Investigation by Linkage Analysis of the XY Pseudoautosomal Region in the Genetic Susceptibility to Schizophrenia

Kalsi, Gursharan; Curtis, David; Brynjólfsson, Jón; Butler, Robert J.; Sharma, Tonmoy; Murphy, Patrick D.; Read, Timothy D.; Pétursson, Hannes; Gurling, Hugh

doi:10.1192/bjp.167.3.390

Cited by 10 publications

(7 citation statements)

References 11 publications

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“…A pseudoautosomal locus for a schizophrenia susceptibility gene that would account for these differences was suggested [Crow et al, 1989]. An early study using sib pair analysis reported evidence of excess sharing at DXYS14 [Collinge et al, 1991], that was supported in one nonparametric replication , but was not supported by a number of other studies using both parametric and nonparametric analyses Wang et al, 1993;Crow et al, 1994;Barr et al, 1994;Maier et al, 1995;Kalsi et al, 1995c]. A large collaborative study examining markers within band Xp11 near the MAO loci found a LOD of 1.97 under a dominant model for DXS7 in a set of 92 sib pairs selected for maternal inheritance.…”

Section: Chromosomementioning

confidence: 98%

Linkage and associated studies of schizophrenia

2000

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Genetic epidemiology has provided consistent evidence over many years that schizophrenia has a genetic component, and that this genetic component is complex, polygenic, and involves epistatic interaction between loci. Molecular genetics studies have, however, so far failed to identify any DNA variant that can be demonstrated to contribute to either liability to schizophrenia or to any identifiable part of the underlying pathology. Replication studies of positive findings have been difficult to interpret for a variety of reasons. First, few have reproduced the initial findings, which may be due either to random variation between two samples in the genetic inputs involved, or to a lack of power to replicate an effect at a given alpha level. Where positive data have been found in replication studies, the positioning of the locus has been unreliable, leading no closer to positional cloning of genes involved. However, an assessment of all the linkage studies performed over the past ten years does suggest a number of regions where positive results are found numerous times. These include regions on chromosomes 1, 2, 4, 5, 6, 7, 8, 9, 10, 13, 15, 18, 22 and the X. All of these data are critically reviewed and their locations compared. Reasons for the difficulty in obtaining consistent results and possible strategies for overcoming them are discussed. Am. J. Med. Genet. (Semin. Med. Genet.) 97:23-44, 2000.

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Section: Chromosomementioning

confidence: 98%

Linkage and associated studies of schizophrenia

2000

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“…Nevertheless, although initially promising [21][22][23], early molecular studies were never able to show a linkage or association with schizophrenia for any region of the sex chromosomes or variants in the genes located there, despite the existence of some good candidates [24][25][26][27][28][29][30][31]. Although there continued to be lack of data to support this hypothesis and interest waned among most investigators in pursuing it further, the sex chromosome hypothesis has never been clearly negated.…”

Section: Doi: 101159/000491489mentioning

confidence: 99%

“…However, the first smaller GWAS of schizophrenia performed demonstrated some evidence of SNPs associated with the X chromosome in their top results [13,30,31]. Wong et al [40] performed a GWAS of schizophrenia in the Han Chinese population and also examined a group of selected candidate genes from prior studies and plausible biological pathways.…”

Section: The Unbiased Screening Of the Genomementioning

confidence: 99%

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The Sex Chromosome Hypothesis of Schizophrenia: Alive, Dead, or Forgotten? A Commentary and Review

Bache

DeLisi

2018

Complex Psychiatry

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The X chromosome has long been an intriguing site for harboring genes that have importance in brain development and function. It has received the most attention for having specific genes underlying the X-linked inherited intellectual disabilities, but has also been associated with schizophrenia in a number of early studies. An X chromosome hypothesis for a genetic predisposition for schizophrenia initially came from the X chromosome anomaly population data showing an excess of schizophrenia in Klinefelter’s (XXY) males and triple X (XXX) females. Crow and colleagues later expanded the X chromosome hypothesis to include the possibility of a locus on the Y chromosome and, specifically, genes on X that escaped inactivation and are X-Y homologous loci. Some new information about possible risk loci on these chromosomes has come from the current large genetic consortia genome-wide association studies, suggesting that perhaps this hypothesis needs to be revisited for some schizophrenias. The following commentary reviews the early and more recent literature supporting or refuting this dormant hypothesis and emphasizes the possible candidate genes still of interest that could be explored in further studies.

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“…The need for such methods is apparent from the numerous studies of schizophrenia that look at potential association with the XY region (Collinge et al 1991;Asherson et al 1992;Gorwood et al 1992;Wang et al 1993; Barr et al 1994;Crow et al 1994;d'Amato et al 1994;Maier et al 1994;Kalsi et al 1995); an excess of same-sex affected pairs has been observed in a few studies (Collinge et al 1991;Asherson et al 1992;Gotwood et al 1992), which has been interpreted as an…”

Section: Figurementioning

confidence: 99%

Multipoint Linkage Analysis of the Pseudoautosomal Regions, Using Affected Sibling Pairs

Dupuis

Eerdewegh

2000

The American Journal of Human Genetics

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Affected sibling pairs are often the design of choice in linkage-analysis studies with the goal of identifying the genes that increase susceptibility to complex diseases. Methods for multipoint analysis based on sibling amount of sharing that is identical by descent are widely available, for both autosomal and X-linked markers. Such methods have the advantage of making few assumptions about the mode of inheritance of the disease. However, with this approach, data from the pseudoautosomal regions on the X chromosome pose special challenges. Same-sex sibling pairs will share, in that region of the genome, more genetic material identical by descent, with and without the presence of a disease-susceptibility gene. This increased sharing will be more pronounced for markers closely linked to the sex-specific region. For the same reason, opposite-sex sibling pairs will share fewer alleles identical by descent. Failure to take this inequality in sharing into account may result in a false declaration of linkage if the study sample contains an excess of sex-concordant pairs, or a linkage may be missed when an excess of sex-discordant pairs is present. We propose a method to take into account this expected increase/decrease in sharing when markers in the pseudoautosomal region are analyzed. For quantitative traits, we demonstrate, using the Haseman-Elston method, (1) the same inflation in type I error, in the absence of an appropriate correction, and (2) the inadequacy of permutation tests to estimate levels of significance when all phenotypic values are permuted, irrespective of gender. The proposed method is illustrated with a genome screen on 350 sibling pairs affected with type I diabetes.

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Investigation by Linkage Analysis of the XY Pseudoautosomal Region in the Genetic Susceptibility to Schizophrenia

Abstract: We conclude that the present study provides no support for the involvement of either the pseudoautosomal region or the nearby region of the sex chromosomes in the aetiology of schizophrenia.

Cited by 10 publications

References 11 publications

Linkage and associated studies of schizophrenia

Linkage and associated studies of schizophrenia

The Sex Chromosome Hypothesis of Schizophrenia: Alive, Dead, or Forgotten? A Commentary and Review

Multipoint Linkage Analysis of the Pseudoautosomal Regions, Using Affected Sibling Pairs

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