Linkage of chromosome 13q32 to schizophrenia in a large veterans affairs cooperative study sample

Faraone, Stephen V.; Skol, Andrew D.; Tsuang, Debby W.; Bingham, Stephen F.; Young, Kimball; Prabhudesai, Sarita; Haverstock, Susan L.; Mena, Felicitas; Menon, Aerath Sri Kumar; Bisset, Darren; Pepple, John R.; Sautter, Frederic J.; Baldwin, Charlene; Weiss, David M.; Collins, Joseph F.; Keith, Tim P.; Boehnke, Michael; Tsuang, Ming T.; Schellenberg, Gerard D.

doi:10.1002/ajmg.10601

Cited by 31 publications

(21 citation statements)

References 26 publications

(25 reference statements)

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“…It is of interest to note genetic linkage studies involving other psychiatric disorders, most notably schizophrenia and bipolar disorder, have also shown linkage to the 13q region (42)(43)(44)(45)(46)(47)(48)(49)(50). A recent metaanalysis of 11 bipolar disorder and 18 schizophrenia genomic screens showed the strongest evidence for linkage for both disorders to be localized to chromosome 13q (51).…”

Section: Discussionmentioning

confidence: 99%

Further genetic evidence for a panic disorder syndrome mapping to chromosome 13q

Hamilton

Fyer

Durner

et al. 2003

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

111

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Substantial evidence supports that there is a genetic component to panic disorder (PD). Until recently, attempts at localizing genes for PD by using standard phenotypic data have not proven successful. Previous work suggests that a potential subtype of PD called the panic syndrome exists, and it is characterized by a number of medical conditions, most notably bladder͞renal disorders. In the current study, a genome scan with 384 microsatellite markers was performed on 587 individuals in 60 multiplex pedigrees segregating PD and bladder͞kidney conditions. Using both single-locus and multipoint analytic methods, we found significant linkage on chromosome 22 (maximum heterogeneity logarithm of odds score ‫؍‬ 4.11 at D22S445) and on chromosome 13q (heterogeneity logarithm of odds score ‫؍‬ 3.57 at D13S793) under a dominantgenetic model and a broad phenotypic definition. Multipoint analyses did not support the observation on chromosome 22. The chromosome 13 findings were corroborated by multipoint findings, and extend our previous findings from 19 of the 60 families. Several other regions showed elevated scores by using when one analytic method was used, but not the other. These results suggest that there are genes on chromosome 13q, and possibly on chromosome 22 as well, that influence the susceptibility toward a pleiotropic syndrome that includes PD, bladder problems, severe headaches, mitral valve prolapse, and thyroid conditions. A mong human psychiatric disorders, panic disorder (PD) is unusual for its combination of physiological and psychological symptoms. Whereas somatoform disorders are characterized by the former, and mood͞psychotic disorders by the latter, it is only in PD that bodily sensations and emotional reactions are so critically intertwined. A formal diagnosis of PD requires having recurrent panic attacks, which are brief episodes of intense fear that are accompanied by a number of physical symptoms, including palpitations, sweating, sensations of shortness of breath or smothering, the feeling of choking, chest pain, paresthesias, and nausea, among others. These attacks must be accompanied by anticipatory anxiety, the fear that one will have additional attacks. The worldwide lifetime prevalence of PD is Ϸ1-3% (1), and numerous family studies suggest a relative risk of Ϸ8 for PD in first-degree relatives of PD probands when compared with the relatives of controls (2). Twin studies provide evidence for a heritability estimate as high as 0.48 (3). The past several years have seen efforts to identify the genetic factors contributing to PD. Three genome scans, a focused genome screen, and a number of candidate-gene studies of PD have been completed by us and others. Our first-stage genome scan of 23 pedigrees revealed six markers that gave logarithm of odds (LOD) scores of Ͼ1.0, but none with scores of Ͼ2.0 (4). Also, using 23 families, Crowe et al. (5) reported, in a second genome scan, a maximum LOD score of 2.23 on chromosome 7p15. This location was just 10 centimorgans (cM) from the location of our ...

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Section: Discussionmentioning

confidence: 99%

Further genetic evidence for a panic disorder syndrome mapping to chromosome 13q

Hamilton

Fyer

Durner

et al. 2003

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

111

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“…Brzustowicz et al [1999], in a study of 21 Canadian families, reported a LOD score of 4.42 at marker D13S793. In the 166 schizophrenia families collected by the Veterans Affairs Cooperative Linkage Study of Schizophrenia, Faraone et al [2002] reported a peak LOD score of 1.43 between markers D13S1241 and D13S159. Although there are some negative reports [Coon et al, 1994;Faraone et al, 1998;Kaufmann et al, 1998;Riley et al, 1998;DeLisi et al, 2000;Levinson et al, 2000;Mowry et al, 2000;Schwab et al, 2000;Gurling et al, 2001], it is notable that the peak LOD scores reported by the positive studies cluster in a region ranging from 65 to 95 cM.…”

Section: Results Of Genome Scanmentioning

confidence: 99%

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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“…Loci have been identified on almost every chromosome, but only a few regions have been replicated across studies. One such region is near the telomere of chromosome 13q (5)(6)(7)(8)(9)(10)(11)(12). Across studies the region of peak linkage is broad, from 13q12 to 13q34.…”

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confidence: 99%

Elucidating the genetic architecture of familial schizophrenia using rare copy number variant and linkage scans

Woodroffe²,

Rodríguez-Murillo³

et al. 2009

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

143

124

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To elucidate the genetic architecture of familial schizophrenia we combine linkage analysis with studies of fine-level chromosomal variation in families recruited from the Afrikaner population in South Africa. We demonstrate that individually rare inherited copy number variants (CNVs) are more frequent in cases with familial schizophrenia as compared to unaffected controls and affect almost exclusively genic regions. Interestingly, we find that while the prevalence of rare structural variants is similar in familial and sporadic cases, the type of variants is markedly different. In addition, using a high-density linkage scan with a panel of nearly 2,000 markers, we identify a region on chromosome 13q34 that shows genome-wide significant linkage to schizophrenia and show that in the families not linked to this locus, there is evidence for linkage to chromosome 1p36. No causative CNVs were identified in either locus. Overall, our results from approaches designed to detect risk variants with relatively low frequency and high penetrance in a well-defined and relatively homogeneous population, provide strong empirical evidence supporting the notion that multiple genetic variants, including individually rare ones, that affect many different genes contribute to the genetic risk of familial schizophrenia. They also highlight differences in the genetic architecture of the familial and sporadic forms of the disease.rare mutations ͉ chromosome 13q34 ͉ chromosome 1p36 ͉ RAPGEF gene family

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Linkage of chromosome 13q32 to schizophrenia in a large veterans affairs cooperative study sample

Cited by 31 publications

References 26 publications

Further genetic evidence for a panic disorder syndrome mapping to chromosome 13q

Further genetic evidence for a panic disorder syndrome mapping to chromosome 13q

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

Elucidating the genetic architecture of familial schizophrenia using rare copy number variant and linkage scans

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