Haplotype-based linkage of tryptophan hydroxylase 2 to suicide attempt, major depression, and cerebrospinal fluid 5-hydroxyindoleacetic acid in 4 populations.

نویسندگان

  • Zhifeng Zhou
  • Alec Roy
  • Robert Lipsky
  • Kavi Kuchipudi
  • Guanshan Zhu
  • Julie Taubman
  • Mary-Anne Enoch
  • Matti Virkkunen
  • David Goldman
چکیده

CONTEXT Tryptophan hydroxylase 2 (TPH2) encodes the rate-limiting enzyme for brain serotonin biosynthesis. It was recently reported that the TPH2 haplotype was linked to depression in humans. OBJECTIVE To determine the association of TPH2 with suicide attempt, major depression, and a neurochemical intermediate phenotype, cerebrospinal fluid 5-hydroxyindoleacetic acid. DESIGN We resequenced TPH2 coding, 5' promoter, 3'-untranslated region, and splice junction regions in 190 individuals selected for ethnic and clinical diversity, determined haplotype structure using 15 single nucleotide polymorphisms spanning 106 kilobases (kb), and performed linkage analysis in 1798 cases and controls representing 4 populations (657 African Americans, including 104 suicide attempters and 135 with major depression; 513 Finnish whites, including 150 suicide attempters; 146 US whites, including 81 with depression, anxiety disorder, or both; and 482 southwestern American Indians, including 123 suicide attempters and 191 with depression, anxiety disorder, or both) and in 94 Finnish whites for cerebrospinal fluid 5-hydroxyindoleacetic acid levels. RESULTS Sixteen single nucleotide polymorphisms, including Pro206Ser, were detected. The 15-locus panel defined and maximized information content from 2 haplotype blocks in whites, 3 haplotype blocks in African Americans, and the single haplotype block spanning TPH2 in southwestern American Indians. Among common Block1b haplotypes were 2 in yin and yang (opposite) configuration, indicating ancient origin. The yin haplotype, 212121, was increased in frequency in suicide attempters in both populations tested (Finnish whites and African Americans). It was associated with major depression and anxiety disorders in US whites and with major depression in African Americans. The yin haplotype was moderately predictive of lower cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations in controls but not in cases. CONCLUSION Haplotype linkage of TPH2 to suicide attempt and major depression and to a mediating phenotype, cerebrospinal fluid 5-hydroxyindoleacetic acid, provides preliminary evidence of a functional locus potentially within a haplotype block at least 52 kb in size.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Cerebrospinal Fluid Suicide Attempts in Amines and Higher-Lethality Depressed Inpatients

Previous studies have found that not all suicide attempters with major depression have reduced serotonergic activity based on low cerebrospinal fluid 5-hydroxyindoleacetic acid (CSF 5-H1AA) levels. In this study we hypothesized that serotonergic function is lower in depressed patients who have carried out high-lethality suicide attempts resulting in more medical damage, which might explain diff...

متن کامل

Role of serotonin in the pathophysiology of depression: focus on the serotonin transporter.

Considerable evidence has accrued in the last two decades to support the hypothesis that alterations in serotonergic neuronal function in the central nervous system occur in patients with major depression. These findings include the following: (a) reduced cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid (5-HIAA), the major metabolite of serotonin (5-HT) in drug-free depres...

متن کامل

P 78: The Role of Kynurenine Pathway in Suicidal Behavior and Depression

According to global statistics, over 80,000 deaths occur by suicide annually. Up to 90% of complete suicides are based on psychiatric disorders specifically major depressive disorder (MDD) and bipolar disorder. Furthermore high levels of inflammation have been indicated in suicidal patients in both central nervous system and the peripheral blood. Two biological mechanisms that play a key role i...

متن کامل

Effect of tryptophan administration on tryptophan, 5-hydroxyindoleacetic acid and indoleacetic acid in human lumbar and cisternal cerebrospinal fluid.

Tryptophan 5-hydroxyindoleacetic acid and indoleacetic acid were measured in cerebrospinal fluid taken during pneumoencephalography from patients, some of whom took a 3 g or 6 g tryptophan load at various times before. Measurements were made on both lumbar and cisternal cerebrospinal fluid and the results showed similarities between indoleamine metabolism in human brain and spinal cord. Our dat...

متن کامل

Risk factors for suicide among patients with schizophrenia: a cohort study focused on cerebrospinal fluid levels of homovanillic acid and 5-hydroxyindoleacetic acid

BACKGROUND The objective of this study was to investigate the association between 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) in cerebrospinal fluid (CSF), bullying, and later suicide among patients with schizophrenia. METHODS Ninety-nine patients with schizophrenia were included. Correlations of clinical factors, 5-HIAA and HVA, and later suicide were investigated. RESU...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:
  • Archives of general psychiatry

دوره 62 10  شماره 

صفحات  -

تاریخ انتشار 2005