonin (5-HT) system have been related to impulsive aggression and suicidal behavior, common features of the borderline personality disorder (BPD). Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in 5-HT biosynthesis. Two isoforms are known, TPH-1 and TPH-2. TPH-1 has been correlated to various psychiatric and behavioral disorders by gene polymorphism association studies. We aimed to determine whether specific TPH-1 haplotypes associate with BPD. A case–control design was employed. The control group included 98 women without psychiatric history. In all, 95 patients were included, all Caucasian women with a BPD diagnosis who had attempted suicide at least twice during their lifetime. Exclusion criteria were: (i) substance dependence; (ii) dementia or other irreversible organic brain syndromes; (iii) psychotic disorders or major depressive illness with melancholic features; (iv) life-threatening eating disorders. Six single-nucleotide polymorphisms (SNPs) were found at significant linkage disequilibrium across 23 kb of the TPH-1 gene in both patients and controls, suggesting a haplotype block structure. While no individual SNP showed association, several haplotypes associated with the BPD group. In particular, one six-SNP haplotype was absent from the control group while representing about one-quarter of all haplotypes in the BPD group (corrected P10^-5). A 'sliding window' analysis attributed the strongest disease association to haplotype configurations located between the gene promoter and intron 3. We conclude that TPH-1 associates with BPD in suicidal women. Our data support the expectation that haplotype analysis is superior to single locus analysis in gene–disease, case–control association studies.