title: Haplotype-based linkage of tryptophan hydroxylase 2 to suicide attempt, major depression, and cerebrospinal fluid 5-hydroxyindoleacetic acid in 4 populations.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville 20852, USA.
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Zhou
authors.forename: Alec
authors.initials: A
authors.lastname: Roy
authors.forename: Robert
authors.initials: R
authors.lastname: Lipsky
authors.forename: Kavi
authors.initials: K
authors.lastname: Kuchipudi
authors.forename: Guanshan
authors.initials: G
authors.lastname: Zhu
authors.forename: Julie
authors.initials: J
authors.lastname: Taubman
authors.forename: Mary-Anne
authors.initials: MA
authors.lastname: Enoch
authors.forename: Matti
authors.initials: M
authors.lastname: Virkkunen
authors.forename: David
authors.initials: D
authors.lastname: Goldman
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics; D016022:Case-Control Studies; D003865:Major Depressive Disorder / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D005387:Finland / Q000453:epidemiology; D014644:Genetic Variation; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D006897:Hydroxyindoleacetic Acid / Q000134:cerebrospinal fluid* / Q000378:metabolism; D007198:Indians, North American / Q000235:genetics; D015810:Linkage Disequilibrium / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011569:Psychiatric Status Rating Scales; D044469:Racial Groups / Q000235:genetics*; D012701:Serotonin / Q000235:genetics / Q000378:metabolism; D013406:Suicide, Attempted / Q000523:psychology* / Q000706:statistics & numerical data; D014365:Tryptophan Hydroxylase / Q000235:genetics* / Q000378:metabolism; D014481:United States / Q000453:epidemiology; D044465:White People / Q000235:genetics
chemical_list: D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; C494784:TPH2 protein, human; D014365:Tryptophan Hydroxylase