A Systematic Genomewide Linkage Study in 353 Sib Pairs with Schizophrenia

Williams, Nigel; Norton, Nadine; Williams, Hywel; Ekholm, Birgit; Hamshere, Marian L.; Lindblom, Yvonne; Chowdari, Kodavali V.; Cardno, A. G.; Zammit, Stanley; Jones, Lesley; Murphy, Kevin; Sanders, Rebecca; McCarthy, Geraldine; Gray, M. Y.; Jones, G.; Holmans, Peter; Nimgaonkar, Vishwajit L.; Adolfson, R.; Ösby, Urban; Terenius, Lars; Sedvall, Göran; O’Donovan, Michael; Owen, Michael John

doi:10.1086/380206

Cited by 109 publications

(95 citation statements)

References 66 publications

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“…98 Evidence for linkage of 6q15, 12q24 and 20q12, but not for 6q24-22, 1q21-22, 13q32-34 and 8p12-22 was also reported. It is notable that the region 12q24 is a novel linkage locus; 99 yet the gene encoding DAO is located close to this area and appears to be a contributory factor to the illness through its interaction with DAOA.…”

Section: Chromosome Xmentioning

confidence: 98%

“…139 Novak reevaluated the results of her previous investigation, using a more accurate method, a larger set of matched samples, and found an upregulation of the isoform Nogo C in schizophrenia. 140 Convergent evidence for the role of the Nogo gene in schizophrenia also comes from 111 Mediates oligo-oligodendrite and oligo-neuron adhesion 111 Provides a trophic signal to oligodendrites, without which oligodendroglial deterioration occurs 101 Regulates the properties of sodium channels at the nodes of Ranvier 111 MAG protein binds to the Nogo-66 receptor and inhibits axonal growth in vitro 112 MAG-deficient mice show delayed myelination and hypomyelination, but the latter is not associated with a loss of oligodendrites 111 MAG-deficient mice demonstrate an age-dependent dysfunction in myelin 98,111 Downregulation of the MAG protein has been shown at anterior frontal cortex 113 2 MAL 2qcen-13 Is expressed only when myelin compaction occurs 111 Is localized close to structural proteins (MBP and PLP1) 111 It may have functional contact with myelin glycosphingolipids 114 Organizes and stabilizes myelin via adhesion 114 Transgenic mice with increased MAL gene dosage revealed alterations of axon-glia interaction 115 MAL-deficient mice show defects in the maintenance of multiple domains of myelinated CNS axons, indicating aberrant protein trafficking 115 MAL-deficient mice demonstrate major alterations on the structural level (e.g. aberrant inclusions of cytoplasm within compact CNS myelin).…”

Section: Oligodendrocyte-related Genes Associated With Schizophreniamentioning

confidence: 99%

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The myelin-pathogenesis puzzle in schizophrenia: a literature review

2007

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Schizophrenia is a serious and disabling mental disorder with symptoms such as auditory hallucinations, disordered thinking and delusions, avolition, anhedonia, blunted affect and apathy. In this review article we seek to present the current scientific findings from linkage studies and susceptible genes and the pathophysiology of white matter in schizophrenia. The article has been reviewed in two parts. The first part deals with the linkage studies and susceptible genes in schizophrenia in order to have a clear-cut picture of the involvement of chromosomes and their genes in schizophrenia. The genetic linkage results seem to be replicated in some cases but in others are not. From these results, we cannot draw a fine map to a single locus or gene, leading to the conclusion that schizophrenia is not caused by a single factor/gene. In the second part of the article we present the oligodendrocyte-related genes that are associated with schizophrenia, as we hypothesize a potential role of oligodendrocyte-related genes in the pathology of the disorder.

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Section: Chromosome Xmentioning

confidence: 98%

Section: Oligodendrocyte-related Genes Associated With Schizophreniamentioning

confidence: 99%

The myelin-pathogenesis puzzle in schizophrenia: a literature review

2007

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“…30 Interest in the proximal region of chromosome 22q as harboring a susceptibility gene for schizophrenia has in part resulted from whole genome linkage scans. Although linkage has not been found in most such scans, proximal chromosome 22q has shown one of the stronger linkages to schizophrenia, [31][32][33][34][35][36][37] especially when considered in recent meta-analyses of schizophrenia genome scans using different methods. 38,39 There are also some linkages here in bipolar disorder studies [40][41][42][43] and meta-analytically.…”

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confidence: 99%

Haplotypic association spanning the 22q11.21 genes COMT and ARVCF with schizophrenia

et al. 2004

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Catechol-O-methyltransferase (COMT) has been implicated in schizophrenia by its function through its roles in monoamine neurotransmitter metabolism and its impact on prefrontal cognition, and also by its position through linkage scans and a strong cytogenetic association. Further support comes from association studies, especially family-based ones examining the COMT variant, Val 108/158 Met. We have studied eight markers spanning COMT and including portions of the two immediately adjacent genes, thioredoxin reductase 2 and armadillo repeat deleted in velocardiofacial syndrome (ARVCF), using association testing in 136 schizophrenia families. We found nominal evidence for association of illness to rs165849 (P ¼ 0.051) in ARVCF, and a stronger signal (global P ¼ 0.0019-0.0036) from three-marker haplotypes spanning the 3 0 portions of COMT and ARVCF, including Val 108/158 Met with Val 108/158 being the overtransmitted allele, consistent with previous studies. We also find Val 108/158 Met to be in linkage disequilibrium with the markers in ARVCF. These findings support previous association signals of schizophrenia to COMT markers, and suggest that ARVCF might contribute to this signal. ARVCF, a member of the catenin family, besides being a positional candidate, is also one due to its function, that is, its potential role in neurodevelopment, which is implicated in schizophrenia pathogenesis by several lines of evidence. Molecular Psychiatry (2005) 10, 353-365.

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“…Suggestive evidence for linkage distal to F-4 was also demonstrated for a modifier gene in Huntington's disease. 54 The fifth focus (F-5) is at 162 Mb with the strongest evidence for linkage on 6q 29 in an SCZ pedigree. Although there are no other supporting linkage studies, altered levels have been shown in the hippocampus of schizophrenics for two proteins encoded by genes in this location (TCP1 and MnSOD).…”

Section: Discussionmentioning

confidence: 99%

“…Williams et al 29 Bailer et al 28 same TRAR4 SNPs with SCZ in the sample that yielded a very significant LOD score at this location (Amann et al). 34 A pioneer work in proteomics has also pointed to the role of genes on chromosome 6q in SCZ.…”

Section: Schizophrenia Bipolar Othermentioning

confidence: 98%

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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A Systematic Genomewide Linkage Study in 353 Sib Pairs with Schizophrenia

Cited by 109 publications

References 66 publications

The myelin-pathogenesis puzzle in schizophrenia: a literature review

The myelin-pathogenesis puzzle in schizophrenia: a literature review

Haplotypic association spanning the 22q11.21 genes COMT and ARVCF with schizophrenia

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

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