Linkage analysis of schizophrenia to chromosome 15

Gejman, Pablo V.; Sanders, Alan R.; Badner, Judith A.; Cao, Qiuhe; Zhang, Jing

doi:10.1002/ajmg.1552

Cited by 52 publications

(31 citation statements)

References 28 publications

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“…0.001) was for marker D15S1360, which is physically close to the ·-7 nicotinic acetylcholine receptor (nAChR) subunit gene (CHRNA7). Additional studies using 15q14 markers have implicated CHRNA7 in schizophrenia using linkage [Coon et al, 1994;Riley et al, 1997;Kaufmann et al, 1998;Leonard et al, 1998;Gejman et al, 2001;Liu et al, 2001;Tsuang et al, 2001] and linkage disequilibrium methods [Riley et al, 2000;Stassen et al, 2000;Freedman et al, 2001;Xu et al, 2001]. In contrast, several studies have not confirmed these results [Moises et al, 1995;Pulver et al, 1995;Faraone et al, 1998;Levinson et al, 1998;Neves-Pereira et al, 1998;Curtis et al, 1999;Hovatta et al, 1999;Ekelund et al, 2000;Gurling et al, 2001].…”

Section: Introductionmentioning

confidence: 58%

“…The individual gene analysis further targets specific genes that may have particular involvement, those being CHRNA2, CHRNB2, and possibly CHRNA7 and CHRNA1. Although more research is necessary, the results for CHRNA7 are compelling because this gene has been implicated in schizophrenia and sensory gating deficits by several prior studies [Coon et al, 1994;Freedman et al, 1997Freedman et al, , 2001Riley et al, 1997Riley et al, , 2000Leonard et al, 1998;Stassen et al, 2000;Gejman et al, 2001;Liu et al, 2001;Tsuang et al, 2001;Xu et al, 2001]. Both the complex and individual analyses helps to further prioritize genes for case control studies relating to smoking in schizophrenics.…”

Section: Results Of Hypothesis Testingmentioning

confidence: 97%

“…Three of the four genes are in regions implicated by prior genome scans of schizophrenia at 8p21, 1q21 and 15q15, respectively. Other schizophrenia studies have already implicated CHRNA7 [Coon et al, 1994;Riley et al, 1997Riley et al, , 2000Kaufmann et al, 1998;Leonard et al, 1998;Stassen et al, 2000;Freedman et al, 2001;Gejman et al, 2001;Liu et al, 2001;Tsuang et al, 2001;Xu et al, 2001]. And, because nicotinic acetylcholine neurons are known to modulate dopaminergic transmission in the frontal-subcortical pathways implicated in schizophrenia [Mereu et al, 1987;Izenwasser et al, 1991], it is reasonable to hypothesize that dysregulation of the nicotinic system is a risk factor for schizophrenia.…”

Section: Limitations and Conclusionmentioning

confidence: 99%

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A Novel Permutation Testing Method Implicates Sixteen Nicotinic Acetylcholine Receptor Genes as Risk Factors for Smoking in Schizophrenia Families

Faraone

Taylor

et al. 2004

Hum Hered

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Smoking is a common correlate of schizophrenia, which leads to medical morbidity. Although twin and adoption studies have consistently implicated genes in the etiology of both smoking and schizophrenia, finding genes has been difficult. Several authors have suggested that clinical or neurobiological features associated with schizophrenia, such as smoking, might improve the ability to detect schizophrenia susceptibility genes by identifying genes related to the etiology of that feature. The objective of this study is to assess evidence for linkage of sixteen nicotinic acetylcholine receptor genes and smoking in schizophrenia families, using data from the NIMH Genetics Initiative for schizophrenia. Sixteen nicotinic acetylcholine receptor genes were selected prior to analysis. We used a multipoint sibling pair linkage analysis program, SIBPAL2, with a smoking trait in schizophrenia families. The significance of the group of candidate genes, in addition to each individual candidate gene, was assessed using permutation testing, which adjusted for multiple comparisons. The group of genes showed significant linkage to the smoking trait after adjusting for multiple comparisons through permutation testing (p = 0.039). In addition, two of the individual candidate genes were significant (CHRNA2, p = 0.044) and (CHRNB2, p = 0.015) and two genes were marginally significant (CHRNA7, p = 0.095; CHRNA1, p = 0.076). The significance of the complex hypothesis, involving sixteen genes, implicates the nicotinic system in smoking for schizophrenic families. Individual gene analysis suggests that CHRNA2 and CHRNB2 may play a particular role in this involvement. Such findings help prioritize genes for future case control studies. In addition, we provide a novel permutation method that is useful in future analyses involving a single hypothesis, with multiple candidate genes.

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Section: Introductionmentioning

confidence: 58%

Section: Results Of Hypothesis Testingmentioning

confidence: 97%

Section: Limitations and Conclusionmentioning

confidence: 99%

See 1 more Smart Citation

A Novel Permutation Testing Method Implicates Sixteen Nicotinic Acetylcholine Receptor Genes as Risk Factors for Smoking in Schizophrenia Families

Faraone

Taylor

et al. 2004

Hum Hered

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“…Chromosome 15q12-15 has been linked with schizophrenia (Freedman et al, 1997(Freedman et al, , 2001Gejman et al, 2001;Liu et al, 2001;Tsuang et al, 2001) and familial catatonic schizophrenia (periodic catatonia) (Stober et al, 2002;Meyer et al, 2002) in several, but not all, studies (Waterwort et al, 2002). The exact genetic markers on 15q12-15 most strongly associated with schizophrenia have varied in different studies, suggesting that more than one gene may be involved.…”

Section: Chromosomal Localization Of Mouse and Human M5 Muscarinic Rementioning

confidence: 99%

Decreased Amphetamine-Induced Locomotion and Improved Latent Inhibition in Mice Mutant for the M5 Muscarinic Receptor Gene Found in the Human 15q Schizophrenia Region

Wang

Hayes

et al. 2004

Neuropsychopharmacol

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M5 muscarinic receptors are coexpressed with D2 dopamine receptors in the ventral tegmentum and striatum, and are important for reward in rodents. Previously, we reported that disruption of the M5 receptor gene in mice reduced dopamine release in the nucleus accumbens. In this study, we established a polymerase chain reaction (PCR) genotyping method for M5 mutant mice, and, using RT-PCR, found that M5 mRNA expression was highest in the ventral tegmentum, striatum, and thalamus in wild-type mice. In the M5 mutant mice, D2 mRNA expression was increased in several brain structures, including the striatum. Genome mapping studies showed the M5 gene is localized to chromosome 2E4 in mice, and to 15q13 in humans in the region that has been linked to schizophrenia. Amphetamineinduced locomotion, but not baseline locomotion or motor functions, decreased in M5 mutant mice, consistent with lower accumbal dopamine release. Previous reports found latent inhibition improvement in rats following nucleus accumbens lesions, or blockade of dopamine D2 receptors with neuroleptic drugs. Here, latent inhibition was significantly increased in M5 mutant mice as compared with controls, consistent with reduced dopamine function in the nucleus accumbens. In summary, our results showed that M5 gene disruption in mice decreased amphetamine-induced locomotion and increased latent inhibition, suggesting that increased M5 mesolimbic function may be relevant to schizophrenia.

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“…The P50 sensory gating deficit, one of the best supported endophenotypes of schizophrenia and bipolar disorder, is strongly linked to this region, 1 as are two idiopathic epilepsies. 2,3 Of the many attempts to demonstrate linkage of schizophrenia and bipolar disorder to this region, two studies showed linkage to bipolar disorder, 4,5 but several found either weak [6][7][8][9][10] or no linkage to schizophrenia. [11][12][13] Both schizophrenia and bipolar disorder have also shown association with 15q13.3 markers.…”

Section: Introductionmentioning

confidence: 99%

Association between the 2-bp deletion polymorphism in the duplicated version of the alpha7 nicotinic receptor gene and P50 sensory gating

et al. 2012

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There is considerable evidence implicating the 15q13.3 region in neuropsychiatric disorders, with the a7 nicotinic receptor gene CHRNA7 the most plausible candidate. This region has multiple duplications and many copy number variants (CNVs). A common CNV involves a partial duplication of CHRNA7 (CHRFAM7A), which occurs in either orientation. We examined the distribution of these alternative genomic arrangements in a large cohort of psychiatric patients, their relatives and controls using the 2-bp deletion polymorphism as a marker for the orientation of CHRFAM7A. We investigated three common alleles for association with psychosis and with the P50 sensory gating deficit, which is strongly associated with psychosis and strongly linked to 15q13.3. We found significant within-family association with P50 (empirical P ¼ 0.004), which is robust to population stratification. Most of the effect came from the 2-bp deletion allele, which tags the variant of CHRFAM7A in the same orientation as CHRNA7. This allele is associated with the presence of the P50 sensory gating deficit (empirical P ¼ 0.0006). Tests comparing within-family and between-family components of association suggest considerable population stratification in the sample. We found no evidence for association with psychosis, but this may reflect lower power using this phenotype. Four out of six previous association studies found association of different psychiatric phenotypes with the same 2-bp deletion allele.

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Linkage analysis of schizophrenia to chromosome 15

Cited by 52 publications

References 28 publications

A Novel Permutation Testing Method Implicates Sixteen Nicotinic Acetylcholine Receptor Genes as Risk Factors for Smoking in Schizophrenia Families

A Novel Permutation Testing Method Implicates Sixteen Nicotinic Acetylcholine Receptor Genes as Risk Factors for Smoking in Schizophrenia Families

Decreased Amphetamine-Induced Locomotion and Improved Latent Inhibition in Mice Mutant for the M5 Muscarinic Receptor Gene Found in the Human 15q Schizophrenia Region

Association between the 2-bp deletion polymorphism in the duplicated version of the alpha7 nicotinic receptor gene and P50 sensory gating

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