A linkage study of the N-methyl-D-aspartate receptor subunit gene loci and schizophrenia in southern African Bantu-speaking families

Bp, Riley; Tahir, Eda; Rajagopalan, S; Mogudi-Carter, M.; Fauré, Sabine; Weissenbach, Jean; Jenkins, T; Williamson, R

doi:10.1097/00041444-199722000-00002

Cited by 39 publications

(18 citation statements)

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“…Thus, the GIST result provides additional evidence joining together the linkage and association results supporting the involvement of GRIN2B in BPI. Further independent support is provided by a recent study reporting an association between GRIN2B variants and BP and schizophrenia, 23 a study by Riley et al 27 in southern African Bantuspeaking families that provided weak linkage evidence and a recent linkage study that applied a variance components method on the age at onset of mania 28 and pointed to marker D12S1292 at 28,992,092 Mb, at the border of our linkage region (Fig. 1).…”

Section: Discussionsupporting

confidence: 71%

Stage II follow-up on a linkage scan for bipolar disorder in the Ashkenazim provides suggestive evidence for chromosome 12p and the GRIN2B gene

Avramopoulos

Lasseter

Fallin

et al. 2007

Genetics in Medicine

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Purpose: We had previously performed a genome-wide linkage scan for bipolar affective disorder in an Ashkenazi Jewish sample, a population likely to have reduced genetic heterogeneity. This study is a second stage follow-up focusing on regions that showed positive linkage scores in our previous scan but were not fine-mapped at that time. Methods:We genotyped an additional 145 highly polymorphic microsatellites and conducted linkage analyses using standard laboratory and analytical methods. Results: We saw an improvement of the evidence for linkage in most regions, with the most notable change on chromosome 12p13.1-p12.3, where the evidence of linkage is now suggestive. This region harbors the gene encoding the ionotropic glutamate receptor subunit 2B (GRIN2B), a gene that previously yielded evidence for association in a candidate gene study on 323 Ashkenazi Jewish bipolar case-parent trios. We find that the evidence for linkage is significantly correlated with the presence of the putative high-risk allele identified in our candidate gene study. Bipolar disorder (BP) is a common, disabling psychiatric disease with a lifetime prevalence reaching 2% (American Psychiatric Association, 1994). Several types of BP are recognized in the Diagnostic and Statistical Manual, fourth edition that vary in the nature and duration of symptoms and the extent of disability. One well-established diagnostic classification focuses on the intensity of manic symptoms recognizing two categories, BPI and BPII, with BPII showing episodes of less severe mania described as hypomania. Evidence from family, twin, and adoption studies strongly supports a genetic component of BP, with heritability estimates of 60 -80% 1 and risk to first-degree relatives of 5-10%. 2 Although segregation analyses have been inconclusive, they suggest a complex and multigenic susceptibility to BP, involving both genes and environment. Many genome-wide linkage scans and three meta-analyses have been reported, 3-13 identifying multiple candidate genomic regions but with inconsistent replication across studies. One potential reason for this lack of consistency in linkage scan results could be the inconsistency in the definition of the affection status across studies, regarding both the diagnosis and the inclusion of BPI, BPII, and schizoaffective disorder, a condition in which patients present both psychotic and affective symptoms, and which some investigators consider a variant of schizophrenia and others a variant of BP. Another likely reason for the inconsistency in linkage results is the high likelihood of locus heterogeneity, especially if individual genes with small or moderate effects on risk are present or possibly genes that interact are involved. One strategy to reduce locus heterogeneity is to study families from a relatively genetically isolated population that originated from a small number of founders. 14, 15 We recently employed this approach in a genome-wide linkage scan of 41 Ashkenazi Jewish (AJ) families with BP. 16 More recently we followed the sa...

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Section: Discussionsupporting

confidence: 71%

Stage II follow-up on a linkage scan for bipolar disorder in the Ashkenazim provides suggestive evidence for chromosome 12p and the GRIN2B gene

Avramopoulos

Lasseter

Fallin

et al. 2007

Genetics in Medicine

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“…Increased allele sharing at this marker was also in pedigrees with bipolar subjects in a National Institute of Mental Health collaborative initiative for genetics of bipolar disorders (40). The region on 17q has been linked to many other diseases, including autoimmune diseases (41) and schizophrenia (42).…”

Section: Discussionmentioning

confidence: 91%

Linkage analysis of ordinal traits for pedigree data

Feng

Leckman

Zhang

2004

Proc. Natl. Acad. Sci. U.S.A.

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Linkage analysis is used routinely to map genes for human diseases and conditions. However, the existing linkage-analysis methods require that the diseases or conditions either be dichotomized or measured by a quantitative trait, such as blood pressure for hypertension. In the latter case, normality is generally assumed for the trait. However, many diseases and conditions, such as cancer and mental and behavioral conditions, are rated on ordinal scales. The objective of this study was to establish a framework to conduct linkage analysis for ordinal traits. We propose a latent-variable, proportional-odds logistic model that relates inheritance patterns to the distribution of the ordinal trait. We use the likelihood-ratio test for testing evidence of linkage. By means of simulation studies, we find that the power of our proposed model is substantially higher than that of the binary-trait-based linkage analysis and that our test statistic is robust with regard to certain parameter misspecifications. By using our proposed method, we performed a genome scan of the hoarding phenotype in a data set with 53 nuclear families, which were collected by the Tourette Syndrome Association International Consortium for Genetics (TSAICG). Standard linkage scans using hoarding as a dichotomous trait were also performed by using GENEHUNTER and ALLEGRO. Both GENEHUNTER and ALLEGRO failed to reveal any marker significantly linked to the binary hoarding phenotypes. However, our method identified three markers at 4q34-35 (P ‫؍‬ 0.0009), 5q35.2-35.3 (P ‫؍‬ 0.0001), and 17q25 (P ‫؍‬ 0.0005) that manifest significant allele sharing.

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“…25 Finally, schizophrenia could be heterogeneous, with different susceptibility loci influencing liability in different families. 26,27 As part of the worldwide search for specific susceptibility genes, two reports from the Irish study of high-density schizophrenia families (ISHDSF) 28 presented evidence in support of the linkage of region 6p24-21 to schizophrenia and schizophrenia-related disorders. 28 The greatest LOD was 3.51 for marker D6S296.…”

Section: Introductionmentioning

confidence: 99%

Identification of a high-risk haplotype for the dystrobrevin binding protein 1 (DTNBP1) gene in the Irish study of high-density schizophrenia families.

et al. 2003

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A recent report showed significant associations between several SNPs in a previously unknown EST cluster with schizophrenia. 1 The cluster was identified as the human dystrobrevin binding protein 1 gene (DTNBP1) by sequence database comparisons and homology with mouse DTNBP1. 2 However, the linkage disequilibrium (LD) among the SNPs in DTNBP1 as well as the pattern of significant SNP-schizophrenia association was complex. This raised several questions such as the number of susceptibility alleles that may be involved and the size of the region where the actual disease mutation(s) could be located. To address these questions, we performed different single-marker tests on the 12 previously studied and 2 new SNPs in DTNBP1 that were re-scored using an improved procedure, and performed a variety of haplotype analyses. The sample consisted of 268 Irish multiplex families selected for high density of schizophrenia. Results suggested a simple structure where the LD in the target region could be explained by 6 haplotypes that together accounted for 96% of haplotype diversity in the whole sample. From these six, a single high-risk haplotype was identified that showed a significant association with schizophrenia and explained the pattern of significant findings in the analyses with individual markers. This haplotype was 30 kb long, had a large effect, could be measured with two tag SNPs only, had a frequency of 6% in our sample, seemed to be of relatively recent origin in evolutionary terms, and was equally distributed over Ireland. Implications of these findings for follow-up and replication studies are discussed.

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A linkage study of the N-methyl-D-aspartate receptor subunit gene loci and schizophrenia in southern African Bantu-speaking families

Cited by 39 publications

References 0 publications

Stage II follow-up on a linkage scan for bipolar disorder in the Ashkenazim provides suggestive evidence for chromosome 12p and the GRIN2B gene

Stage II follow-up on a linkage scan for bipolar disorder in the Ashkenazim provides suggestive evidence for chromosome 12p and the GRIN2B gene

Linkage analysis of ordinal traits for pedigree data

Identification of a high-risk haplotype for the dystrobrevin binding protein 1 (DTNBP1) gene in the Irish study of high-density schizophrenia families.

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