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

Abstract

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...

Searching Susceptibility Loci for Bipolar Disorder: A Sib Pair Study on Chromosome 12

“…Our results, even if preliminary, are consistent with previous positive findings in the literature showing the role of chromosome 12 in susceptibility to bipolar disorders [23,25] .…”

“…It encodes for a subunit of the NMDA receptor, an ionotropic glutamate receptor. This receptor is a heteromeric pentamer composed of at least 1 NR1 subunit and 1 or more of the 4 different NR2 subunits: NR2A, NR2B (the product of GRIN2B), NR2C and NR2D [23] . There are already important evidences for an association between this gene and Huntington disease, epilepsy, dementia and also schizophrenia and bipolar disorder [3,[40][41][42] .…”

“…Since many familial genome scans evidenced and confirmed the potential role of some areas of chromosome 12 in determining susceptibility to bipolar disorders [22][23][24][25][26] , our research group chose this chromosome for a preliminary genome scan, with the aim to identify 1 or more genome-specific liability regions.…”

Association Analysis Between 12 Genetic Variants of Ten Genes and Personality Traits in a Young Chinese Han Population

“…The gene is a member of metabotropic glutamate receptors, which is mediated by a G-protein-coupled second messenger system involved in the central action of glutamate (Marin and Chen 2004;Namkoong et al 2007). Another, some reports indicated GRIN2B, a member of ionotropic glutamate receptors, is related to obsessive-compulsive disorder, schizophrenia, bipolar disorder, and some other psychotic disorders (Martucci et al 2006;Avramopoulos et al 2007;Arnold et al 2009). Of the 5-HT receptors, the 5-HT2A gene is involved in the development of temperament and borderline personality disorder (Jokela et al 2007;Soloff et al 2007) and the 5-HT6 gene roles in differences in novelty-seeking behavior (Ballaz et al 2007).…”

Psychosis and relapse in bipolar disorder are related to GRM3, DAOA, and GRIN2B genotype

“…21 Associations have been observed between several polymorphisms in the GRIN2B gene and the 12p13.1-p12.3 region (containing the GRIN2B gene) and BD. 16,22,23 Miyatake et al have observed that the T allele of the GRIN2B rs1019385 SNP results in increased luciferase transporter activity in the presence of nerve growth factor (NGF). 24 The presence of a G allele had no effect on reporter activity, suggesting that GRIN2B rs1019385 may have a role in transcriptional control of the GRIN2B transcript.…”