The chromosome workshops at the 5th International Congress of Psychiatric Genetics — the weight of the evidence from genome scans

Crow, Timothy J.; DeLisi, L.E.

doi:10.1097/00041444-199800820-00006

Cited by 24 publications

(13 citation statements)

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“…While one obvious explanation for our results is that there is no gene for schizophrenia on X, and there are one or more genes elsewhere on autosomes, no definitive region of autosomal linkage has been identified. Several independent genome‐wide investigations have yielded inconsistent results [DeLisi, 1999; DeLisi and Crow, 1999; Crow and DeLisi, 1998; DeLisi, in press]. Many putative positive observations have emerged that are not replicated in larger studies (i.e.…”

Section: Discussionmentioning

confidence: 99%

Failure to establish linkage on the X chromosome in 301 families with schizophrenia or schizoaffective disorder

DeLisi

Shaw²,

Sherrington³

et al. 2000

Am. J. Med. Genet.

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The hypothesis that a gene for susceptibility to psychosis (specifically in the X-Y homologous class) is located on the sex chromosomes has been proposed. Such a gene would account for the excess of sex chromosome anomalous males and females in populations of patients with psychosis, a tendency towards concordance by sex within families, and sex differences associated with psychosis and its underlying brain pathology. In earlier studies we observed small positive LOD scores in Xp11, and in a more recent and larger cohort of 178 sibling pairs, a peak multipoint nonparametric LOD score of 1. 55 at the locus DXS8032 in Xq21. The present study with a new set of markers extended the cohort to 301 ill sibling pairs and their parents. Despite the increase in sample size, the LOD score did not increase. A peak NPL of 1.55 was observed at the locus DXS1068 in proximal Xp, a region remote from the previous report. Separating families into those who were more likely to have X chromosome inheritance (maternal with no male to male transmission) did not yield stronger findings. In spite of the evidence that psychosis is related to a sex-dependent dimension of cerebral asymmetry, it is concluded that no consistent linkage of schizophrenia to the X chromosome can be demonstrated. In the context of the general failure of replication of linkage in psychosis, the possibility that the genetic predisposition to psychosis is contributed to by epigenetic modification rather than variations in the nucleotide sequence has to be considered.

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Section: Discussionmentioning

confidence: 99%

Failure to establish linkage on the X chromosome in 301 families with schizophrenia or schizoaffective disorder

DeLisi

Shaw²,

Sherrington³

et al. 2000

Am. J. Med. Genet.

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“…9 However, after initial enthusiasm it was quickly realized that a single genetic risk factor with strong effect would most likely not explain the susceptibility to BD even in severely affected multigenerational families. 10–12 Instead, mathematical model fitting suggested an oligogenic risk profile as the most likely cause of the disease, but indicated also substantial interfamilial heterogeneity. 13 Early linkage studies were not equipped to perform well under this scenario and knowledge about the human genome was still in its infancy.…”

Section: Introductionmentioning

confidence: 99%

Rare deleterious mutations are associated with disease in bipolar disorder families

et al. 2016

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Bipolar disorder (BD) is a common, complex, and heritable psychiatric disorder characterized by episodes of severe mood swings. The identification of rare, damaging genomic mutations in families with BD could inform about disease mechanisms and lead to new therapeutic interventions. To determine whether rare, damaging mutations shared identity-by-descent in families with BD could be associated with disease, exome sequencing was performed in multigenerational families of the NIMH BD Family Study followed by in silico functional prediction. Disease association and disease specificity was determined using 5 090 exomes from the Sweden-Schizophrenia (SZ) Population-Based Case-Control Exome Sequencing study. We identified 14 rare and likely deleterious mutations in 14 genes that were shared identity-by-descent among affected family members. The variants were associated with BD (p<0.05 after Bonferroni correction) and disease specificity was supported by the absence of the mutations in patients with SZ. In addition, we found rare, functional mutations in known causal genes for neuropsychiatric disorders including holoprosencephaly and epilepsy. Our results demonstrate that exome sequencing in multigenerational families with BD is effective in identifying rare genomic variants of potential clinical relevance and also disease modifiers related to coexisting medical conditions. Replication of our results and experimental validation are required before disease causation could be assumed.

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“…In summary, the strongest evidence to date supports the existence of schizophrenia susceptibility loci on chromosomes 6 and 8, but the magnitude of the statistical evidence and the existence of nonreplications demonstrate that these are clearly not confirmed, convincing findings [7]. Reported linkages to chromosomes 3, 5, 9, 20 and 22 are less compelling [6,25].…”

Section: Introductionmentioning

confidence: 99%

Genome Scan for Susceptibility Loci for Schizophrenia

Bailer¹,

Leisch

Meszaros³

et al. 2000

Neuropsychobiology

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Objective: Schizophrenia is a relatively common, often chronic and debilitating mental illness. Evidence from various studies has clearly demonstrated that genetic factors contribute substantially to the etiology. The goal of this study was to identify chromosomal regions likely to contain schizophrenia susceptibility genes. Methods: A genome-wide map of 388 microsatellite DNA markers was genotyped in 5 schizophrenia families. Nonparametric linkage analysis (Genehunter) was used to assess the pattern of allele sharing at each marker locus relative to the presence of disease. Results: Nonparametric linkage scores did not reach a genome-wide level of statistical significance (p < 0.00002) or a p value suggestive of linkage (p < 0.007) for any marker; however, one p value suggested replicated linkage (p < 0.01) at chromosome 6p24 in region D6S309 (p = 0.0047). Furthermore, 11 markers resulted in p < 0.05 at chromosomes 6p, 6q, 10q, 12q and 14q. Conclusions: Despite the differences in diagnostic schemes, in markers used and methods of analyses between studies published so far, we think that our result supports the notion that there is possibly some consistent evidence for replicated linkage of a schizophrenia susceptibility locus around the region of D6S309 at chromosome 6p24.

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The chromosome workshops at the 5th International Congress of Psychiatric Genetics — the weight of the evidence from genome scans

Cited by 24 publications

References 0 publications

Failure to establish linkage on the X chromosome in 301 families with schizophrenia or schizoaffective disorder

Failure to establish linkage on the X chromosome in 301 families with schizophrenia or schizoaffective disorder

Rare deleterious mutations are associated with disease in bipolar disorder families

Genome Scan for Susceptibility Loci for Schizophrenia

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