Positive association of the PDE4B (phosphodiesterase 4B) gene with schizophrenia in the Japanese population

The phosphodiesterase 4B (PDE4B) gene is located at 1p31, a susceptibility region for schizophrenia (SZ). Moreover, PDE4B interacts with DISC1, which is a known genetic risk factor for SZ. Recently, it was reported that the PDE4B gene is associated with SZ in Caucasian and African American populations. In this study, case-controlled association analyses were performed in the Japanese population to determine if the PDE4B gene is implicated in SZ. Thirteen single nucleotide polymorphisms (SNPs) were analyzed in 444 schizophrenic patients and 452 control subjects. Three SNPs (rs2180335, rs910694 and rs472952) were significantly associated with SZ after applying multiple test correction (p = 0.039, 0.004 and 0.028). In addition, a significant association was found between specific haplotypes (rs2180335 and rs910694) and SZ (permutation p = 0.001). Our result suggests that variations at the PDE4B locus may play a significant role in the etiology of SZ in the Japanese population.     

Dopaminergic gene polymorphisms and cognitive function in a north Indian schizophrenia cohort

Background

Associations of polymorphisms from dopaminergic neurotransmitter pathway genes have mostly been reported in Caucasian ancestry schizophrenia (SZ) samples. As studies investigating single SNPs with SZ have been inconsistent, more detailed analyses utilizing multiple SNPs with the diagnostic phenotype as well as cognitive function may be more informative. Therefore, these analyses were conducted in a north Indian sample.

Methods

Indian SZ case-parent trios (n = 601 families); unscreened controls (n = 468) and an independent set of 118 trio families were analyzed. Representative SNPs in the Dopamine D3 receptor (DRD3), dopamine transporter (SLC6A3), vesicular monoamine transporter 2 (SLC18A2), catechol-o-methyltransferase (COMT) and dopamine beta-hydroxylase (DBH) were genotyped using SNaPshot/SNPlex assays (n = 59 SNPs). The Trail Making Test (TMT) was administered to a subset of the sample (n = 260 cases and n = 302 parents).

Results

Eight SNPs were nominally associated with SZ in either case-control or family based analyses (p < 0.05, rs7631540 and rs2046496 in DRD3; rs363399 and rs10082463 in SLC18A2; rs4680, rs4646315 and rs9332377 in COMT). rs6271 at DBH was associated in both analyses. Haplotypes of DRD3 SNPs incorporating rs7631540-rs2134655-rs3773678-rs324030-rs6280-rs905568 showed suggestive associations in both case-parent and trio samples. At SLC18A2, rs10082463 was nominally associated with psychomotor performance and rs363285 with executive functions using the TMT but did not withstand multiple corrections.

Conclusions

Suggestive associations with dopaminergic genes were detected in this study, but convincing links between dopaminergic polymorphisms and SZ or cognitive function were not observed.     

Evaluation of HLA Polymorphisms in Relation to Schizophrenia Risk and Infectious Exposure

Background:

Genome-wide association studies (GWAS) implicate single nucleotide polymorphisms (SNPs) on chromosome 6p21.3-22.1, the human leukocyte antigen (HLA) region, as common risk factors for schizophrenia (SZ). Other studies implicate viral and protozoan exposure. Our study tests chromosome 6p SNPs for effects on SZ risk with and without exposure. Method: GWAS-significant SNPs and ancestry-informative marker SNPs were analyzed among African American patients with SZ (n = 604) and controls (n = 404). Exposure to herpes simplex virus, type 1 (HSV-1), cytomegalovirus (CMV), and Toxoplasma gondii (TOX) was assayed using specific antibody assays. Results: Five SNPs were nominally associated with SZ, adjusted for population admixture (P < .05, uncorrected for multiple comparisons). These SNPs were next analyzed in relation to infectious exposure. Multivariate analysis indicated significant association between rs3130297 genotype and HSV-1 exposure; the associated allele was different from the SZ risk allele. Conclusions: We propose a model for the genesis of SZ incorporating genomic variation in the HLA region and neurotropic viral exposure for testing in additional, independent African American samples.Key words: HLA, gene, HSV-1, cytomegalovirus, schizophrenia, African American, kwd>     

Positive association of the PDE4B (phosphodiesterase 4B) gene with schizophrenia in the Japanese population

The phosphodiesterase 4B (PDE4B) gene is located at 1p31, a susceptibility region for schizophrenia (SZ). Moreover, PDE4B interacts with DISC1, which is a known genetic risk factor for SZ. Recently, it was reported that the PDE4B gene is associated with SZ in Caucasian and African American populations. In this study, case-controlled association analyses were performed in the Japanese population to determine if the PDE4B gene is implicated in SZ. Thirteen single nucleotide polymorphisms (SNPs) were analyzed in 444 schizophrenic patients and 452 control subjects. Three SNPs (rs2180335, rs910694 and rs472952) were significantly associated with SZ after applying multiple test correction (p = 0.039, 0.004 and 0.028). In addition, a significant association was found between specific haplotypes (rs2180335 and rs910694) and SZ (permutation p = 0.001). Our result suggests that variations at the PDE4B locus may play a significant role in the etiology of SZ in the Japanese population.     

Association of miR-122, miR-124 miR-126 and miR-143 gene polymorphisms with ischemic stroke in the northern Chinese Han population

Abstract

Objectives: Single nucleotide polymorphisms (SNPs) in microRNA (miRNA) genes can have diverse functional consequence by affecting the processing and target selection of miRNA. Recent evidence indicates that miRNA play important roles in the pathogenesis of atherosclerosis, which is a major cause of ischemic stroke (IS). The aim of this study was to clarify whether genetic variations in four miRNA genes (miR-143 rs4705342, miR-122 rs17669, miR-126 rs4636297, and miR-124 rs531564) contribute to IS susceptibility.

Methods: A case-control study was used to explore miRNA genetic polymorphisms in 567 IS patients and 552 control subjects that were frequency matched by age and gender. We genotyped four SNPs using polymerase chain reaction/ligation detection reaction.

Results: The miR-126 gene rs4636297 polymorphism was associated with decreased small vessel stroke risk (GA vs. GG: odds ratio (OR)?=?0.62, p?=?.015; GA?+?AA vs. GG: OR?=?0.637, p?=?.018; A vs. G: OR?=?0.696, p?=?.033). Using logistic regression analysis, this significant association remained after adjusting for confounding risk factors (adjusted OR?=?0.626, 95% confidence interval (CI)?=?0.426–0.921). However, the three other miRNA (miR-143 rs4705342, miR-122 rs17669, and miR-124 r531564) were not associated with IS risk under allele or genotype, nor in different inheritance models. In addition, there were no significant associations with stroke subtypes for these three miRNA SNPs.

Conclusion: Our study suggests that the miR-126 gene rs4636297 polymorphism may play an important role in the pathogenesis of small vessel occlusive stroke in the northern Chinese Han population.     

Association Study Between the Pericentrin (PCNT) Gene and Schizophrenia

Disrupted-in-schizophrenia 1 (DISC1), a known genetic risk factor for schizophrenia (SZ) and major depressive disorder (MDD), interacts with several proteins and some of them are reported to be genetically associated with SZ. Pericentrin (PCNT) also interacts with DISC1 and recently single-nucleotide polymorphisms (SNPs) within the PCNT gene have been found to show significant associations with SZ and MDD. In this study, case-controlled association analysis was performed to determine if the PCNT gene is implicated in SZ. Nine SNPs were analyzed in 1,477 individuals (726 patients with SZ and 751 healthy controls). No significant difference was observed between the controls and the patients in allelic frequencies or genotypic distributions of eight SNPs. Although allelic distribution of rs11702684 was different between the two groups (P = 0.042), the difference did not reach statistical significance after permutation correction for multiple comparisons. In the haplotypic analysis, we could not find any significant association in our subjects, either. This gene may not play a major role independently in the etiology of SZ in the Japanese population.     

Association study in the 5q31-32 linkage region for schizophrenia using pooled DNA genotyping

Background

Several linkage studies suggest that chromosome 5q31-32 might contain risk loci for schizophrenia (SZ). We wanted to identify susceptibility genes for schizophrenia within this region.

Methods

We saturated the interval between markers D5S666 and D5S436 with 90 polymorphic microsatellite markers and genotyped two sets of DNA pools consisting of 300 SZ patients of Bulgarian origin and their 600 parents. Positive associations were followed-up with SNP genotyping.

Results

Nominally significant evidence for association (p < 0.05) was found for seven markers (D5S0023i, IL9, RH60252, 5Q3133_33, D5S2017, D5S1481, D5S0711i) which were then individually genotyped in the trios. The predicted associations were confirmed for two of the markers: D5S2017, localised in the SPRY4-FGF1 locus (p = 0.004) and IL9, localized within the IL9 gene (p = 0.014). Fine mapping was performed using single nucleotide polymorphisms (SNPs) around D5S2017 and IL9. In each region four SNPs were chosen and individually genotyped in our full sample of 615 SZ trios. Two SNPs showed significant evidence for association: rs7715300 (p = 0.001) and rs6897690 (p = 0.032). Rs7715300 is localised between the TGFBI and SMAD5 genes and rs6897690 is within the SPRY4 gene.

Conclusion

Our screening of 5q31-32 implicates three potential candidate genes for SZ: SMAD5, TGFBI and SPRY4.

     

Association study of RELN polymorphisms with schizophrenia in Han Chinese population

Schizophrenia (SZ) is a common and complex psychiatric disorder with a strong genetic component. Previous research suggests that mutations altering genes in neurodevelopmental pathways contribute to SZ. Reelin gene (RELN) maps to chromosome 7q22.1, the encoded protein plays a pivotal role in guiding neuronal migration, lamination and connection during embryonic brain development. Several reports had indicated that reduced RELN expression is associated with human mental illnesses such as SZ, mood disorders and autism. In this study, case-control association analyses were performed in the Han Chinese population to determine if the RELN gene is a susceptibility gene for SZ. Thirty-seven single nucleotide polymorphisms (SNPs) were genotyped in 528 paranoid SZ patients and 528 control subjects. A significant association was found between rs12705169 and SZ (p = 0.001). Moreover, the haplotypes constructed from five SNPs showed significant differences between cases and controls (p = 0.041). When subjects were divided by gender, rs12705169 remained significant difference only in females (OR = 0.24, 95%CI = 0.14-0.40 for CC and OR = 0.40, 95%CI = 0.27-0.58 for AC), both in the allele and genotype (p = 0.0001 for both). This study describes a positive association between RELN and SZ in the Han Chinese population, and provides genetic evidence to support the gender difference of SZ.     

Association study of the CNS patterning genes and autism in Han Chinese in Taiwan

Autism is a complex neurodevelopmental disorder with high heritability. Despite different approaches worldwide to identify susceptibility loci or genes for autism spectrum disorders (ASDs), no consistent result has been reported. CNS patterning genes have been recognized as candidate genes for autism based on neuroimage and neuropathology evidence. This study investigated four candidate genes (WNT2, EN2, SHANK3, and FOXP2) by a tag SNP approach in a family-based association study. The trio samples include 1164 subjects from 393 families, including 393 probands (aged 9.1 ± 4.0 years; male, 88.6%) diagnosed with autistic disorder (n = 373) or Asperger's disorder (n = 20) according to the DSM-IV diagnostic criteria and confirmed by the Chinese ADI-R interview. Three tag SNPs of EN2 (7q36), 6 SNPs of WNT2 (7q31-33), 5 SNPs of SHANK3 (22q13.3), 3 SNPs of FOXP2 (7q31) were genotyped. TDT analysis was done to test the association of each tag SNP and haplotype. There was no association with autism for 17 tag SNPs of WNT2, EN2, SHANK3, and FOXP2 based on SNP analyses. Haplotype analyses did not reveal significant association except for the 6 tag SNPs of WNT2 gene showing a significant association on one haplotype composed of rs2896218 and rs6950765 (G-G) (p = 0.0095). Other haplotypes composed of rs2896218 and rs6950765 (G-G) were also significantly associated with autism. The present study indicates that SHANK3 may not be a critical gene for the etiology of ASDs in Han Chinese population. Inconsistent findings in EN2 and FOXP2 in the Han Chinese population need further clarification. A haplotype of WNT2 (rs2896218-rs6950765: G-G) is significantly associated with ASDs in our trios samples, this finding warrants further validation by different sample and confirmation by functional study.     

Association study of 21 circadian genes with bipolar I disorder, schizoaffective disorder, and schizophrenia

Objective:  Published studies suggest associations between circadian gene polymorphisms and bipolar I disorder (BPI), as well as schizoaffective disorder (SZA) and schizophrenia (SZ). The results are plausible, based on prior studies of circadian abnormalities. As replications have not been attempted uniformly, we evaluated representative, common polymorphisms in all three disorders.
Methods:  We assayed 276 publicly available 'tag' single nucleotide polymorphisms (SNPs) at 21 circadian genes among 523 patients with BPI, 527 patients with SZ/SZA, and 477 screened adult controls. Detected associations were evaluated in relation to two published genome-wide association studies (GWAS).
Results:  Using gene-based tests, suggestive associations were noted between EGR3 and BPI (p = 0.017), and between NPAS2 and SZ/SZA (p = 0.034). Three SNPs were associated with both sets of disorders ( NPAS2 : rs13025524 and rs11123857; RORB: rs10491929; p < 0.05). None of the associations remained significant following corrections for multiple comparisons. Approximately 15% of the analyzed SNPs overlapped with an independent study that conducted GWAS for BPI; suggestive overlap between the GWAS analyses and ours was noted at ARNTL .
Conclusions:  Several suggestive, novel associations were detected with circadian genes and BPI and SZ/SZA, but the present analyses do not support associations with common polymorphisms that confer risk with odds ratios greater than 1.5. Additional analyses using adequately powered samples are warranted to further evaluate these results.     

Genome-wide pathway analysis in attention-deficit/hyperactivity disorder

This study aimed to (1) to identify candidate single-nucleotide polymorphisms (SNPs) and mechanisms of attention-deficit/hyperactivity disorder (ADHD) and (2) to generate SNP-to-gene-to-pathway hypotheses. An ADHD genome-wide association study (GWAS) dataset that included 428,074 SNPs in 924 trios (2,758 individuals) of European descent was used in this study. The Identify candidate Causal SNPs and Pathways (ICSNPathway) analysis was applied to the GWAS dataset. ICSNPathway analysis identified 11 candidate SNPs, 6 genes, and 6 pathways, which provided 6 hypothetical biological mechanisms. The strongest hypothetical biological mechanism was that rs2532502 alters the role of CD27 in the context of the pathways of positive regulation of nucleocytoplasmic transport [nominal p < 0.001; false discovery rate (FDR) = 0.028]. The second strongest mechanism was the rs1820204, rs1052571, rs1052576 → CASP9 → mitochondrial pathway (nominal p < 0.001; FDR = 0.032). The third mechanism was the rs1801516 → ATM → CD25 pathway (nominal p < 0.001; FDR = 0.034). By applying the ICSNPathway analysis to the ADHD GWAS data, 11 candidate SNPs, 6 genes that included CD27, CASP9, ATM, CD12orf65, OXER1, and ACRY, and 6 pathways were identified that may contribute to ADHD susceptibility.     

Specific and common genes implicated across major mental disorders: A review of meta-analysis studies

Major efforts have been directed at family-based association and case–control studies to identify the involvement of candidate genes in the major disorders of mental health. What remains unknown is whether candidate genes are associated with multiple disorders via pleiotropic mechanisms, and/or if other genes are specific to susceptibility for individual disorders. Here we undertook a review of genes that have been identified in prior meta-analyses examining specific genes and specific mental disorders that have core disruptions to emotional and cognitive function and contribute most to burden of illness– major depressive disorder (MDD), anxiety disorders (AD, including panic disorder and obsessive compulsive disorder), schizophrenia (SZ) and bipolar disorder (BD) and attention deficit hyperactivity disorder (ADHD). A literature review was conducted up to end-March 2013 which included a total of 1519 meta-analyses across 157 studies reporting multiple genes implicated in one or more of the five disorders studied. A total of 134 genes (206 variants) were identified as significantly associated risk variants for MDD, AD, ADHD, SZ or BD. Null genetic effects were also reported for 195 genes (426 variants). 13 genetic variants were shared in common between two or more disorders (APOE e4, ACE Ins/Del, BDNF Val66Met, COMT Val158Met, DAOA G72/G30 rs3918342, DAT1 40-bp, DRD4 48-bp, SLC6A4 5-HTTLPR, HTR1A C1019G, MTHR C677T, MTHR A1298C, SLC6A4 VNTR and TPH1 218A/C) demonstrating evidence for pleiotrophy. Another 12 meta-analyses of GWAS studies of the same disorders were identified, with no overlap in genetic variants reported. This review highlights the progress that is being made in identifying shared and unique genetic mechanisms that contribute to the risk of developing several major psychiatric disorders, and identifies further steps for progress.     

Association of single nucleotide polymorphisms in the gene encoding platelet endothelial cell adhesion molecule-1 with the risk of myocardial infarction: a systematic review and meta-analysis

Background

Single nucleotide polymorphisms (SNPs) within the platelet endothelial cell adhesion molecule-1 (PECAM-1) gene have been proposed as predisposing factors for myocardial infarction (MI) but published reports have given conflicting findings.

Objective

The present study aimed to clarify the association between SNPs in PECAM-1 and MI using a meta-analysis of published studies.

Methods

Medline, HuGE Navigator and SCOPUS Library databases were searched to identify case-control studies which examined the association of SNPs in PECAM-1 and MI. Data were extracted using standardized methods. Combined odds ratios (OR) with 95% confidence intervals (CI) for the association of SNPs with MI were calculated using a random effect approach and under additive, dominant and recessive models of inheritance.

Results

A total of 7 studies comprising 3886 cases and 4097 controls fulfilled the inclusion criteria. Three SNPs in PECAM-1 were investigated, namely rs668 (Leu125Val), rs12953 (Ser563Asn) and rs1131012 (Arg670Gly). The GG genotype of rs1131012 was associated with a reduced risk of MI under a recessive (OR: 0.81; 95%CI: 0.69-0.94; p = 0.010), but not additive and dominant models (p > 0.05). This association was robust in sensitivity analyses and not subject to heterogeneity. No significant association was detected between rs668 and rs12953 with MI under any of the inheritance models.

Conclusion

The results of the current meta-analysis suggest that homozygous polymorphic genotype (GG) of the rs1131012 SNP may confer protection against MI. The impact of this variant on the expression and function of PECAM-1 needs to be elucidated in future investigations.     

Common Variants on Xq28 Conferring Risk of Schizophrenia in Han Chinese

Schizophrenia is a highly heritable, severe psychiatric disorder affecting approximately 1% of the world population. A substantial portion of heritability is still unexplained and the pathophysiology of schizophrenia remains to be elucidated. To identify more schizophrenia susceptibility loci, we performed a genome-wide association study (GWAS) on 498 patients with schizophrenia and 2025 controls from the Han Chinese population, and a follow-up study on 1027 cases and 1005 controls. In the follow-up study, we included 384 single nucleotide polymorphisms (SNPs) which were selected from the top hits in our GWAS (130 SNPs) and from previously implicated loci for schizophrenia based on the SZGene database, NHGRI GWAS Catalog, copy number variation studies, GWAS meta-analysis results from the international Psychiatric Genomics Consortium (PGC) and candidate genes from plausible biological pathways (254 SNPs).Within the chromosomal region Xq28, SNP rs2269372 in RENBP achieved genome-wide significance with a combined P value of 3.98×10⁻⁸ (OR of allele A = 1.31). SNPs with suggestive P values were identified within 2 genes that have been previously implicated in schizophrenia, MECP2 (rs2734647, P _combined = 8.78×10⁻⁷, OR = 1.28; rs2239464, P _combined = 6.71×10⁻⁶, OR = 1.26) and ARHGAP4 (rs2269368, P _combined = 4.74×10⁻⁷, OR = 1.25). In addition, the patient sample in our follow-up study showed a significantly greater burden for pre-defined risk alleles based on the SNPs selected than the controls. This indicates the existence of schizophrenia susceptibility loci among the SNPs we selected. This also further supports multigenic inheritance in schizophrenia. Our findings identified a new schizophrenia susceptibility locus on Xq28, which harbor the genes RENBP, MECP2, and ARHGAP4.Key words: schizophrenia, genome-wide association study, Han Chinese, MECP2, ARHGAP4, RENBP     

Cytokine polymorphisms are associated with daytime napping in adults living with HIV

Objective/backgroundDaytime napping longer than one hour has been associated with an increased risk for all-cause mortality. Associations between cytokine polymorphisms and daytime napping in chronic illnesses such as HIV, however, have not been well described. The purpose of this study was to examine cytokine polymorphisms associated with long daytime napping in adults living with HIV.MethodsA cross-sectional analysis was conducted using a convenience sample of 257 adults living with HIV. Daytime napping was assessed with wrist actigraphy data collected over three days. Participants categorized as long nappers (≥60 min) were compared to short nappers and non-nappers (<60 min). Single nucleotide polymorphisms (SNPs) for 15 candidate genes involved in cytokine signaling were analyzed. Genes included: interferon-gamma (IFNG), IFNG receptor 1 (IFNGR1), interleukins (IL1B, IL1R, IL1R2, IL2, IL4, IL6, IL8, IL10, IL13, IL17A), nuclear factors of kappa light polypeptide gene enhancer in B cells (NFKB1 and NFKB2), and tumor necrosis factor alpha (TNFA).ResultsAfter adjusting for relevant demographic and clinical characteristics, long daytime napping was associated with 12 SNPs from seven genes: 1) IFNG rs2069728; 2) IL1B rs1143642, rs1143627, and rs16944; 3) IL2 rs2069763; 4) IL6 rs4719714, rs1554606, and rs2069845; 5) IL17A rs3819024 and rs8193036; 6) NFKB1 rs4648110; and 7) NFKB2 rs1056890.ConclusionsCytokine genetic variations may have a role in physiological regulation of daytime napping as well as nocturnal sleep. Cytokine polymorphisms associated with long daytime napping could help identify adults with HIV who may benefit from targeted therapeutic interventions.     

Association between Common Genetic Variants in the Opioid Pathway and Smoking Behaviors in Chinese Men

Background

There is biological evidence that the brain opioidergic system plays a critical role in the addictive properties of nicotine. The purpose of the present study was to examine the associations of single nucleotide polymorphisms (SNPs) in the genes encoding mu-opioid receptor (MOR) and the MOR-interacting proteins (including OPRM1, ARRB2, and HINT1) with smoking behaviors in Chinese men.

Methods

A total of 284 subjects (including current and ex-smokers) were recruited. Special questionnaires were used to assess smoking behaviors including age of smoking initiation, daily cigarette consumption, and Fagerström test for nicotine dependence (FTND) score. Participant samples were genotyped for six SNPs in the opioid pathway genes: rs1799971 in OPRM1, rs1045280, rs2036657 and rs3786047 in ARRB2, rs3852209 and rs2278060 in HINT1. Linear and logistic regression models were used to determine single-locus and haplotype-based association analyses.

Results

There was no significant association between any of SNPs analyzed and smoking behaviors. Logistic regression analyses under dominant, recessive, and additive models showed no significant associations of the six SNPs with smoking status (current vs. ex-smokers). After adjustment for age at enrollment and smoking initiation age, HINT1 rs3852209 was significantly associated with smoking status with an OR of 0.54 (95% CI, 0.31-0.95; P?=?0.03) under dominant inheritance model. No haplotypes in ARRB2 or HINT1 were related to smoking status.

Conclusions

The present study indicates no significant association between common genetic variations in MOR and MOR-interacting proteins and smoking behaviors in Chinese men, and gives suggestive evidence that HINT1 rs3852209 may be related to smoking status. The findings require confirmation from further studies in additional larger samples.     

The genetics of symptom-based phenotypes: toward a molecular classification of schizophrenia

Objective: Genetic linkage studies in schizophrenia (SZ) have primarily focused on the phenotype of disease susceptibility. A limited number of studies, however, have reported suggestive linkage to specific SZ symptom domains including regions on chromosomes 6, 8, and 20. We examined these chromosomal regions for association to positive, negative, and disorganized symptom clusters, using a dense set of single-nucleotide polymorphisms (SNPs). Methods: We ascertained 178 Caucasian patients with SZ for lifetime severity of clinical symptomatology using a structured diagnostic interview. The cohort was genotyped with the Affymetrix 500K microarray, from which we selected, a priori, 4833 intragenic SNPs located within chromosomal regions previously linked to specific SZ symptom clusters. Parametric tests, corrected for multiple testing, were used to compare the effects of allelic variation within these SNPs to the lifetime severity of the specific symptom domain that had been implicated by prior linkage studies. Results: We were able to extend previous reports of linkage between chromosome 6q and both positive and disorganized symptoms. Lifetime severity of positive symptoms was significantly (P = 2.50 × 10⁻⁵) associated with a SNP within the origin recognition complex subunit 3–like (ORC3L) gene, a gene implicated in synaptic plasticity. Level of disorganized symptoms was significantly (P < 6.00 × 10⁻⁵) associated 2 SNPs within the brain-specific angiogenesis inhibitor 3 (BAI3) gene, which is highly expressed in brain during development. Conclusions: These data point toward specific candidate genes located within previously implicated linkage peaks for clinical symptomatology. Identification of functional variants within these regions and a characterization of the effect of these risk genotypes on the treatment of specific clinical symptoms are needed.