Association analysis of the chromosome 4p-located G protein-coupled receptor 78 (GPR78) gene in bipolar affective disorder and schizophrenia

The orphan G protein-coupled receptor 78 (GPR78) gene lies within a region of chromosome 4p where we have previously shown linkage to bipolar affective disorder (BPAD) in a large Scottish family. GPR78 was screened for single-nucleotide polymorphisms (SNPs) and a linkage disequilibrium map was constructed. Six tagging SNPs were selected and tested for association on a sample of 377 BPAD, 392 schizophrenia (SCZ) and 470 control individuals. Using standard chi(2) statistics and a backwards logistic regression approach to adjust for the effect of sex, SNP rs1282, located approximately 3 kb upstream of the coding region, was identified as a potentially important variant in SCZ (chi(2) P=0.044; LRT P=0.065). When the analysis was restricted to females, the strength of association increased to an uncorrected allele P-value of 0.015 (odds ratios (OR)=1.688, 95% confidence intervals (CI): 1.104-2.581) and uncorrected genotype P-value of 0.015 (OR=5.991, 95% CI: 1.545-23.232). Under the recessive model, the genotype P-value improved further to 0.005 (OR=5.618, 95% CI: 1.460-21.617) and remained significant after correcting for multiple testing (P=0.017). No single-marker association was detected in the SCZ males, in the BPAD individuals or with any other SNP. Haplotype analysis of the case-control samples revealed several global and individual haplotypes, with P-values <0.05, all but one of which contained SNP rs1282. After correcting for multiple testing, two haplotypes remained significant in both the female BPAD individuals (P=0.038 and 0.032) and in the full sample of affected female individuals (P=0.044 and 0.033). Our results provide preliminary evidence for the involvement of GPR78 in susceptibility to BPAD and SCZ in the Scottish population.     

Evidence for a relationship between genetic variants at the brain-derived neurotrophic factor (BDNF) locus and major depression.

BACKGROUND: Previous genetic studies investigating a possible involvement of variations at the brain derived neurotrophic factor (BDNF) gene locus in major depressive disorder (MDD), bipolar affective disorder (BPAD), and schizophrenia have provided inconsistent results. METHODS: We performed single-marker and haplotype analyses using three BDNF polymorphisms in 2,376 individuals (465 MDD, 281 BPAD, 533 schizophrenia, and 1,097 control subjects). RESULTS: Single-marker analysis did not provide strong evidence for association. Haplotype analysis of marker combination rs988748-(GT)n-rs6265 produced nominally significant associations for all investigated phenotypes (global p values: MDD p = .00006, BPAD p = .0057, schizophrenia p = .016). Association with MDD was the most robust finding and could be replicated in a second German sample of MDD patients and control subjects (p = .0092, uncorrected). Stratification of our schizophrenia sample according to the presence or absence of a lifetime history of depressive symptoms showed that our finding in schizophrenia might be attributable mainly to the presence of depressive symptoms. CONCLUSIONS: Association studies of genetic variants of the BDNF gene with various psychiatric disorders have been published with reports of associations and nonreplications. Our findings suggest that BDNF may be a susceptibility gene for MDD and schizophrenia-in particular, in a subgroup of patients with schizophrenia with a lifetime history of depressive symptoms.     

MLC1 gene is associated with schizophrenia and bipolar disorder in Southern India.

BACKGROUND: Chromosome 22q13 has shown linkage with schizophrenia (SCZ) and bipolar affective disorder (BPAD). A missense mutation in MLC1 (putative cation-channel gene on 22q13) co-segregating with periodic catatonic schizophrenia has been reported. We have investigated the relationship of MLC1 with SCZ and BPAD in Southern India. METHODS: All exons and flanking intronic sequences of MLC1 were screened for novel variations. Case-control (216 BPAD, 193 SCZ, 116 control subjects) and family-based analyses (113 BPAD, 107 SCZ families) were performed to evaluate association of MLC1 with these disorders. RESULTS: We found 33 MLC1 sequence variations, including three novel mutations: Val210Ile, Leu308Gln, and Arg328His in six BPAD cases and Val210Ile in one control individual. Minor allele of a common variation, ss16339182 (in approximately 6 Kb Linkage-Disequilibrium [LD]-block) was associated with BPAD in case-control (p = .03) and family-based analyses (transmitted/nontransmitted [T/NT]-44/20; p = .003). Association was observed for rs2235349 and rs2076137 with SCZ and ss16339163 with BPAD in case-control study. Using Block 2 haplotype tagging single nucleotide polymorphisms (htSNPs), GC haplotype revealed association (p = .02) and excess transmission (p = .002) with BPAD. CONCLUSIONS: Association of MLC1 with SCZ and BPAD suggests involvement of a common pathway. Rare missense mutations and common variants associated with BPAD favors hypothesis about likely involvement of both rare and common polymorphisms in etiology of this complex disorder.     

Associations between major psychiatric disorder polygenic risk scores and blood-based markers in UK biobank

Major depressive disorder (MDD), schizophrenia (SCZ), and bipolar disorder (BD) have both shared and discrete genetic risk factors, and are associated with peripheral abnormalities. The relationships between such genetic architectures and blood-based markers are, however, unclear.We investigated relationships between polygenic risk scores (PRS) for these disorders and peripheral markers in the UK Biobank cohort. We calculated polygenic risk scores for n = 367,329 (MDD PRS), n = 366,465 (SCZ PRS), and n = 366,383 (BD PRS) UK Biobank cohort subjects. We then examined associations between disorder PRS and 58 inflammatory/immune, hematological, bone, cardiovascular, hormone, liver, renal and diabetes-associated blood markers using two generalized linear regression models: ‘minimally adjusted’ controlling for variables such as age and sex, and ‘fully adjusted’ including additional lifestyle covariates: BMI, alcohol and smoking status, and medication intake.There were 38/58 MDD PRS, 32/58 SCZ PRS, and 20/58 BD PRS-blood marker associations detected for our minimally adjusted model. Of these, 13/38 (MDD PRS), 14/32 (SCZ PRS), and 10/20 (BD PRS) associations remained significant after controlling for lifestyle factors. Many were disorder-specific, with 8/13 unique MDD PRS associations identified. Several disorder-specific associations for MDD and SCZ were immune-related, with mostly positive and negative associations identified for MDD and SCZ PRS respectively.This study suggests that MDD, SCZ and BD have both shared and distinct peripheral markers associated with disorder-specific genetic risk. The results also implicate inflammatory dysfunction in MDD and SCZ, albeit with differences in patterns between the two conditions, and enrich our understanding of potential underlying pathophysiological mechanisms in major psychiatric disorders.     

Analysis of association between common SNPs in ErbB4 and bipolar affective disorder, major depressive disorder and schizophrenia in the Han Chinese population

Neuregulin-1 (NRG1) is associated with schizophrenia. As one of the receptors of NRG1, v-erb-a erythroblastic leukemia viral oncogene homolog 4 (ErbB4) has also been reported to be associated with schizophrenia. Since there can be shared genetic variants among bipolar affective disorder, major depressive disorder and schizophrenia, we tested the association between ErbB4 and these three major psychiatric disorders in the Han Chinese population. Five single nucleotide polymorphisms (SNPs) were selected based on previous positive reports and linkage disequilibrium information of the HapMap Han Chinese individuals from Beijing (CHB) + individuals from Tokyo, Japan (JPT) population. These SNPs were genotyped in 1140 bipolar affective disorder (BPAD) patients, 1140 schizophrenia (SCZ) patients, 1139 major depressive disorder (MDD) patients and 1140 normal controls. Two SNPs (rs707284 and rs839523) showed nominal significance in the BPAD patients but this was eliminated after permutation. No significant association between ErbB4 and the two other psychiatric disorders was observed, nor did haplotype analysis reveal any positive signal.     

Association of the trace amine associated receptor 6 (TAAR6) gene with schizophrenia and bipolar disorder in a Korean case control sample

Trace amines and their receptors may be implicated in the pathogenesis of psychiatric disorders. Previous studies have reported association of the trace amine associated receptor 6 (TAAR6) gene with susceptibility to schizophrenia and bipolar disorder but results have not been consistent. The purpose of this study was to examine these associations in Korean patients and also to test for association of TAAR6 with susceptibility to major depressive disorder (MDD). A case control sample consisting of 281 patients with schizophrenia, 190 patients with bipolar disorder, 187 patients with MDD and 288 psychiatrically healthy control subjects, was examined. Patients with schizoaffective disorder were not included in any of the psychiatric samples. Five single nucleotide polymorphisms (SNPs: rs4305745; rs8192625; rs7452939; rs6903874 and rs6937506) were genotyped in the TAAR6 gene and in the 3' regulatory region, using pyrosequencing. SNP rs6903874 was significantly associated with schizophrenia (p = 0.012) and bipolar disorder (p = 0.004). A three SNP haplotype consisting of alleles GCT from SNPs rs7452939, rs6903874 and rs6937506, respectively, was significantly over-represented in patients with schizophrenia (p = 0.0003) and bipolar disorder (p = 0.00002). A second three SNP haplotype (GTT) derived from the same SNPs was significantly under-represented in patients with bipolar disorder (p = 0.001). The GTT haplotype associations withstand the most rigorous corrections for multiple testing. These findings strongly support association of the TAAR6 gene with susceptibility to both schizophrenia and bipolar disorder in Korean patients. Further studies are needed to confirm these findings in this and other populations and to identify functional variants in TAAR6 that may be implicated in pathogenesis.     

Examination of G72 and D-amino-acid oxidase as genetic risk factors for schizophrenia and bipolar affective disorder

A recent study has suggested that the brain-expressed genes for G72 and D-amino-acid oxidase (DAAO) exert an influence on susceptibility to schizophrenia. Our aim was to replicate this finding in German schizophrenic patients and to assess whether G72 and DAAO might also contribute to the development of bipolar affective disorder. We genotyped seven single-nucleotide polymorphisms (SNPs) in the G72 gene and three in the DAAO gene in 599 patients (299 schizophrenic, 300 bipolar) and 300 controls. At G72, individual SNPs and a four-marker haplotype were associated with schizophrenia. The most significant SNP as well as the haplotype were also associated with bipolar affective disorder (BPAD). DAAO was associated with schizophrenia, but not with BPAD. The association of variation at G72 with schizophrenia as well as BPAD provides molecular support for the hypothesis that these two major psychiatric disorders share some of their etiologic background.     

Common SNPs in CSF2RB are associated with major depression and schizophrenia in the Chinese Han population

Abstract

Objectives. Colony stimulating factor 2 receptor β (CSF2RB) encodes the protein which is the common β chain of the high affinity receptor for IL-3, IL-5 and CSF. It locates in the linkage region 22q12.3 of both bipolar disorder and schizophrenia, and is expressed in most cells. Methods. We carried out a large scale case–control study to test the association between CSF2RB and three major mental disorders in the Chinese Han population. Seven single nucleotide polymorphisms were genotyped in 1140 bipolar affective disorder patients (including 645 type I bipolar affective disorder patients), 1140 schizophrenia patients, 1139 major depressive disorder patients and 1140 healthy controls. Results. Three SNPs were found to be associated with both schizophrenia and major depressive disorder. Haplotype association analysis revealed one protective haplotype (P value = 0.014 for SCZ and 0.0004 for MDD) and one risk haplotype (P value = 0.006 for SCZ and 0.001 for MDD). Additional 52 SNPs were analyzed for population stratification, which demonstrated that our positive results were not caused by population stratification. Conclusions. Our results support CSF2RB as a risk factor common to both schizophrenia and major depression in the Chinese Han population.     

Analysis of genome-wide CAG/CTG repeats, and at SEF2-1B and ERDA1 in schizophrenia and bipolar affective disorder.

A shift towards larger CAG/CTG triplet repeats and schizophrenia (SCZ) and bipolar affective disorder (BPAD) has been detected by several recent studies, using the Repeat Expansion Detection (RED) technique, however no specific loci have been shown to be responsible for this shift. Further analyses by our group of RED (CTG)10 ligation products amongst an extended sample of patients and comparison with controls matched for age, sex and ethnicity show no significant differences in distribution (P= 0.23, n=95; P=0.93, n=91, for SCZ and BPAD respectively). Alleles at two recently discovered unstable trinucleotide repeat loci at 18q21.1 (SEF2-1B) and 17q21.3 (ERDA1) have also been analysed in affecteds and matched controls. We observed no increase in frequency of larger alleles (>37 repeats) in affected individuals at SEF2-1B (BPAD: P=0.95, n= 100; SCZ: P=0.61, n=97) or at ERDA1 (BPAD: P= 0.4, n = 101; SCZ: P= 0.05, n = 151, with larger alleles more frequent in controls). Our findings suggest that larger CAG/CTG repeats at these loci are neither major contributory factors to the etiology of psychosis, nor in linkage disequilibrium with a gene that is. Furthermore, when the RED results were compared to allele sizes at SEF2-1B and ERDA1, it was observed that a majority of SCZ, BPAD and control individuals with large RED products had a large allele at either or both sites (78% for RED products > or =270 bp; 62% for RED products > or =180 bp).     

Genome-wide association study of major depressive disorder: new results, meta-analysis, and lessons learned

Major depressive disorder (MDD) is a common complex disorder with a partly genetic etiology. We conducted a genome-wide association study of the MDD2000+ sample (2431 cases, 3673 screened controls and >1?M imputed single-nucleotide polymorphisms (SNPs)). No SNPs achieved genome-wide significance either in the MDD2000+ study, or in meta-analysis with two other studies totaling 5763 cases and 6901 controls. These results imply that common variants of intermediate or large effect do not have main effects in the genetic architecture of MDD. Suggestive but notable results were (a) gene-based tests suggesting roles for adenylate cyclase 3 (ADCY3, 2p23.3) and galanin (GAL, 11q13.3); published functional evidence relates both of these to MDD and serotonergic signaling; (b) support for the bipolar disorder risk variant SNP rs1006737 in CACNA1C (P=0.020, odds ratio=1.10); and (c) lack of support for rs2251219, a SNP identified in a meta-analysis of affective disorder studies (P=0.51). We estimate that sample sizes 1.8- to 2.4-fold greater are needed for association studies of MDD compared with those for schizophrenia to detect variants that explain the same proportion of total variance in liability. Larger study cohorts characterized for genetic and environmental risk factors accumulated prospectively are likely to be needed to dissect more fully the etiology of MDD.     

Association between serotonin 4 receptor gene polymorphisms and bipolar disorder in Japanese case-control samples and the NIMH Genetics Initiative Bipolar Pedigrees

Possible irregularities in serotonergic neurotransmission have been suggested as causes of a variety of neuropsychiatric diseases. We performed mutation and association analyses of the HTR4 gene, on 5q32, encoding the serotonin 4 receptor in mood disorders and schizophrenia. Mutation analysis was performed on the HTR4 exons and exon/intron boundaries in 48 Japanese patients with mood disorders and 48 patients with schizophrenia. Eight polymorphisms and four rare variants were identified. Of these, four polymorphisms at or in close proximity to exon d, g.83097C/T (HTR4-SVR (splice variant region) SNP1), g.83159G/A (HTR4-SVRSNP2), g.83164 (T)9-10 (HTR4-SVRSNP3), and g.83198A/G (HTR4-SVRSNP4), showed significant association with bipolar disorder with odds ratios of 1.5 to 2. These polymorphisms were in linkage disequilibrium, and only three common haplotypes were observed. One of the haplotypes showed significant association with bipolar disorder (P = 0.002). The genotypic and haplotypic associations with bipolar disorder were confirmed by transmission disequilibrium test in the NIMH Genetics Initiative Bipolar Pedigrees with ratios of transmitted to not transmitted alleles of 1.5 to 2.0 (P = 0.01). The same haplotype that showed association with bipolar disorder was suggested to be associated with schizophrenia in the case-control analysis (P = 0.003) but was not confirmed when Japanese schizophrenia families were tested. The polymorphisms associated with mood disorder were located within the region that encodes the divergent C-terminal tails of the 5-HT(4) receptor. These findings suggest that genomic variations in the HTR4 gene may confer susceptibility to mood disorder.     

A genome scan and follow-up study identify a bipolar disorder susceptibility locus on chromosome 1q42

In this study, we report a genome scan for psychiatric disease susceptibility loci in 13 Scottish families. We follow up one of the linkage peaks on chromosome 1q in a substantially larger sample of 22 families affected by schizophrenia (SCZ) or bipolar affective disorder (BPAD). To minimise the effect of genetic heterogeneity, we collected mainly large extended families (average family size >18). The families collected were Scottish, carried no chromosomal abnormalities and were unrelated to the large family previously reported as segregating a balanced (1:11) translocation with major psychiatric disease. In the genome scan, we found linkage peaks with logarithm of odds (LOD) scores >1.5 on chromosomes 1q (BPAD), 3p (SCZ), 8p (SCZ), 8q (BPAD), 9q (BPAD) and 19q (SCZ). In the follow-up sample, we obtained most evidence for linkage to 1q42 in bipolar families, with a maximum (parametric) LOD of 2.63 at D1S103. Multipoint variance components linkage gave a maximum LOD of 2.77 (overall maximum LOD 2.47 after correction for multiple tests), 12 cM from the previously identified SCZ susceptibility locus DISC1. Interestingly, there was negligible evidence for linkage to 1q42 in the SCZ families. These results, together with results from a number of other recent studies, stress the importance of the 1q42 region in susceptibility to both BPAD and SCZ.     

Findings in an independent sample support an association between bipolar affective disorder and the G72/G30 locus on chromosome 13q33

Markers near the nested genes G72 and G30 on chromosome 13q33 have been implicated in the etiology of schizophrenia and, recently, bipolar affective disorder (BPAD). Hattori et al (2003) reported that single-nucleotide polymorphisms (SNPs) near the G72/G30 locus were associated with BPAD in a sample of 22 pedigrees, and that SNP haplotypes were associated in a second, larger sample of triads. The present study attempts to replicate this finding in an independent case-control sample. Six SNPs near the G72/G30 locus, including the most strongly associated markers in the previous study, were tested in 139 cases and 113 ethnically matched controls. Significant association was detected between BPAD and two adjacent SNPs (smallest P=0.007; global P=0.024). Haplotype analysis produced additional support for association (smallest P=0.004; global P=0.004). Analysis of 31 unlinked microsatellite markers detected no population stratification in the cases or controls studied. Although the associated alleles and haplotypes differ from those previously reported, these new results provide further evidence, in an independent sample, for an association between BPAD and genetic variation in the vicinity of the genes G72 and G30.     

FGFR2 is associated with bipolar disorder: A large-scale case–control study of three psychiatric disorders in the Chinese Han population

Objectives. Repetitive linkage analyses have indicated 10q25–q26 as a shared risk region for schizophrenia (SCZ) and bipolar disorder (BPD). A genome-wide association study and follow-up recently identified a significant association between a single nucleotide polymorphism (SNP) of this region (rs17101921) and SCZ. The nearest gene to this SNP is fibroblast growth factor receptor 2 (FGFR2). Methods. We carried out a large scale case–control study to test the association between FGFR2 and three major psychiatric disorders: SCZ, BPD and major depressive disorder (MDD) in the Chinese Han population. Eight tag SNPs were genotyped using Taqman assay in 1139 BPD patients, 1112 SCZ patients, 1119 MDD patients and 1135 shared healthy controls. Results. After correcting the multiple tests by permutation, one SNP (rs11199993), and a haplotype including this SNP, was found to be significantly associated with BPD. Potential population stratification in our samples was analyzed using 70 additional random SNPs dispersed on different chromosomes. No population stratification was detected, so our results could not be affected by this cofounding factor. Limitations of our study include incomplete coverage and insufficient power to detect association for relatively small odds ratio. Conclusions. Association between FGFR2 and BPD is worthy of further confirmation.     

A novel relationship for schizophrenia,bipolar and major depressive disorder Part 3: Evidence from chromosome 3 high density association screen

Familial clustering of schizophrenia (SCZ), bipolar disorder (BPD), and major depressive disorder (MDD) was systematically reported (Aukes et al, Genet Med 2012, 14, 338‐341) and convergent evidence from genetics, symptomatology, and psychopharmacology imply that there are intrinsic connections between these three major psychiatric disorders, for example, any two or even three of these disorders could co‐exist in some families. A total of 60, 838 single‐nucleotide polymorphisms (SNPs) on chromosome 3 were genotyped by Affymetrix Genome‐Wide Human SNP array 6.0 on 119 SCZ, 253 BPD (type‐I), 177 MDD patients and 1,000 controls. The population of Shandong province was formed in 14 century and believed that it belongs to homogenous population. Associated SNPs were systematically revealed and outstanding susceptibility genes (CADPS, GRM7,KALRN, LSAMP, NLGN1, PRICKLE2, ROBO2) were identified. Unexpectedly, flanking genes for the associated SNPs distinctive for BPD and/or MDD were replicated in an enlarged cohort of 986 SCZ patients. The evidence from this chromosome 3 analysis supports the notion that both of bipolar and MDD might be subtypes of schizophrenia rather than independent disease entity. Also, a similar finding was detected on chromosome 5, 6, 7, and 8 (Chen et al. Am J Transl Res 2017;9 (5):2473–2491; Curr Mol Med 2016;16(9):840–854; Behav Brain Res 2015;293:241–251; Mol Neurobiol 2016. doi: 10.1007/s12035‐016‐0102‐1). Furthermore, PRICKLE2 play an important role in the pathogenesis of three major psychoses in this population.     

DISC1 association, heterogeneity and interplay in schizophrenia and bipolar disorder

Disrupted in schizophrenia 1 (DISC1) has been associated with risk of schizophrenia, schizoaffective disorder, bipolar disorder, major depression, autism and Asperger syndrome, but apart from in the original translocation family, true causal variants have yet to be confirmed. Here we report a harmonized association study for DISC1 in European cohorts of schizophrenia and bipolar disorder. We identify regions of significant association, demonstrate allele frequency heterogeneity and provide preliminary evidence for modifying interplay between variants. Whereas no associations survived permutation analysis in the combined data set, significant corrected associations were observed for bipolar disorder at rs1538979 in the Finnish cohorts (uncorrected P=0.00020; corrected P=0.016; odds ratio=2.73+/-95% confidence interval (CI) 1.42-5.27) and at rs821577 in the London cohort (uncorrected P=0.00070; corrected P=0.040; odds ratio=1.64+/-95% CI 1.23-2.19). The rs821577 single nucleotide polymorphism (SNP) showed evidence for increased risk within the combined European cohorts (odds ratio=1.27+/-95% CI 1.07-1.51), even though significant corrected association was not detected (uncorrected P=0.0058; corrected P=0.28). After conditioning the European data set on the two risk alleles, reanalysis revealed a third significant SNP association (uncorrected P=0.00050; corrected P=0.025). This SNP showed evidence for interplay, either increasing or decreasing risk, dependent upon the presence or absence of rs1538979 or rs821577. These findings provide further support for the role of DISC1 in psychiatric illness and demonstrate the presence of locus heterogeneity, with the effect that clinically relevant genetic variants may go undetected by standard analysis of combined cohorts.     

Identification of a biological signature for schizophrenia in serum

Biomarkers are now used in many areas of medicine but are still lacking for psychiatric conditions such as schizophrenia (SCZ). We have used a multiplex molecular profiling approach to measure serum concentrations of 181 proteins and small molecules in 250 first and recent onset SCZ, 35 major depressive disorder (MDD), 32 euthymic bipolar disorder (BPD), 45 Asperger syndrome and 280 control subjects. Preliminary analysis resulted in identification of a signature comprised of 34 analytes in a cohort of closely matched SCZ (n=71) and control (n=59) subjects. Partial least squares discriminant analysis using this signature gave a separation of 60-75% of SCZ subjects from controls across five independent cohorts. The same analysis also gave a separation of ~50% of MDD patients and 10-20% of BPD and Asperger syndrome subjects from controls. These results demonstrate for the first time that a biological signature for SCZ can be identified in blood serum. This study lays the groundwork for development of a diagnostic test that can be used as an aid for distinguishing SCZ subjects from healthy controls and from those affected by related psychiatric illnesses with overlapping symptoms.     

Allelic association of G72/G30 with schizophrenia and bipolar disorder: a comprehensive meta-analysis

The G72/G30 gene complex (G72 also known as D-amino acid oxidase activator, DAOA) and its chromosomal region 13q32-34 have been linked and associated with both schizophrenia (SCZ) and bipolar disorder (BP) in multiple studies, including our initial association report on BP. However, the inconsistency of associated variants across studies is obvious. Previous meta-analyses had small data sets. The present meta-analysis combined 18 association articles published before April of 2007. There were 19 independent studies of SCZ, with 4304 cases, 5423 controls, and 1384 families, and four independent studies of BP with 1145 cases, 1829 controls, and 174 families. Of 15 single nucleotide polymorphisms (SNPs) analyzed in the 95-kb G72/G30 gene region, M18/rs947267 and M22/rs778293 showed association with SCZ in Asians, and M24/rs1421292 with SCZ in Europeans. The associations of C allele at M18 and A allele at M22 with SCZ in Asians survived conservative Bonferroni correction for multiple testing for 15 markers and subgroup analysis (adjusted P=0.0000253 for M18; adjusted P=0.009 for M22). No single maker showed evidence of overall association with BP. These results suggest that G72/G30 may influence susceptibility to schizophrenia with weak effects.     

Intron 12 in NTRK3 is associated with bipolar disorder

Based on the important role of neurotrophic factors in brain development and plasticity and reports of association between schizophrenia and the gene neurotrophic tyrosine kinase receptor 3 (NTRK3), we investigated associations of bipolar disorder with polymorphisms in NTRK3. Recently, our group reported evidence for a possible association of NTRK3 polymorphisms with hippocampal function and schizophrenia. In the present study, we used a homogenous Norwegian case-control sample (the TOP study) consisting of 194 patients diagnosed with bipolar disorder and 336 healthy controls genotyped on the Affymetrix Genome-wide Human SNP Array 6.0. In total 149 markers were investigated for SNP-disease association. Polymorphisms in over 20 markers were nominally associated with bipolar disorder, covering intron 5 to intron 12. Interestingly, our markers appeared to be located close or within the linkage regions reported in schizophrenia, early-onset major depressive disorder and eating disorder, supporting the hypothesis that some genes influence risk beyond traditional diagnostic boundaries.     

Association analysis of the chromosome 4p15-p16 candidate region for bipolar disorder and schizophrenia

Several independent linkage studies have identified chromosome 4p15-p16 as a putative region of susceptibility for bipolar disorder (BP), schizophrenia (SCZ) and related phenotypes. Previously, we identified two subregions (B and D) of the 4p15-p16 region that are shared by three of four 4p-linked families examined. Here, we describe a large-scale association analysis of regions B and D (3.8 and 4.5 Mb, respectively). We selected 408 haplotype-tagging single nucleotide polymorphisms (SNPs) on a block-by-block basis from the International HapMap project and tested them in 368 BP, 386 SCZ and 458 control individuals. Nominal significance thresholds were determined using principal component analysis as implemented in the program SNPSpD. In region B, overlapping SNPs and haplotypes met the region-wide threshold (P相似文献