Polymorphisms in the Trace Amine Receptor 4 (TRAR4) Gene on Chromosome 6q23.2 Are Associated with Susceptibility to Schizophrenia  Jubao Duan, Maria Martinez, Alan R. Sanders, Cuiping Hou, Naruya Saitou, Takashi Kitano, Bryan J. Mowry, Raymond R. Crowe, Jeremy M. Silverman, Douglas F. Levinson, Pablo V. Gejman  The American Journal of Human Genetics  Volume 75, Issue 4, Pages 624-638 (October 2004) DOI: 10.1086/424887 Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 1 Genomic structure of the 6q23.2 gene cluster and association mapping of the initial screening. The genomic positions are based on the UCSC July 2003 assembly of the human genome (see the UCSC Genome Bioinformatics Web site). a, The relative position of the 6q23.2 gene cluster to the peak markers from various linkage studies: D6S424 (Cao et al. 1997; Martinez et al. 1999), D6S416 (Cao et al. 1997), D6S292 (Lerer et al. 2003), and D6S264 (Lindholm et al. 2001). b, Genes in the 6q23.2 gene cluster. c, The −log transformation of the FBAT P value for the 31 SNP markers analyzed in the initial association screening. Each data point of the markers points to its relative position in the gene cluster shown in panel b. The most significant marker is rs4305745, with a P value of .0014 (see table A5 [online only], for FBAT P values and other detailed information for all the initially selected markers, and table 1, for the single-marker association results for all the additional TRAR4 markers examined in the dense mapping effort). The American Journal of Human Genetics 2004 75, 624-638DOI: (10.1086/424887) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 2 Pairwise LD in 192 founders for the TRAR4 region. a, Relative physical position of 23 markers in the TRAR4 region (shown in table 1). The SNPs ss28447862, ss28447876, ss28447865, rs8192624, and ss28447866 were excluded in the following LD measurements because of their low minor-allele frequencies. b, LD pattern in AA subjects (left panel) and EA subjects (right panel). The graph was generated by GOLD (Abecasis and Cookson 2000). In each LD pattern, the D′ values (upper left diagonal) and the P values (lower right diagonal, converted to log P values) are calculated from the program ldmax of the GOLD package (Abecasis and Cookson 2000). The American Journal of Human Genetics 2004 75, 624-638DOI: (10.1086/424887) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 3 Expression pattern of TRAR4 in human tissues. a, TRAR4 expression pattern in various human brain regions. Lane 1 is a 100-bp molecular weight standard ladder (Promega). Lanes 2–13 are human brain, human fetal brain, cerebellum, fetal liver, placental, spinal cord, control (no reverse transcriptase added), basal ganglia, frontal cortex, substantia nigra, amygdala, and hippocampus. RT-PCR products from total RNAs are displayed in the photograph of the ethidium bromide–stained agarose gel; β-actin was used as internal control. b, Quantitative real-time PCR determined the relative abundance of the TRAR4 transcript in various human brain regions. c, Comparison of gene expression of TRAR4 with TRAR1. Samples S1–S6 in panels b and c are basal ganglia, frontal cortex, substantia nigra, amygdala, hippocampus, and cerebellum. The American Journal of Human Genetics 2004 75, 624-638DOI: (10.1086/424887) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure A1 Conserved noncoding regions defined by VISTA (Couronne et al. 2003) and the relative position to associated markers. a, TRAR4 3′-flanking conserved regions, generated by comparing human genome with mouse, rat, and chimpanzee genomes (upper, middle, and lower plots, respectively). The region with sequence similarity reaching 70% is defined as a conserved region, and such peak areas are shaded pink. b, Transformed −log FBAT P values of TRAR4 SNPs versus their relative genomic positions. Panels a and b are aligned according to the genomic position (UCSC Genome Bioinformatics Web site [July 2003 genome draft]). c, The local genomic sequence alignment (human-mouse) around rs4305745 and two other polymorphisms (ss28447873 and rs7452939) in perfect LD with rs4305745. The American Journal of Human Genetics 2004 75, 624-638DOI: (10.1086/424887) Copyright © 2004 The American Society of Human Genetics Terms and Conditions