A weak association between TH and DRD2 genes and bipolar affective disorder in a Spanish sample.

Genetic factors play an important role in the aetiology of bipolar affective disorder (BP). So far, results of linkage studies have been largely disappointing. We have searched for a possible association between polymorphic DNA markers of two candidate genes (tyrosine hydroxylase, TH; dopamine D2 receptor gene, DRD2) and BP in a population from central Spain. Our results are consistent with the existence of a weak association between these two genes and BP, in such a way that TH and DRD2 could be considered as minor genes contributing to susceptibility.     

DNA linkage analysis in Von Recklinghausen neurofibromatosis.

We have used DNA linkage analysis in 11 families with Von Recklinghausen neurofibromatosis (VRNF) in order to search for the chromosomal localisation of the defective gene causing this serious neurological disorder. Three groups of polymorphic DNA markers were used: (1) markers for chromosome 22, because of possible allelic genetic heterogeneity between VRNF and bilateral acoustic neurofibromatosis; (2) markers near the centromere of chromosome 4, since there was preliminary evidence for linkage between the VRNF gene and Gc; and (3) oncogenes and growth factors as possible candidate genes for VRNF. Our data exclude close linkage between any of these markers and the gene for VRNF.     

Alleles at the dopamine D4 receptor locus do not contribute to the genetic susceptibility to schizophrenia in a large Swedish kindred

The discovery of a functional polymrphism within the dopamine D₄ receptor gene (DRD4) has not only strengthened the hypotheses implicating DRD4 in the etiology of neuropyschiatic disorders, but also provided a genetic marker for testing these hypotheses. The possibility of the dopamine D₄ receptor as a candidate gene for schizophrenia was investigated in a large Swedish kindred segregating for schizophrenia. Linkage to schizophrenia was tested by linkage analyses of 6 polymorphic markers (at 4 loci) in chromosome 11p15.5 including the dopamine D₄ receptor (DRD4) and the tyrosine hydroxylase (TH) loci. Schizophrenia was excluded from close linkage to the DRD4 locus using two of the polymorphisms located within the dopamine D₄ receptor gene. The first DRD4 polymorphism consists of variation in the number of a 48 bp imperfect direct repeat in the third exon; the second consists of a variable number of repeated G nucleotides in the first intron. In addition, some of the individuals homozygous for four or seven copies of 48 bp repeat alleles were tested for previously reported sequence variation among repeats. No single haplotype of the DRD4 alleles or haplotype of other markers in chromosome 11p15.5 was found to be common to the schizophrenic individuals in this family. Therefore, we find no evidence for linkage of the D₄ receptor, or this region of 11p15.5, with genetic susceptibility to schizophrenia in this kindred. © 1993 Wiley-Liss, Inc.     

Tests of linkage and allelic association between markers in the 1p36 PRKCZ (protein kinase C zeta) gene region and bipolar affective disorder

Three linkage studies of families with multiple cases of bipolar disorder and/or unipolar affective disorder have confirmed the involvement of the chromosome 1p36 region in the etiology of affective disorders with LOD scores of 2.7, 3.6, and 3.97. We investigated the protein kinase C zeta gene (PRKCZ) as a susceptibility locus for bipolar disorder because it is highly brain expressed and is localized close to the marker D1S243 which was linked to affective disorder in a single large UCL bipolar disorder family with a LOD of 3.1. PRKCZ encodes an unusual type of protein kinase which affects axonal differentiation through Wnt-signaling. We genotyped four microsatellite markers and nine single nucleotide polymorphism (SNP) markers within or near the PRKCZ gene in the UCL case-control sample of 600 bipolar disorder patients and up to 605 supernormal controls. Markers D1S243 and rs3128396 were significantly associated with bipolar disorder (empirical P = 0.037 and P = 0.040, respectively). We also included data from eight SNPs which were genotyped as part of our GWA study on bipolar disorder for association analysis. Tests of haplotypic association found that a haplotype block comprising markers rs3128296, rs2503706, and rs3128309 was associated with bipolar disorder (empirical P = 0.004). A previous linkage study had shown greater evidence for linkage within female cases compared to males. Therefore, to assess if the association was sex-specific, we performed a female-only allelic-association analysis, which resulted in SNPs rs3128296 and rs3128309 becoming associated with bipolar disorder (P = 0.004 and P = 0.016, respectively). PRKCZ may play a role in susceptibility to bipolar affective disorder.     

Chromosome 4 Workshop Summary: Sixth World Congress on Psychiatric Genetics, Bonn, Germany, October 6-10, 1998.

This report summarizes the findings presented at the Chromosome 4 Workshop of the Sixth World Congress on Psychiatric Genetics (October 1998, Bonn, Germany). Chromosome 4 linkage and association results for several psychiatric phenotypes including bipolar affective disorder, schizophrenia, alcoholism, and mental retardation are reviewed. In bipolar affective disorder, positive linkage results for markers on 4q35 were reported by three independent groups. In addition, findings in bipolar disorder were reported for markers spanning 4p14-16, and of particular interest are the results that coincide with the original Blackwood et al. [1996: Nat Genet 12:427-430] region at 4p16. For schizophrenia, modest positive results were reported for 4q31, as well as for marker D4S2917 at a region of 4q close to the centromere. Chromosome 4 continues to demonstrate interesting results in alcoholism, particularly in the region of the alcohol dehydrogenase gene cluster; however, it is not clear how to interpret the contrast in the susceptibility versus protective loci that are being reported in this region.     

Tyrosine hydroxylase polymorphism and phenotypic heterogeneity in bipolar affective disorder: a multicenter association study.

Tyrosine hydroxylase (TH), the rate-limiting enzyme in the metabolism of catecholamines, is considered a candidate gene in bipolar affective disorder (BPAD) and has been the subject of numerous linkage and association studies. Taken together, most results do not support a major gene effect for the TH gene in BPAD. Genetic and phenotypic heterogeneity may partially explain the difficulty of confirming the exact role of this gene using both association and linkage methods. Four hundred one BPAD patients and 401 unrelated matched controls were recruited within a European collaborative project (BIOMED1 project in the area of brain research, European Community grant number CT 92-1217, project leader: J. Mendlewicz) involving 14 centers for a case-control association study with a tetranucleotide polymorphism in the TH gene. Patients and controls were carefully matched for geographical origin. Phenotypic heterogeneity was considered and subgroup analyses were performed with relevant variables: age at onset, family history, and diagnostic stability. No association was observed in the total sample or for subgroups according to age at onset (n = 172), family history alone (n = 159), or high degree of diagnostic stability and a positive family history (n = 131). The results of this association study do not confirm the possible implication of TH polymorphism in the susceptibility to BPAD.     

Examination of genetic linkage of chromosome 15 to schizophrenia in a large Veterans Affairs Cooperative Study sample*

Previous studies have reported genetic linkage evidence for a schizophrenia gene on chromosome 15q. Here, chromosome 15 was examined by genetic linkage analysis using 166 schizophrenia families, each with two or more affected subjects. The families, assembled from multiple centers by the Department of Veterans Affairs Cooperative Study Program, consisted of 392 sampled affected subjects and 216 affected sibling pairs. By DSM‐III‐R criteria, 360 subjects (91.8%) had a diagnosis of schizophrenia and 32 (8.2%) were classified as schizo‐affective disorder, depressed. Participating families had diverse ethnic backgrounds. The largest single group were northern European American families (n = 62, 37%), but a substantial proportion was African American kindreds (n = 60, 36%). The chromosome 15 markers tested were spaced at intervals of approximately 10 cM over the entire chromosome and 2–5 cM for the region surrounding the α‐7 nicotinic cholinergic receptor subunit gene (CHRNA7). These markers were genotyped and the data analyzed using semiparametric affecteds‐only linkage analysis. In the European American families, there was a maximum Z‐score of 1.65 between markers D15S165 and D15S1010. These markers are within 1 cM from CHRNA‐7, the site previously implicated in schizophrenia. However, there was no evidence for linkage to this region in the African America kindreds. © 2001 Wiley‐Liss, Inc.     

Association study of bipolar disorder with candidate genes involved in catecholamine neurotransmission: DRD2, DRD3, DAT1, and TH genes

Despite strong evidence for genetic involvement in the etiology of affective disorders (from twin adoption and family studies), linkage and association methodologies are still exploring the nature of genetic factors in these diseases. Interesting testable hypotheses have been described, including candidate genes involved in catecholamine neurotransmission. We studied 69 bipolar patients and 69 matched controls (for age, sex, and geographical origin) for association and linkage disequilibrium with DNA markers at the following genes: the tyrosine hydroxylase gene, dopamine transporter gene, and dopamine D2 and D3 receptor genes. Association and linkage disequilibrium were excluded between bipolar affective disorder and these four candidate genes in our sample. © 1996 Wiley-Liss, Inc.     

Lack of association between bipolar affective disorder and tyrosine hydroxylase DNA marker

Sixty-eight patients with bipolar affective disorder and 88 controls were investigated for genetic association of tyrosine hydroxylase (TH) restriction fragment length polymorphisms (RFLPs). No significant association between bipolar affective disorder and TH was found. Thus the hypothesis that TH is involved in the pathogenesis of bipolar affective disorder was not supported. © 1993 Wiley-Liss, Inc.     

Linkage studies of bipolar disorder in the region of the Darier's disease gene on chromosome 12q23-24.1

We have recently described a family in which there is cosegregation of major affective disorder with Darier's disease and have mapped this autosomal dominant skin disorder to 12q23-q24.1. This has provided an interesting candidate region for genetic studies of bipolar disorder. We have studied the segregation of seven markers spanning the Darier's disease locus in 45 bipolar disorder pedigrees and found modest evidence in support of linkage under heterogeneity for 5 of these markers. Nonparametric analyses were suggestive of linkage with a marker at the gene encoding a secretory form of phospholipase A2. Our sample has relatively low power to detect linkage under heterogeneity and independent researchers should examine markers from this region in further samples of bipolar pedigrees. © 1995 Wiley-Liss, Inc.     

X-linkage in bipolar affective illness: Perspectives on genetic heterogeneity,pedigree analysis and the X-chromosome map

The search for genetic markers is a powerful strategy in psychiatric genetics. The present article examines four areas relevant to discrepancies among X-linkage studies in bipolar affective disorder. These are questions of ascertainment, analytic methods, the X-chromosome map and genetic heterogeneity. The following conclusions are reached: (a) Positive linkage findings cannot be attributed to ascertainment bias or association between affective illness and colorblindness. (b) The possibility that falsely positive linkage results were obtained by using inappropriate analytic methods is ruled out. (c) Reported linkages of bipolar illness to colorblind and G6PD loci are compatible with known map distances between X-chromosome loci. Linkage to the Xg antigen remains uncertain. (d) The discrepancy among the various data sets on affective illness and colorblindness is best explained by significant linkage heterogeneity among pedigrees informative for the two traits.     

Linkage study between manic-depressive illness and chromosome 21

Chromosome 21, of interest as potentially containing a disease gene for manic-depressive illness as possible evidence for a gene predisposing to affective disorder, has recently been reported in a single large family as well as samples of families. The present study investigates for linkage between manic-depressive illness and markers covering the long arm of chromosome 21 in two manic-depressive families, using ten microsatellite polymorphisms as markers. No conclusive evidence for a disease gene on the long arm of chromosome 21 was found. Assuming either a dominant or recessive mode of inheritance, close linkage to the marker PFKL, which has been reported as possibly linked to affective disorder, seems unlikely in the families studied here. PFKL and more telomeric markers yielded small positive lod scores at higher recombination fractions in the largest family, and small positive lod scores at lower recombination fractions in the affecteds-only analyses in the smallest family. © 1996 Wiley-Liss, Inc.     

Close linkage of bipolar disorder to chromosome 11 markers is excluded in two large Australian pedigrees.

The relationship between bipolar disorder and chromosome 11 markers remains uncertain. Whilst re-analysis of the Amish pedigree weakened previous evidence for close linkage (but could not exclude the possibility of genetic heterogeneity), a recent French study has found a significant association between this condition and tyrosine hydroxylase polymorphisms. We aimed to determine if bipolar disorder in two large Australian pedigrees (of Irish and English extraction respectively) was linked to these markers. Of the 84 family members available for testing, nine were diagnosed as bipolar I, one as bipolar II and six had recurrent unipolar depression. Linkage of bipolar disorder and recurrent depression to the chromosome 11p15 markers c-Harvey ras, insulin and tyrosine hydroxylase was tested using a series of genetic models with varying penetrance levels. Additionally, linkage was examined using a series of levels of definitions of affective status (ranging from bipolar I alone to all affective illnesses). Close linkage to these markers was strongly excluded using each model and definition. The findings also persisted when a wide range of rates of 'sporadic' (non-genetic) presentations of illness were incorporated in the analysis. These results are consistent with other recent studies indicating that bipolar disorder is not linked to chromosomal region 11p15.     

Analysis and metaanalysis of two polymorphisms within the tyrosine hydroxylase gene in bipolar and unipolar affective disorders

Tyrosine hydroxylase (TH) is the rate-limiting enzyme in the synthesis of dopamine and noradrenaline. While positive associations between TH and bipolar affective disorder have been found in several studies, many studies have failed to reproduce these results. In order to clarify this situation, association studies of bipolar and unipolar affective disorder groups and metaanalyses of published data on the TH tetranucleotide repeat polymorphism were done. The association studies used the TH tetranucleotide repeat polymorphism in intron 1 and a PstI polymorphism at the 3' end of the gene. The study comprised 124 unrelated bipolar patients, 126 unipolar patients, and 242 controls. There was no significant association of either bipolar or unipolar affective disorder with the TH tetranucleotide repeat polymorphism. However, a weak association (chi2 = 3.946, 1 df, P = 0.047; odds ratio, allele 2 vs. allele 1 = 0.71 (95% CI, 0.51-0.996)) was observed in the unipolar sample with the TH-PstI polymorphism. Three metaanalyses of published data on the TH tetranucleotide repeat polymorphism in major affective disorder were performed: bipolar I + II vs. control using 583 cases and 745 controls; unipolar vs. control using 204 cases and 359 controls; and bipolar + unipolar vs. control using 846 cases and 823 controls. In each analysis there was no association of the TH tetranucleotide repeat polymorphism and affective disorder. These results do not support the tyrosine hydroxylase gene having a major role in the etiology of bipolar affective disorder. However, our data suggest that this locus should be examined in larger samples of unipolar affective disorder.     

Adjacent genetic markers on chromosome 11p15.5 at or near the tyrosine hydroxylase locus that show population linkage disequilibrium with each other do not show allelic association with bipolar affective disorder

BACKGROUND: Linkage and association studies have suggested genetic susceptibility to bipolar affective disorder in a region of chromosome 11 around the tyrosine hydroxylase locus. We attempted to test the hypothesis that there was allelic association between polymorphisms around the tyrosine hydroxylase locus and bipolar affective disorder. METHODS: A case-control association study was employed using four polymorphic markers, which span a region of approximately 2 cM across the tyrosine hydroxylase locus. RESULTS: No evidence for allelic association between bipolar affective disorder and any of these markers was found. However, linkage disequilibrium between the markers was detected. CONCLUSIONS: This finding diminishes the probability that genes in this region influence susceptibility to bipolar affective disorder, at least in our sample.     

Association of polymorphisms in P2RX7 and CaMKKb with anxiety disorders

BACKGROUND: There is considerable evidence that genetic factors play an important role in the pathophysiology of affective disorders including bipolar disorder, major depressive disorder and anxiety disorders. Long-term follow up studies as well as drug treatment studies suggest that these clinical conditions share a number of pathophysiological commonalities including genetic variables. One possible candidate region is located on chromosome 12q24.31, originated from previous linkage and association studies with bipolar disorder and unipolar depression. This region contains two candidate genes for purinergic ligand-gated ion channels, P2RX7 and P2RX4, and one gene coding for calmodulin-dependent protein kinase kinase b (CaMKKb). METHODS: In the present study, we investigated the genetic associations between 15 SNPs in the candidate genes P2RX7, P2RX4 and CaMKKb on chromosome 12q24.31 in 179 patients with anxiety disorders and syndromal panic attacks versus 462 healthy controls. RESULTS: One nominal case-control association could be detected for a SNP in the 5'UTR region of P2RX4, which did not remain significant after correction for multiple testing. We found, however, a prominent association between severity of panic- and agoraphobia symptoms and an exonic SNP (rs3817190) in the CaMKKb gene and a trend for association with an exonic SNP in P2RX7 (rs1718119) with severity scores in the panic- and agoraphobia scale. CONCLUSION: The locus 12q24.31 seems to be an important genetic region for anxiety, bipolar and unipolar disorders, suggesting a genetic overlap in the group of affective disorders. The specific contribution of the herein reported gene polymorphisms to the clinical condition is still unclear and warrants further analysis.     

Evaluation of association of SNPs in the TNF alpha gene region with schizophrenia.

The association of the tumor necrosis factor alpha (TNFalpha) -G308A promoter polymorphism with schizophrenia has complemented clinical findings of increased levels of the TNFalpha cytokine in schizophrenic patients, with some support for a functional consequence of the variant. Our previous studies of genetic causes in schizophrenia supported findings of linkage to the major histocompatibility complex (MHC) region where the TNFalpha gene is located as well as association with the -G308A promoter polymorphism. While the common G-allele shows association in our sample, association with the A-allele has been reported by other groups. This suggests linkage disequilibrium (LD) rather than direct involvement in the disorder. In order to define LD of DNA variants with the disorder in this area, we analyzed 36 SNPs in a 165-kb region around this polymorphism. We detected nominally significant associations (P < 0.05) of three markers (including the -G308A promoter polymorphism) and multiple haplotypes with schizophrenia in our sample of 204 families (79 sib-pairs and 125 trios). The association is largely restricted to a 30 kb high LD region/block and should assist in the identification of a schizophrenia susceptibility gene within the block or elsewhere in the MHC.     

Association study between two variants in the DOPA decarboxylase gene in bipolar and unipolar affective disorder

Irregularities of dopaminergic and serotonergic neurotransmission have been implicated in a variety of neuropsychiatric disorders. DOPA decarboxylase (DDC), also known as aromatic L-amino acid decarboxylase, is an enzyme involved directly in the synthesis of dopamine and serotonin and indirectly in the synthesis of noradrenaline. Therefore, the DDC gene can be considered as a candidate gene for affective disorders. Recently, two novel variants were reported in the DDC gene: a 1-bp deletion in the promoter and a 4-bp deletion in the untranslated exon 1. Subsequently, an association case-control study including 112 English patients and 80 Danish patients with bipolar affective disorder (BPAD) revealed a significant association with the 1-bp deletion. This finding prompted us to analyze whether this effect was also present in a larger and ethnically homogeneous sample of 228 unrelated German patients with BPAD (208 patients with BP I disorder, 20 patients with BP II disorder), 183 unrelated patients with unipolar affective disorder (UPAD), and 234 healthy control subjects. For both BPAD and UPAD we could not detect a genetic association with either variant. Thus, our results do not support an involvement of the 1-bp or 4-bp deletion within the DDC gene in the etiology of affective disorders.