title: Non-synonymous variants in the AMACR gene are associated with schizophrenia.
abstract: BACKGROUND
  The AMACR gene is located in the schizophrenia susceptibility locus on chromosome 5p13, previously identified in a large Puerto Rican pedigree of Spanish origin. The AMACR-encoded protein is an enzyme involved in the metabolism of branched-chain fatty and bile acids. The enzyme deficiency causes structural and functional brain changes, and disturbances in fatty acid and oxidative phosphorylation pathways observed in individuals with schizophrenia. Therefore, AMACR is both a positional and functional candidate gene for susceptibility to schizophrenia.
  
  
  METHODS
  The study had a two-step design: we performed mutation analysis of the coding and flanking regions of AMACR in affected members of the pedigree, and tested the detected sequence variants for association with schizophrenia in a Puerto Rican case-control sample (n=383) of Spanish descent.
  
  
  CONCLUSIONS
  We identified three missense variants segregating with the disorder in the family, rs2278008, rs2287939 and rs10941112. Two of them, rs2278008 and rs2287939, demonstrated significant differences in genotype (P = 4 × 10-4, P = 4 × 10-4) and allele (P = 1 × 10-4, P = 9.5 × 10-5) frequencies in unrelated male patients compare to controls, with the odds ratios (OR) 2.24 (95% CI: 1.48-3.40) and 2.25 (95% CI: 1.49-3.38), respectively. The G-C-G haplotype of rs2278008-rs2287939-rs10941112 revealed the most significant association with schizophrenia (P = 4.25 × 10-6, OR = 2.96; 95% CI: 1.85-4.76) in male subjects. There were no statistically significant differences in genotype, allele, and haplotype frequencies between female schizophrenia subjects and controls. Our results suggest that AMACR may play a significant role in susceptibility to schizophrenia in male patients.
authors.affiliation: Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA. irina.bespalova@mssm.edu
authors.forename: Irina N
authors.initials: IN
authors.lastname: Bespalova
authors.forename: Martina
authors.initials: M
authors.lastname: Durner
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Ritter
authors.forename: Gary W
authors.initials: GW
authors.lastname: Angelo
authors.forename: Enrique
authors.initials: E
authors.lastname: Rossy-Fullana
authors.forename: Jose
authors.initials: J
authors.lastname: Carrion-Baralt
authors.forename: James
authors.initials: J
authors.lastname: Schmeidler
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Silverman
mesh_terms: D024509:3' Flanking Region / Q000235:genetics; D024506:5' Flanking Region / Q000235:genetics; D000328:Adult; D000483:Alleles; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D005190:Family / Q000523:psychology; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D016366:Open Reading Frames / Q000235:genetics; D010375:Pedigree; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011647:Puerto Rico; D019998:Racemases and Epimerases / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics*; D012737:Sex Factors; D035781:Siblings / Q000523:psychology
chemical_list: D019998:Racemases and Epimerases; C108352:alpha-methylacyl-CoA racemase