Dopamine beta-hydroxylase gene (DbetaH) -1021C-->T influences self-reported paranoia during cocaine self-administration.

BACKGROUND: Variation in the gene for dopamine beta-hydroxylase (DbetaH) has been reported to associate with cocaine-induced paranoia as assessed by retrospective self-report. This association has yet to be tested prospectively. METHODS: Visual analog scale (VAS) ratings of paranoia were obtained in 31 cocaine users during three cocaine self-administration sessions (8, 16, and 32 mg/70 kg). Pharmacogenetic interactions between cocaine and a putative functional polymorphism in DbetaH (-1021C-->T) were assessed. RESULTS: VAS self-ratings showed significant or trend-level interactions of genotype and time during each session (p = .004, .09 and .003, respectively) with TT homozygotes endorsing greater paranoia over time than either CT or CC individuals. Interactions were significant at all doses in African Americans (n = 19; p = .02, .04 and .05). No other demographic or experimental variable distinguished genotypic groups. CONCLUSIONS: Results indicate that individuals homozygous for the 'very low-activity' T allele at DbetaH -1021C-->T show an increased propensity to paranoia over time during cocaine self-administration.     

Genotype-controlled analysis of plasma dopamine beta-hydroxylase activity in psychotic unipolar major depression.

BACKGROUND: Plasma activity of dopamine beta-hydroxylase (DbetaH), the enzyme that converts dopamine to norepinephrine, is reportedly lower in patients with unipolar major depression with psychotic features (UDPF) than in those with nonpsychotic unipolar major depression (UD). Plasma DbetaH is under genetic control by the structural locus encoding DbetaH protein, DBH. This study tested the hypothesis that diagnosis-specific allelic variation at DBH accounts for lower plasma DbetaH in UDPF. METHODS: Plasma DbetaH activity was measured in samples from patients with UDPF (n = 33) and UD (n = 45). Genotypes were determined at several functional DBH polymorphisms, including C-1021T, a single nucleotide polymorphism (SNP) in the proximal 5' region that associates with variation in plasma DbetaH activity. RESULTS: Mean plasma DbetaH activity was significantly lower in UDPF than in UD. Genotyping at DBH did not reveal genetic associations distinguishing UDPF from UD. A two-way analysis of variance showed significant effects of genotype and diagnostic group but no significant interaction. CONCLUSIONS: Although the effects of the diagnosis of UDPF, and of DBH allele status, on plasma DbetaH activity were replicated, the lower plasma DbetaH in patients with UDPF was not accounted for by DBH genotype. Several explanations for this result are possible. First, other variants at DBH, or at other loci, could account for the findings. Second, nongenetic factors could account for the differences in plasma DbetaH. In this regard, we hypothesize that abnormal regulation of hypothalamic-pituitary-adrenal function in UDPF lowers expression of DbetaH protein, which could in turn alter the ratio of dopamine and norepinephrine in noradrenergic neurons, thereby promoting development of psychotic symptoms.     

A single nucleotide polymorphism at DBH, possibly associated with attention-deficit/hyperactivity disorder, associates with lower plasma dopamine beta-hydroxylase activity and is in linkage disequilibrium with two putative functional single nucleotide polymorphisms.

BACKGROUND: The DBH gene regulates plasma dopamine beta-hydroxylase activity (pDbetaH). Two single nucleotide polymorphisms (SNPs), -1021C-->T (rs1611115; SNP1) and +1603C-->T (rs6271; SNP3), independently influence pDbetaH. Another SNP, commonly known as DBH Taq1A (rs2519152; SNP2) is associated with attention-deficit/hyperactivity disorder (ADHD) in some (but not all) studies. We tested whether 1) SNP2 associates with pDbetaH; and 2) whether linkage disequilibrium (LD) between SNP2 and the other SNPs explains that association. METHODS: Plasma dopamine beta-hydroxylase activity and genotypes at the SNPs were determined in Caucasian subjects (n = 418). Associations to pDbetaH were examined using analyses of variance (ANOVAs) and LD among the SNPs using estimation maximization. RESULTS: 1) Each polymorphism analyzed alone associated with pDbetaH; 2) SNP2 was in strong LD with SNP1 and SNP3, respectively, but there was no significant LD between SNP1 and SNP3; and 3) analyzed jointly, each SNP contributed significantly and uniquely to plasma DbetaH activity. CONCLUSIONS: 1) SNP2 associates with pDbetaH; 2) SNP2 shows LD with SNP1 and SNP3; 3) most of the association between SNP2 and pDbetaH simply reflects that LD; however, 4) SNP2 also appears to exert a small independent effect on pDbetaH, suggesting that SNP2, or another variant in LD with it, uniquely influences pDbetaH.     

A genotype-controlled analysis of plasma dopamine beta-hydroxylase in healthy and alcoholic subjects: evidence for alcohol-related differences in noradrenergic function.

BACKGROUND: Norepinephrine and dopamine mediate important aspects of alcoholism and alcohol withdrawal. Dopamine-beta-hydroxylase (DbetaH) converts dopamine to norepinephrine. A recent study demonstrated a strong association between variance in plasma DbetaH activity and a novel polymorphism (DBH-1021C-->T) at the structural locus (DBH) encoding DbetaH protein. METHODS: Our study investigated whether the DBH-1021C-->T polymorphism and plasma DbetaH activity were associated with alcoholism or with delirium tremens (DT) during alcohol withdrawal by analyzing 207 German alcoholic and 102 healthy control subjects. We also examined the influence of the polymorphism on enzyme activity. RESULTS: Mean (+SD) plasma DbetaH activity measured in alcoholic subjects abstinent was significantly lower than that observed in control (27.7 + 16.7 vs. 35.6 + 18.8; p =.01). It did not differ between subjects with DT during withdrawal and subjects with mild withdrawal symptoms. The T allele of the DBH-1021C-->T polymorphism was significantly associated with lower plasma DbetaH activity. None of the alleles or genotypes were associated with alcoholism or DT. CONCLUSIONS: The data indicate that the alcoholism-related reduction in plasma DbetaH activity is independent of genotype at DBH-1021C-->T and replicate the finding that DBH-1021C-->T is strongly associated with plasma DbetaH activity in a native Western European population.     

Haplotype-based localization of an alcohol dependence gene to the 5q34 {gamma}-aminobutyric acid type A gene cluster

CONTEXT: Pharmacobehavioral and pharmacogenetic evidence links gamma-aminobutyric acid type A (GABA(A)) receptors and chromosomal regions containing GABA(A) receptor genes to ethanol-related responses. The GABA(A) gene cluster on chromosome 5q34 is of particular interest in the genetics of alcohol dependence because of the gamma2 subunit requirement for ethanol's modulatory action on GABA(A) receptors, previous linkage findings in mice and humans implicating both GABRA6 and GABRG2, and reported associations of GABRA6, GABRB2, and GABRG2 alleles with alcohol dependence. OBJECTIVE: To determine whether variation at the 5q34 GABA(A) gene cluster is implicated in differential susceptibility to alcohol dependence. METHODS: Two large psychiatrically interviewed samples, a Southwestern Native American population sample (N = 433) and a Finnish sample (N = 511) with alcohol-dependent subjects and unaffected individuals, were genotyped for 6 single nucleotide polymorphisms at the 5q34 GABA(A) gene cluster. In addition to sib-pair linkage and case-control association analyses, linkage disequilibrium mapping with haplotypes was used. RESULTS: Sib-pair linkage of GABRG2 to alcohol dependence was observed in Finns (P = .008). Association of the GABRB2 1412T allele with alcohol dependence was detected in both populations (Finns, P = .01; Southwestern Native Americans, P = .008), and the GABRA6 1519T allele was associated in both Finns (P = .01) and Southwestern Native Americans (P = .03). Linkage disequilibrium mapping with 3-locus haplotypes yielded evidence for an alcohol-dependence locus at the GABA(A) gene cluster region in both populations. The most highly significant signals were at 3-locus haplotypes that included 1 or more GABRA6 polymorphisms, with the peak signal at a GABRA6 3-locus haplotype (Finns, empirical P = .004; Southwestern Native Americans, empirical P = .02). CONCLUSIONS: We detected sib-pair linkage of 5q34 GABA(A) receptor genes to alcohol dependence in Finns and found association both in Finns and in Southwestern Native Americans. In both populations, the haplotype localization implicates the region containing the Pro385Ser GABRA6 polymorphism and 2 other polymorphisms at GABRA6.     

VKORC1 haplotypes and their impact on the inter-individual and inter-ethnical variability of oral anticoagulation

In order to elucidate the role of VCORC1 sequence variants in warfarin sensitivity, we established a complete SNP map of the VKORC1 gene locus in 200 blood donors from Western Germany. Nearly all of the genetic variability of the VKORC1 gene in Europeans is reflected by three main haplotypes. Recently described polymorphisms associated with low warfarin dose requirement (dbSNP:rs9934438; dbSNP:rs17878363) were found in complete linkage disequilibrium with the VKORC1*2 haplotype. In two patient cohorts of European origin with either increased coumarin sensitivity (n= 14) or partial coumarin resistance (n=36) the VKORC1*2 frequency varied highly significant between the two groups and also when compared to 200 blood donor controls (coumarin sensitive 96%, coumarin resistant 7%, controls 42%) thus demonstrating a strong association between these two phenotypes and the VKORC1 haplotype (p = 1.6 x 10(-8) for coumarin sensitive and p = 1.9 x 10(-8) for coumarin resistant). Analysis of database derived VKORC1 genotypes of African Americans and Chinese revealed that haplotype frequencies in these populations differ significantly from the European sample (for VKORC1*2: Europeans 42%, Chinese 95%, African Americans 14%). These observations suggest VKORC1 as principal genetic modulator of the ethnic differences in warfarin response. Since hereditary pharmacodynamic (VKORC1) and pharmacokinetic (CYP2C9) factors account for up to 50% of the inter-individual variability of the warfarin response, these genetic markers may serve as clinically relevant predictors of warfarin dosing in future studies.     

Association of galanin haplotypes with alcoholism and anxiety in two ethnically distinct populations

The neuropeptide galanin (GAL) is widely expressed in the central nervous system. Animal studies have implicated GAL in alcohol abuse and anxiety: chronic ethanol intake increases hypothalamic GAL mRNA; high levels of stress increase GAL release in the central amygdala. The coding sequence of the galanin gene, GAL, is highly conserved and a functional polymorphism has not yet been found. The aim of our study was, for the first time, to identify GAL haplotypes and investigate associations with alcoholism and anxiety. Seven single-nucleotide polymorphisms (SNPs) spanning GAL were genotyped in 65 controls from five populations: US and Finnish Caucasians, African Americans, Plains and Southwestern Indians. A single haplotype block with little evidence of historical recombination was observed for each population. Four tag SNPs were then genotyped in DSM-III-R lifetime alcoholics and nonalcoholics from two population isolates: 514 Finnish Caucasian men and 331 Plains Indian men and women. Tridimensional Personality Questionnaire harm avoidance (HA) scores, a dimensional measure of anxiety, were obtained. There was a haplotype association with alcoholism in both the Finnish (P=0.001) and Plains Indian (P=0.004) men. The SNPs were also significantly associated. Alcoholics were divided into high and low HA groups (>or= and 相似文献   

A functional dopamine-β-hydroxylase gene promoter polymorphism is associated with impulsive personality styles,but not with affective disorders

Dopamine-beta-hydroxylase (DbetaH) catalyzes the conversion of dopamine to norepinephrine in central noradrenergic and adrenergic neurons and thus is critically involved in the biosynthesis of catecholamines. There are equivocal findings concerning the question whether or not DssH activity levels are altered in affective disorders or in subtypes of affective disorders. Moreover, information about the role of dopamine beta-hydroxylase (DBH) genotype, which explains a large part of the variance of enzymatic activity, in affective disorders and personality dimensions is limited. To resolve these inconsistencies, association tests were performed using four independent samples, healthy volunteers (N = 387), patients with affective disorders (N = 182), adult attention deficit hyperactivity disorder (ADHD) patients (N = 407), and patients with personality disorders (N = 637). In the latter two samples, the revised NEO personality inventory (NEO-PI-R) was administered. All participants were genotyped for a putatively functional single nucleotide polymorphism (C-1021T, rs1611115). No differences in DBH C-1021T genotype distribution were observed between patients with affective disorders and healthy control subjects. Also when the patient sample was divided into uni- and bipolar patients versus controls, no significant differences emerged. Furthermore, no clear-cut association was detected between the TT genotype and personality disorder clusters while there was a significant association with adult ADHD. However, personality disorder patients carrying the DBH TT genotype exhibited higher neuroticism and novelty seeking scores as compared to individuals with the CC or CT genotype. Analyses on the level of the neuroticism and novelty seeking subscales revealed that the DBH TT genotype was primarily associated with personality features related to impulsiveness and aggressive hostility. Also adult ADHD patients carrying the homozygous TT genotypes displayed by significantly increased neuroticism scores; when both personality disorder and adult ADHD patient were analyzed together, TT carriers also displayed by significantly lower conscientiousness levels. Our results thus do not implicate the DBH C-1021T polymorphism in the pathophysiology of depressive disorders or personality disorders, yet homozygosity at this locus appears to increase the risk towards personality traits related to impulsiveness, aggression and related disease states, namely adult ADHD. These data argue for a dimensional rather than categorical effect of genetic variance in DBH activity; accordingly, the inconsistency of previous findings concerning DbetaH levels in affective disorders might be caused by the underlying association of the TT genotype at DBH-1021 with impulsive personality traits.     

Brain-derived neurotrophic factor variants are associated with childhood-onset mood disorder: confirmation in a Hungarian sample

Brain-derived neurotrophic factor (BDNF) is a nerve growth factor that has been implicated in the neurobiology of depression. Our group has previously reported an association between a BDNF variant and childhood-onset mood disorder (COMD) in an adult sample from Pittsburgh. We hypothesize that variants at the BDNF locus are associated with COMD. Six BDNF polymorphisms were genotyped in 258 trios having juvenile probands with childhood-onset DSM-IV major depressive or dysthymic disorder. BDNF markers included the (GT)n microsatellite, Val66Met and four other single-nucleotide polymorphisms (SNPs) distributed across the BDNF gene. Family-based association and evolutionary haplotype analysis methods were used. Analysis of linkage disequilibrium (LD) revealed substantial LD among all six polymorphisms. Analyses of the Val66Met polymorphism demonstrated significant overtransmission of the val allele (chi2=7.12, d.f.=1, P=0.0076). Consistent with the pattern of LD, all other SNPs showed significant biased transmission. The (GT)n microsatellite alleles also indicated a trend towards biased transmission (170 bp: Z=2.095, P=0.036). Significant haplotypes involved Val66Met and BDNF2 (P=0.0029). In this Hungarian sample, we found all five BDNF SNPs tested and a haplotype containing the BDNF Val66Met Val allele to be associated with COMD. These results provide evidence that BDNF variants affect liability to juvenile-onset mood disorders, supported by data from two independent samples.     

Association of Neuregulin 1 with schizophrenia and bipolar disorder in a second cohort from the Scottish population

Neuregulin 1 (NRG1) is a strong candidate for involvement in the aetiology of schizophrenia. A haplotype, initially identified as showing association in the Icelandic and Scottish populations, has shown a consistent effect size in multiple European populations. Additionally, NRG1 has been implicated in susceptibility to bipolar disorder. In this first study to select markers systematically on the basis of linkage disequilibrium across the entire NRG1 gene, we used haplotype-tagging single-nucleotide polymorphisms to identify single markers and haplotypes associated with schizophrenia and bipolar disorder in an independently ascertained Scottish population. Haplotypes in two regions met an experiment-wide significance threshold of P=0.0016 (Nyholt's SpD) and were permuted to correct for multiple testing. Region A overlaps with the Icelandic haplotype and shows nominal association with schizophrenia (P=0.00032), bipolar disorder (P=0.0011), and the combined case group (P=0.0017). This region includes the 5' exon of the NRG1 GGF2 isoform and overlaps the expressed sequence tag (EST) cluster Hs.97362. However, no haplotype in Region A remains significant after permutation analysis (P>0.05). Region B contains a haplotype associated with both schizophrenia (P=0.00014), and the combined case group (P=0.000062), although it does not meet Nyholt's threshold in bipolar disorder alone (P=0.0022). This haplotype remained significant after permutation analysis in both the schizophrenia and combined case groups (P=0.024 and P=0.016, respectively). It spans a approximately 136 kb region that includes the coding sequence of the sensory and motor neuron derived factor (SMDF) isoform and 3' exons of all other known NRG1 isoforms. Our study identifies a new of NRG1 region involved in schizophrenia and bipolar disorder in the Scottish population.     

A functional polymorphism regulating dopamine beta-hydroxylase influences against Parkinson's disease

A functional --1021C --> T polymorphism in the dopamine beta-hydroxylase gene has been demonstrated to regulate plasma DBH activity. We report that individuals with genetically determined low serum DBH activity (genotype T/T) have protection against Parkinson's disease (p = 0.01). In particular, we observed an underrepresentation of the T/T genotype odds ratio = 0.46 (CI = 0.27-0.8). Rather than identifying a haplotype, or a marker in linkage disequilibrium with the risk variant, this to our knowledge is the first report directly linking PD susceptibility with a proven functional variant.     

Serotonin transporter gene and autism: a haplotype analysis in an Irish autistic population

The role of the serotonin transporter (5-HTT) in the development of neuropsychiatric disorders has been widely investigated. Two polymorphisms, an insertion/deletion in the promoter region and a 12 repeat allele in a variable nucleotide tandem repeat (VNTR) in intron 2, drive higher expression of the 5-HTT gene. Four studies have shown nominally significant excess transmission of alleles of the 5-HTT gene in autism, while three studies have reported no excess transmission. This present study investigates the role of 5-HTT in the genetically homogenous Irish population. In all, 84 families were genotyped for five polymorphisms (three SNPs, a VNTR and an in/del). The analysis of allele transmissions using the transmission disequilibrium test (TDT) was undertaken and indicated preferential transmission of the short promoter allele (TDT P-value=0.0334). Linkage disequilibrium between markers was calculated and haplotypes were assessed for excess transmission and odds ratios (ORs) to affected children. A number of haplotypes, especially those involving and surrounding SNP10, showed evidence of association. The ORs ranged from 1.2 to 2.4. The most significant haplotype associated with transmission to affected probands was the SNP10-VNTR-SNP18 haplotype (chi(2)=7.3023, P=0.0069, odds ratio=1.8). This haplotype included the 12 repeat allele of the VNTR, which is associated with increased expression and may play a subtle role in the early development of the brain in affected probands.     

Haplotype analysis reveals tryptophan hydroxylase (TPH) 1 gene variants associated with major depression.

BACKGROUND: Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the biosynthesis of serotonin (5-HT) and might be related to the pathogenesis of major depression (MD). Two isoforms are known, TPH-1 and TPH-2. Tryptophan hydroxylase-1 association with MD is still debated. METHODS: A single nucleotide polymorphism (SNP) screening strategy was used to define TPH-1 haplotypes spanning over 23 kilobase (kb) of the 29 kb gene length. Genotyping was performed in 228 MD patients and 253 healthy control subjects. RESULTS: Six SNPs were found at linkage disequilibrium in both patients and control subjects, suggesting a haplotype block structure. Single marker association analyses showed only one SNP significantly associated with MD. Several haplotypes were associated with MD. When all six locus haplotypes were divided into two groups, above or below a 5% threshold, the compound haplotype group below a 5% frequency resulted as associated with the disease (31.6% vs. 18.0% in control subjects, p < 10(-5)). A "sliding window" analysis attributed the strongest disease association to a haplotype configuration localized between introns 7 and 8 (p < 10(-5)). CONCLUSIONS: Haplotype analysis indicates that TPH-1 associates with MD. The most common TPH-1 variants appear to carry no risk, while some of the less frequent variants might contribute to genetic predisposition to MD.     

Novel, replicated associations between dopamine D3 receptor gene polymorphisms and schizophrenia in two independent samples.

BACKGROUND: Meta-analyses have suggested an association between schizophrenia (SZ) and a coding polymorphism (rs6280/Ser9Gly) at the dopamine D3 receptor gene (DRD3), but results have been inconsistent. Because most studies have evaluated only rs6280, the inconsistencies might reflect associations with other variants. METHODS: We analyzed polymorphisms spanning 109kb in two independent samples (United States: 13 single nucleotide polymorphisms (SNPs), 331 cases, 151 trios, 274 control subjects; India: 11 SNPs, 141 trios). RESULTS: In the U.S. samples, significant associations were detected with eight SNPs, including rs6280 (p = .001, odds ratio: 1.5). Consistent associations in the case-control and family-based analyses were detected with a common haplotype spanning intron 1 to the 3' region of the gene (rs324029-rs7625282-rs324030-rs2134655-rs10934254; case-control, p = .002; transmission disequilibrium test [TDT], p = .0009; global p-values = .002 and .007, respectively). In the Indian sample, one SNP was associated (rs10934254, p = .03). Moreover, over-transmission of the same common haplotype as the U.S. sample was observed in this cohort (TDT, p = .005; global test, p = .009). Ser9Gly (rs6280) was associated with SZ against this haplotype background but not other haplotypes. CONCLUSIONS: These data suggest previous inconsistencies might have resulted from associations with other DRD3 variants. A liability locus might be in linkage disequilibrium (LD) with or carried against, an associated haplotype 3' to rs6280. Comprehensive SNP evaluation in larger samples is needed.     

Dopamine-β-hydroxylase in cerebrospinal fluid and plasma: Effects of α-adrenergic agents

Dopamine-β-hydroxylase (DBH) and norepinephrine are both localized in noradrenergic storage vesicles. When noradrenergic nerves fire, both norepinephrine and DBH are released by exocytosis. DBH released from the peripheral nervous system and the adrenal medullae is found in blood, while DBH in cerebrospinal fluid (CSF) is presumably of central origin. This study was designed to: (1) investigate the effect of drugs which alter central noradrenergic activity on DBH activity in CSF; and (2) compare the effects of these drugs on DBH in CSF and plasma in cats. Phenoxybenzamine was given subcutaneously at 6 mg/kg and DBH was measured 8 h later. This treatment significantly increased DBH activity in CSF (n= 10, P < 0.005). There were no consistent changes in plasma DBH, although there was a tendency for DBH to increase from low basal levels and to decrease from high basal levels. Clonidine was administered in 4 subcutaneous injections (100, 50, 50, 50 μg/kg) over a 19-h period, and blood and CSG were taken 5 h after the last injection. This treatment caused a significant decrease in CSF DBH activity (P < 0.05, n= 8). The effect of clonidine on plasma DBH was strongly dependent on the basal enzyme level. The 3 lowest DBH values increased and the 5 highest DBH values decreased on drug treatment. These results are discussed with respect to the theory that changes in CSF DBH may reflect central noradrenergic activity.     

The H2 MAPT haplotype is associated with familial frontotemporal dementia

There is now considerable evidence that the gene encoding for tau protein (MAPT) is implicated in frontotemporal dementia (FTD). The role of MAPT haplotypes in neurodegenerative diseases has been suggested, but their contribution in familial dementia has not been extensively investigated. Here, we investigated (1) the association between the MAPT haplotypes and sporadic (sFTD) or familial FTD (FFTD) (controls n = 99, sFTD n = 53, FFTD n = 50), (2) the interactive effect between MAPT haplotypes and APOE gene. We found an overrepresentation of H2 haplotype (OR = 1.83, P = 0.029) and of H2H2 genotype in FFTD patients (OR = 6.09, P = 0.007). This association was even stronger in APOE e4 negatives FFTD (H2: OR = 2.9, P = 0.001; H2H2: OR = 12.67, P = 0.001). Our results support idea that the MAPT H2 haplotype is a risk factor for FFTD. This locus could contain this or other inheritable genetic determinants contributing to increase risk of developing dementia.     

Haplotype-based linkage of tryptophan hydroxylase 2 to suicide attempt, major depression, and cerebrospinal fluid 5-hydroxyindoleacetic acid in 4 populations

CONTEXT: 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. DESIGN: 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. CONCLUSION: 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.     

HLA class II associated risk and protection against multiple sclerosis-a Finnish family study.

We analyzed the HLA class II haplotypes in 249 Finnish nuclear families and compared the frequencies of parental haplotypes transmitted or non-transmitted to multiple sclerosis (MS) patients. The most important predisposing haplotype was DRB1*15-DQB1*0602 (P<10(-6)) as expected and a weak predisposing effect of DRB1*04-DQB1*0302 was revealed after the elimination of DRB1*15-DQB1*0602. HLA-DRB1*01-DQB1*0501 and DRB1*13-DQB1*0603 were negatively associated with MS in transmission disequilibrium test, but only the DRB1*13-DQB1*0603 association remained significant (P=0.008) after the elimination of DRB1*15-DQB1*0602 haplotypes. Based on this study HLA class II haplotypes exhibit both predisposing and protective effects in MS.     

Association study of CSF2RB with schizophrenia in Irish family and case - control samples

Colony stimulating factor 2 receptor, beta (CSF2RB) is the shared subunit of receptors for interleukin 3 (IL3), colony stimulating factor 2 (CSF2) and IL5, and is responsible for the initiation of signal transduction triggered by ligand binding. In our previous study, we showed the evidence that the IL3 gene is associated with schizophrenia and the associations observed are sex-specific and dependent on family history (FH). In this article, we studied 10 single-nucleotide polymorphisms in the CSF2RB gene in the Irish Study of High-Density Schizophrenia Families (ISHDSF) and the Irish Case - Control Study of Schizophrenia (ICCSS), and tested allele and haplotype associations with schizophrenia. Using the pedigree disequilibrium test, we found that two markers (rs11705394 and rs7285064) reached nominal significance. In sex-stratified analyses, for both the markers the association signals were mainly derived from male subjects. In the ICCSS sample, we found that several markers (rs2072707, rs2284031 and rs909486) showed sex-specific and FH-dependent associations with schizophrenia. In multimarker haplotype analyses, both ISHDSF and ICCSS samples showed globally significant associations in multiple linkage disequilibrium (LD) blocks sharing minimal LD. Since CSF2RB is essential for IL3 signaling, the findings that both IL3 and CSF2RB showed sex-specific and FH-dependent associations suggest that the IL3 pathway is involved in schizophrenia.     

Further localization of a multiple sclerosis susceptibility gene on chromosome 7q using a new T cell receptor beta-chain DNA polymorphism

Multiple sclerosis (MS) has been associated with particular HLA haplotypes and has recently been reported to also be associated with the T cell receptor (TCR) beta-chain complex. We have tried to determine the source of the TCR-beta/MS association by exploiting the pattern of linkage disequilibrium within the TCR-beta complex. We describe a new DNA polymorphism with the TCR variable region gene segment V beta 15 which appears to localize between the constant region and V beta 11. When the distribution of V beta 11-V beta 15 haplotypes in MS patients was compared to healthy controls, the strength of the V beta 11-V beta 15 MS association (p = 0.107) was much less than the MS association with the adjacent V beta 8-V beta 11 haplotype (p = 0.0010). On the basis we exclude an MS susceptibility gene telomeric to V beta 11. The reported MS association with the TCR-beta gene complex therefore does not appear to be due to genes within the diversity, joining, or constant region but more likely involves a specific gene(s) within the variable region.