A high-density genome scan detects evidence for a bipolar-disorder susceptibility locus on 13q32 and other potential loci on 1q32 and 18p11.2

Detera‐Wadleigh, Sevilla D.; Badner, Judith A.; Berrettini, Wade H.; Yoshikawa, Takeo; Goldin, Lynn R.; Turner, Gordon; Rollins, Denise Y.; Moses, Tracy; Sanders, Alan R.; Karkera, Jayaprakash D.; Esterling, Lisa E.; Zeng, Jin; Ferraro, Thomas N.; Guroff, Juliet J.; Kazuba, Diane; Maxwell, Mary E.; Nürnberger, John I.; Gershon, Elliot S.

doi:10.1073/pnas.96.10.5604

Cited by 381 publications

(292 citation statements)

References 37 publications

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“…51 An LOD score of 2.6 was identified at marker GATA124F08, which is located about 550 kb upstream of PLXNA2. Family and twin studies have suggested hereditary overlap between bipolar disorder and schizophrenia; additionally, bipolar symptoms frequently overlap with those of other psychiatric disorders including schizophrenia.…”

Section: Discussionmentioning

confidence: 99%

Identification of the semaphorin receptor PLXNA2 as a candidate for susceptibility to schizophrenia

et al. 2006

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The discovery of genetic factors that contribute to schizophrenia susceptibility is a key challenge in understanding the etiology of this disease. Here, we report the identification of a novel schizophrenia candidate gene on chromosome 1q32, plexin A2 (PLXNA2), in a genomewide association study using 320 patients with schizophrenia of European descent and 325 matched controls. Over 25 000 single-nucleotide polymorphisms (SNPs) located within approximately 14 000 genes were tested. Out of 62 markers found to be associated with disease status, the most consistent finding was observed for a candidate locus on chromosome 1q32. The marker SNP rs752016 showed suggestive association with schizophrenia (odds ratio (OR) = 1.49, P = 0.006). This result was confirmed in an independent casecontrol sample of European Americans (combined OR = 1.38, P = 0.035) and similar genetic effects were observed in smaller subsets of Latin Americans (OR = 1.26) and Asian Americans (OR = 1.37). Supporting evidence was also obtained from two family-based collections, one of which reached statistical significance (OR = 2.2, P = 0.02). High-density SNP mapping showed that the region of association spans approximately 60 kb of the PLXNA2 gene. Eight out of 14 SNPs genotyped showed statistically significant differences between cases and controls. These results are in accordance with previous genetic findings that identified chromosome 1q32 as a candidate region for schizophrenia. PLXNA2 is a member of the transmembrane semaphorin receptor family that is involved in axonal guidance during development and may modulate neuronal plasticity and regeneration. The PLXNA2 ligand semaphorin 3A has been shown to be upregulated in the cerebellum of individuals with schizophrenia. These observations, together with the genetic results, make PLXNA2 a likely candidate for the 1q32 schizophrenia susceptibility locus.

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Section: Discussionmentioning

confidence: 99%

Identification of the semaphorin receptor PLXNA2 as a candidate for susceptibility to schizophrenia

et al. 2006

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“…59 These findings replicate and further clarify previous linkage findings in BD in these two chromosomal regions. 12,13,19,20,[60][61][62] They are especially interesting as the same regions may encompass susceptibility genes for schizophrenia. [63][64][65][66][67][68][69][70] Park et al 71 made similar conclusions in a study of psychotic BD in which most areas of linkage overlapped with those reported in previous investigations of schizophrenia.…”

Section: Psychotic Symptoms In Bdmentioning

confidence: 99%

“…In particular, findings in 4p, 4q, 8q, 10p, 12q24, 13q, 18p, 18q, 21q, and 22q have been supported by more than one study. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] However, these studies have not identified any specific genes, and a recent metaanalysis of available genome scans showed no regions with a conclusive evidence of linkage. 20 The relatively slow progress of gene-mapping efforts is often explained by the 'complex' nature of the illness and of the genotype-phenotype relation.…”

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confidence: 99%

The phenotypes of bipolar disorder: relevance for genetic investigations

2005

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The search for susceptibility genes for bipolar disorder (BD) depends on appropriate definitions of the phenotype. In this paper, we review data on diagnosis and clinical features of BD that could be used in genetic studies to better characterize patients or to define homogeneous subgroups. Clinical symptoms, long-term course, comorbid conditions, and response to prophylactic treatment may define groups associated with more or less specific loci. One such group is characterized by symptoms of psychosis and linkage to 13q and 22q. A second group includes mainly bipolar II patients with comorbid panic disorder, rapid mood switching, and evidence of chromosome 18 linkage. A third group comprises typical BD with an episodic course and favourable response to lithium prophylaxis. Reproducibility of cognitive deficits across studies raises the possibility of using cognitive profiles as endophenotypes of BD, with deficits in verbal explicit memory and executive function commonly reported. Brain imaging provides a more ambiguous data set consistent with heterogeneity of the illness. Keywords: bipolar disorder; genetics; endophenotype; neurocognitive function; brain imaging Bipolar disorder (BD) has a genetic basis with heritability of at least 80%. 1 A number of studies have attempted to map the susceptibility loci giving evidence of linkage in multiple genomic regions. In particular, findings in 4p, 4q, 8q, 10p, 12q24, 13q, 18p, 18q, 21q, and 22q have been supported by more than one study. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] However, these studies have not identified any specific genes, and a recent metaanalysis of available genome scans showed no regions with a conclusive evidence of linkage. 20 The relatively slow progress of gene-mapping efforts is often explained by the 'complex' nature of the illness and of the genotype-phenotype relation. The complexity most likely includes heterogeneity, interactions of multiple loci, incomplete penetrance, as well as phenotypes resulting from environmental effects-either alone or in interaction with the genetic predisposition. The goal of psychiatric genetic research is identification of (heritable) variations in DNA sequence or function that influence behaviour or give rise to mental illness. By definition, in complex (multifactorial) traits, this link is not unique and specific. That is, a particular change in gene sequence does not necessarily lead to a specific behaviour, and similar behaviours (symptoms) may be due to distinct (sets of) genes. Moreover, we must consider the possibility that the path between the genotype and behaviour is not unidirectional. Emerging examples point not only to general effects of environment, for instance stress, on behaviour, but also to specific behaviours influencing gene function that can be transmitted onto the next generation. 21 No single method is considered clearly superior in identifying susceptibility genes for complex traits such as BD. Most researchers agree that a combination of strategies is most lik...

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“…As well, human linkage studies in bipolar disorder suggest that the 11p13-14 region could harbor polymorphisms affecting susceptibility to mood disorders. 18,19 The BDNF gene is located in this region, making it not only a functional, but a positional candidate risk locus for mood disorders.…”

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confidence: 99%

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

et al. 2005

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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. Keywords: neurotrophic factors; mood disorder; childhood-onset; genetic association; haplotype Mood disorders rank fourth among the most significant global public health problems. 1 The prevalence of the juvenile-onset subtype of depressive disorder increases dramatically across the years of childhood and adolescence, with an estimated lifetime prevalence close to 20% by late adolescence. 2 Juvenile-onset mood disorders are associated with serious morbidity, including recurrence, impaired interpersonal functioning, and increased risks of bipolar disorder and suicide. 2,3 The influence of hereditary factors on susceptibility to major depression has been documented based on twin and adoption studies. 4 Twin studies in youth have identified significant heritability for depressive symptoms. 5,6 It has also been proposed that genetic aspects of liability to mood disorder may be more readily identified in families of childhood-and adolescentonset probands. 7 Accordingly, first-degree relatives of childhood-onset mood disorder probands have higher rates of affective disorder than do first-degree relatives of adult-onset mood disorder probands. 8 Evidence from both preclinical and clinical studies implicates brain-derived neurotrophic factor (BDNF) in mood disorders. Altered BDNF expression in stress-related depression via cellular signalling has been described in animal models. Repeated antidepressant administration, including electroconvulsive seizures, is associated with increased hippocampal BDNF expression, neuronal plasticity and neurogenesis. 9-11 Human neuroimaging 12,13 post mortem 14 and clinical [15][16][17] investigations indirectly support the hypothesis that neurotrophic factors play a key role in depression. As well, human linkage studies in

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A high-density genome scan detects evidence for a bipolar-disorder susceptibility locus on 13q32 and other potential loci on 1q32 and 18p11.2

Cited by 381 publications

References 37 publications

Identification of the semaphorin receptor PLXNA2 as a candidate for susceptibility to schizophrenia

Identification of the semaphorin receptor PLXNA2 as a candidate for susceptibility to schizophrenia

The phenotypes of bipolar disorder: relevance for genetic investigations

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

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