Twin studies of schizophrenia: From bow-and-arrow concordances to Star Wars Mx and functional genomics

Cardno, Alastair G.; Gottesman, Irving I.

doi:10.1002/(sici)1096-8628(200021)97:1<12::aid-ajmg3>3.0.co;2-u

Cited by 780 publications

(292 citation statements)

References 36 publications

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“…In fact, by consideration of much larger concordance of Scz for monozygotic (Mz) than dizygotic (Dz) twins, estimates of heritability to Scz vary around 80% (Cardno and Gottesman 2000). Such high rates of heritability in the affected generation are not compatible with our hypothesis that some of the genetic vulnerability to Scz lies in the maternal generation.…”

Section: Discussioncontrasting

confidence: 58%

Genetic liability to schizophrenia in Oceanic Palau: a search in the affected and maternal generation

et al. 2007

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While liability to schizophrenia (Scz) is due to genetic and environmental factors, specific factors are largely unknown. We postulate a two-hit model for Scz, in which initial liability is generated during fetal brain development: this "hit" is precipitated by environmental stressors biologically interacting with maternal genetic vulnerability to the stress. Additional liability to Scz is generated by individual genetic vulnerability. To evaluate these putative levels of vulnerability, we search in the genome of both affected individuals and their mothers for variation that differs, statistically, from that in the general population. For parental analyses, mothers were treated as "affected," rather than their offspring, and the fathers were treated as "controls". We used a sample from the Palauan population: 175 individuals diagnosed with Scz, broadly defined; 87 mothers and 45 fathers of affected individuals. Pedigree and diagnostic data were available on 2,953 living and deceased subjects. DNA from 553 individuals was genotyped for short tandem repeats (STR) spaced approximately every 10 cM across the genome. We tested for association between affection status and STR alleles; such an approach was reasonable, despite the widely spaced markers, because this population has far-ranging linkage disequilibrium (LD). Results for the truly affected individuals were modest, whereas results from the maternal generation were promising. For a recessive model and a test for excess allele matching across mothers, significant findings occurred for D20S481, D10S1221, D6S1021, D13S317, and D18S976. Regions in which at least two adjacent markers produced substantial association statistics include 2p12-11.2, 2q24.1-32.1, 6q12-14.1, 10q23.2-24.21, 12q23.2-24.21 and 17q23.2-23.3.

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Section: Discussioncontrasting

confidence: 58%

Genetic liability to schizophrenia in Oceanic Palau: a search in the affected and maternal generation

et al. 2007

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“…Strong evidence for a genetic basis of schizophrenia was first provided by the Danish adoption studies (Kety et al 1976) and was further verified by studies of the relative concordance rates among monozygotic versus dizygotic twin pairs (Cardno and Gottesman 2000;Sullivan et al 2003). It is assumed that for most individuals with this disorder, the genetic liability for schizophrenia is due to the interaction of risk alleles for multiple genes, rather than a single genetic defect (Gottesman and Shields 1967).…”

Section: Introductionmentioning

confidence: 91%

Age-related changes in the expression of schizophrenia susceptibility genes in the human prefrontal cortex

Colantuoni

Hyde²,

Mitkus³

et al. 2008

Brain Struct Funct

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The molecular basis of complex neuropsychiatric disorders most likely involves many genes. In recent years, specific genetic variations influencing risk for schizophrenia and other neuropsychiatric disorders have been reported. We have used custom DNA microarrays and qPCR to investigate the expression of putative schizophrenia susceptibility genes and related genes of interest in the normal human brain. Expression of 31 genes was measured in Brodmann's area 10 (BA10) in the prefrontal cortex of 72 postmortem brain samples spanning half a century of human aging (18-67 years), each without history of neuropsychiatric illness, neurological disease, or drug abuse. Examination of expression across age allowed the identification of genes whose expression patterns correlate with age, as well as genes that share common expression patterns and that possibly participate in common cellular mechanisms related to the emergence of schizophrenia in early adult life. The expression of GRM3 and RGS4 decreased across the entire age range surveyed, while that of PRODH and DARPP-32 was shown to increase with age. NRG1, ERBB3, and NGFR show expression changes during the years of greatest risk for the development of schizophrenia. Expression of FEZ1, GAD1, and RGS4 showed especially high correlation with one another, in addition to the strongest mean levels of absolute correlation with all other genes studied here. All microarray data are available at NCBI's Gene Expression Omnibus: GEO Series accession number GSE11546 (http://www.ncbi.nlm.nih.gov/geo) [corrected]

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“…They are familial disorders, Wrst degree relatives of an aVected individual having 8-10 times the risk of the corresponding disorder in the general population which is about 1%. Most of the variance in risk for each disorder is genetic, twin studies revealing heritabilities for schizophrenia and BD of around 80% or more (Cardno and Gottesman 2000;McGuYn et al 2003) with largely unknown environmental factors also being involved. Given their high heritabilities and the diYculties inherent in direct physiological and pathological studies of living human brain, the identiWcation of speciWc risk loci potentially oVers researchers the best chance of understanding pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

Genetics of psychosis; insights from views across the genome

2009

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The major psychotic illnesses, schizophrenia and bipolar disorder (BD), are among the most heritable common disorders, but finding specific susceptibility genes for them has not been straightforward. The reasons are widely assumed to include lack of valid phenotypic definition, absence of good theories of pathophysiology for candidate gene studies, and the involvement of many genes, each making small contributions to population risk. Within the last year or so, a number of genome wide association (GWAS) of schizophrenia and BD have been published. These have produced stronger evidence for association to specific risk loci than have earlier studies, specifically for the zinc finger binding protein 804A (ZNF804A) locus in schizophrenia and for the calcium channel, voltage-dependent, L type, alpha 1C subunit (CACNA1C) and ankyrin 3, node of Ranvier (ANK3) loci in bipolar disorder. The ZNF804A and CACNA1C loci appear to influence risk for both disorders, a finding that supports the hypothesis that schizophrenia and BD are not aetiologically distinct. In the case of schizophrenia, a number of rare copy number variants have also been detected that have fairly large effect sizes on disease risk, and that additionally influence risk of autism, mental retardation, and other neurodevelopmental disorders. The existing findings point to some likely pathophysiological mechanisms but also challenge current concepts of disease classification. They also provide grounds for optimism that larger studies will reveal more about the origins of these disorders, although currently, very little of the genetic risk of either disorder is explained.

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Twin studies of schizophrenia: From bow-and-arrow concordances to Star Wars Mx and functional genomics

Cited by 780 publications

References 36 publications

Genetic liability to schizophrenia in Oceanic Palau: a search in the affected and maternal generation

Genetic liability to schizophrenia in Oceanic Palau: a search in the affected and maternal generation

Age-related changes in the expression of schizophrenia susceptibility genes in the human prefrontal cortex

Genetics of psychosis; insights from views across the genome

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