Genomewide Linkage Analysis of Bipolar Disorder by Use of a High-Density Single-Nucleotide–Polymorphism (SNP) Genotyping Assay: A Comparison with Microsatellite Marker Assays and Finding of Significant Linkage to Chromosome 6q22

Middleton, Frank A.; Pato, Michele T.; Gentile, Karen L.; Morley, Christopher P.; Zhao, Xinzhi; Eisener, Amy F.; Brown, Andrea M.; Petryshen, Tracey L.; Kirby, Andrew; Medeiros, Helena; Carvalho, Célia Barreto; Macedo, António; Dourado, Ana; Coelho, Isabel; Valente, J.; Soares, M.J.; Ferreira, Carlos Paz; Ma, Liang; Azevedo, Maria Helena Pinto de; Kennedy, James L.; Daly, Mark J.; Sklar, Pamela; Pato, Carlos N.

doi:10.1086/420775

Cited by 162 publications

(121 citation statements)

References 25 publications

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“…Of these, chromosomes 2q24 and 1q44 have been implicated in previous studies of BP. A study by Cichon et al 15 showed suggestive evidence of linkage across a broad region on chromosome 2q21-33 and this region was also implicated in Middleton et al 16 On chromosome 1q44, Cheng et al 17 reported a finding at D1S1609, the same marker where our peak occurred. Interestingly, DISC1, which has been the focus of extensive research in both schizophrenia and BP disorder, 18 is approximately 11 Mb away.…”

Section: Discussionsupporting

confidence: 68%

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Genome-wide linkage scan of 98 bipolar pedigrees and analysis of clinical covariates

et al. 2007

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Despite compelling evidence that genetic factors contribute to bipolar disorder (BP), attempts to identify susceptibility genes have met with limited success. This may be due to the genetic heterogeneity of the disorder. We sought to identify susceptibility loci for BP in a genome-wide linkage scan with and without clinical covariates that might reflect the underlying heterogeneity of the disorder. We genotyped 428 subjects in 98 BP families at the Center for Inherited Disease Research with 402 microsatellite markers. We first carried out a nonparametric linkage analysis with MERLIN, and then reanalyzed the data with LODPAL to incorporate clinical covariates for age at onset (AAO), psychosis and comorbid anxiety. We sought to further examine the top findings in the covariate analysis in an independent sample of 64 previously collected BP families. In the non-parametric linkage analysis, three loci were nominally significant under a narrow diagnostic model and seven other loci were nominally significant under a broader model. The top findings were on chromosomes 2q24 and 3q28. The covariate analyses yielded additional evidence for linkage on 3q28 with AAO in the primary and independent samples. Although none of the linked loci were genome-wide significant, their congruence with prior results and, for the covariate analyses, their identification in two separate samples increases the likelihood that they are true positives and deserve further investigation. These findings further demonstrate the value of considering clinical features that may reflect the underlying heterogeneity of disease in order to facilitate gene mapping.

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Section: Discussionsupporting

confidence: 68%

“…This was on chromosome 11p11. While this locus has not been previously reported in linkage analyses of BP with psychosis, it has been implicated in a scan of BP 16 and in another of schizophrenia. 41 Additionally, this region is < 18 Mb away from BDNF, which has been associated with both BP and schizophrenia.…”

Section: Discussionmentioning

confidence: 84%

Genome-wide linkage scan of 98 bipolar pedigrees and analysis of clinical covariates

et al. 2007

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“…This concern naturally raises a great deal of interest in comparing these two types of markers for a number of aspects important in linkage studies. Factors considered to date include information content [Matise et al, 2003;Evans and Cardon, 2004;Sawcer et al, 2004;John et al, 2004], strength of linkage signals [Middleton et al, 2004;Schaid et al, 2004;John et al, 2004], and effect of linkage disequilibrium [John et al, 2004;Schaid et al, 2004]. We note in passing that there were earlier works looking into some of these issues as well [e.g., Kruglyak, 1997;Terwilliger et al, 1992], but the numbers of SNPs considered were not quite at the scale of those available today.…”

Section: Introductionmentioning

confidence: 99%

Microsatellites versus single‐nucleotide polymorphisms in confidence interval estimation of disease loci

Papachristou

Lin

2005

Genetic Epidemiology

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With cost-effective high-throughput Single Nucleotide Polymorphism (SNP) arrays now becoming widely available, it is highly anticipated that SNPs will soon become the choice of markers in whole genome screens. This optimism raises a great deal of interest in assessing whether dense SNP maps offer at least as much information as their microsatellite (MS) counterparts. Factors considered to date include information content, strength of linkage signals, and effect of linkage disequilibrium. In the current report, we focus on investigating the relative merits of SNPs vs. MS markers for disease gene localization. For our comparisons, we consider three novel confidence interval estimation procedures based on confidence set inference (CSI) using affected sib-pair data. Two of these procedures are multipoint in nature, enabling them to capitalize on dense SNPs with limited heterozygosity. The other procedure makes use of markers one at a time (two-point), but is much more computationally efficient. In addition to marker type, we also assess the effects of a number of other factors, including map density and marker heterozygosity, on disease gene localization through an extensive simulation study. Our results clearly show that confidence intervals derived based on the CSI multipoint procedures can place the trait locus in much shorter chromosomal segments using densely saturated SNP maps as opposed to using sparse MS maps. Finally, it is interesting (although not surprising) to note that, should one wish to perform a quick preliminary genome screening, then the two-point CSI procedure would be a preferred, computationally cost-effective choice. Genet. Epidemiol.

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“…53 The third focus (F-3) is for BPD and is located at 126 Mb with a very significant finding from one study of Portuguese pedigrees. 45 The fourth focus (F-4) is centered at 136 Mb, with significant findings in SCZ-related disorders coming from one linkage study 31,32 and one association study, 14 and weak support from other studies in SCZ. 26,39 Support for this focus also comes from linkage and association studies in BPD 38,48,49 and from a meta-analysis of linkage studies in BPD 5 as well as from the presence of AHI1, a gene causing a severe neuropsychiatric disorder (Joubert Syndrome) in this location.…”

Section: Discussionmentioning

confidence: 99%

“…In a study of pedigrees from the Portuguese islands and mainland, 44,45 25 pedigrees were genotyped with both a dense map of microsatellite markers and SNPs. The best multipoint NPL (4.2, empirical Po0.05) and LOD (3.56) were on 6q at 126 Mb.…”

Section: Schizophrenia Bipolar Othermentioning

confidence: 99%

Excitement and confusion on chromosome 6q: the challenges of neuropsychiatric genetics in microcosm

Kohn¹,

Lerer²

2005

Mol Psychiatry

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The search for genes that are implicated in the pathogenesis of schizophrenia (SCZ), bipolar disorder (BPD) and other complex neuropsychiatric phenotypes has yielded a plethora of positive findings, but has also engendered a substantial degree of confusion. Exciting findings include positive linkage results in a number of chromosomal regions and the identification of several genes that have been associated with SCZ and to a lesser extent with BPD. Confusing aspects include the difference between studies in localization of linkage peaks in the same chromosomal regions, raising the possibility that these regions may harbor more than one gene, the fact that positive linkage findings as well as associated genes appear in several cases to be shared by more than one disorder, and the failure to identify thus far the precise pathogenic variants in associated genes. Recent findings of linkage and association studies on chromosome 6q illustrate the current status of neuropsychiatric genetics in intriguing microcosm. Positive findings from linkage and association studies are reviewed in order to identify approaches that may help to settle apparent contradictions and allow an interpretation of the results that may prove useful in application to findings from other chromosomal regions. Not only SCZ and BPD but also other psychiatric and neurological phenotypes are considered. Taking a topographic approach, we identify five foci of positive findings on chromosome 6q and suggest that each may harbor gene(s) that confer susceptibility to SCZ or BPD or may modify their onset or clinical course. We further suggest that in searching for these genes the possibility that they may be implicated in more than one disorder should be taken into account. We also discuss the potential contribution of rare genetic variants identified in homogeneous, isolated populations to the subsequent identification of common variants in the same gene that contribute to disease susceptibility in outbred populations. Keywords: schizophrenia; bipolar disorder; chromosome 6q; molecular genetics; linkageThe last three decades have seen considerable advances in the field of psychiatric genetics. First, family twin and adoption studies conclusively established that genes play a major role in the etiology of many psychiatric disorders. Then, an increasing number of groups embarked on linkage studies aiming at localizing these genes. With ever improving technology, whole genome scans became the standard vehicle for these endeavors. Studies became more and more sophisticated, involving larger samples of carefully characterized affected individuals, using denser maps of markers and employing increasingly powerful statistical tools. Over the years, linkage studies have repeatedly implicated several chromosomal regions as linked to major psychiatric disorders, particularly schizophrenia (SCZ) and bipolar disorder (BPD) (for reviews, see Riley and McGuffin, 1 Berrettini,2 Kohn and Lerer 3 and Mathews and Reus 4 ). Recent meta-analyses of linkage studies have establi...

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Genomewide Linkage Analysis of Bipolar Disorder by Use of a High-Density Single-Nucleotide–Polymorphism (SNP) Genotyping Assay: A Comparison with Microsatellite Marker Assays and Finding of Significant Linkage to Chromosome 6q22

Cited by 162 publications

References 25 publications

Genome-wide linkage scan of 98 bipolar pedigrees and analysis of clinical covariates

Genome-wide linkage scan of 98 bipolar pedigrees and analysis of clinical covariates

Microsatellites versus single‐nucleotide polymorphisms in confidence interval estimation of disease loci

Excitement and confusion on chromosome 6q: the challenges of neuropsychiatric genetics in microcosm

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