genetics of psychosis lecture 5 severe mental health

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  • Created by: Cruick96
  • Created on: 08-12-17 15:00
who carried out the 1st studies of SZ and what happened with them?
Ernst Rudin - served w/ Heinrich Himmler on a committee which in 1933 drafted legislation enabling the compulsory sterilisation of psychiatric patients
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what did Kallman do?
student of Rudin. advocated the sterilisation of not only mentally ill people but their relatives too. forced to move from Germany to US as was half Jewish
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what were Kallmans family history studies?
in 1938 reported family histories of 1000+ SZ patients, examining hospital records of those admitted to Berlin state mental hospital from 1893-1902. traced relatives of those still alive (23%) and assessed mental state - concluded high rate of SZ
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what were Kallman's 1946 twin studies?
in New York, attempted to track down relatives of all twins diagnosed w/ SZ (691 pairs & 3394 relatives) - reported pairwise concordance rates of 86% for MZ twins and 15 for DZ twins
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what did Kallman determine?
zygosity (visual assessment) & diagnosis. suspected untreated co-twins included as suffering from SZ, raising raw concordance rates from 59% to 69% in MZ, 9 to 10% in DZ
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what is Mendellian inheritance?
certain traits controlled by single, discrete, hereditary determinant (gene). they can exist in alternative forms (alleles). each indiv has 2 copies of each gene in each cell. sex cells each contain only 1 memver of each gene pair. alles halve
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what is known about expressivity and penetrence?
because of either the additional effects of other genes or environmental factors, not every person who inherits a gene shows the resulting trait to the same degree
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what is heritability?
defined as proportion of shared phenotypic variation attributable to genes - variance with genes/variance with genes + variance with environment
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what is falconer's method?
simplest method for finding heritability. heritability = difference in correlation between MZ and DZ twins
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what did Turkheimer find in his twin study?
60% of variance in IQ in impoverished environment is attributable to shared environmental effects w/ close to 0 genetic effects. reverse was true in middle class families - shows if variance in environment is low, heritability is high (problem)
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what are some issues of heritability?
fails to take in to account complex gene-environment interactions (if gene causes someone to crave cigs, may be mistaken for gene for lung cancer). even heritability estimates don't exclude very large environmental affects
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what is the molecular basis of genes?
sequence nucleotides: Adenine, Guananine, Cytosine & Thymine on DNA (controls manufacture of proteins)
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what does the molecular basis of genes say about heritability?
genes can't cause mental illness - can't precisely determine development of specific neural pathways - 30,000 genes in human genome, 100 trillion synapses in brain
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what are epigenetic effects?
environment affects whether genes are switched on or off in different parts of body through process called methylation which leads to epigenetic effects
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what is the logic of family studies?
indivs who are closely related should most likely share a genetic trait. 1st degree relatives (sibs, parents, children) share 50% of genes. second degree (grandma, cousins etc) share 25%
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what were nicol and gottsman's findings from their family studies of SZ?
risk of developing it - 48% MZ twins, 46% offspring (way too high), 6% parents, 17% DZ and siblings,
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what are the methodological problems with twin studies?
issue w/ determination of zygosity is often by questionnaires. only reliable method is DNA. determination of diagnosis - must be blind to zygosity
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what is pairwise concordance?
50% - in half of pairs, both twins affected. more commonsensical and gives lower rates
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what is probandwise concordance?
15 affected twins in total, 10 of these have twins w/ SZ - preferred by statisticians
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what is the Weinberg method?
some patients in high risk periods may not have had opportunity to become ill - double observed concordance rate for these people
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what was Joseph's twin study data in 2003?
compiled pairwise conc for MZ & DZ from 15 studies of SZ. pooling data from studies, rate for MZ = 40.4%, DZ 7.4%. earlier studies subject to greatest methodological flaws gave much higher rates than more recent careful ones
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what would be the result if only 9 of the most recent carefully planned out studies were included in Joseph's data?
pairwise conc would be 22.4% for MZ, 4% for DZ
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what is the logic behind adoption studies?
to overcome limitations of twin studies. conclusive proof for inheritance of SZ?
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what was Hestons adoption study?
47 children of SZ parents placed for adoption at < 1 month of age w/ 50 control adoptees. 5 probands vs 0 controls diagnosed w/ SZ. 37 probands compared w/ 9 controls had psych diagnosis
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what was kety et al's study?
began w/ SZ and normal adoptees and traced bio relatives. 34 index cases identifies vs 34 matched controls. 150 bio and 156 adoptive relatives traced. 1 SZ traced in each group. introduced SZ spectrum concept - 8.7% bio, 1.9% controls
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what did rose et al find?
reviewed kety et al - researchers had interviewed dead relatives
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what was rosenthal's study?
began w/ SZ % healthy p's who had given up children for adoption. only 1 adoptee hospitalised for SZ. follow up after 10 years found no evidence of increased spectrum cases in adopted away children of SZ parents
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what was tianari et al's adoption study?
identified 19,447 women admitted to hospital for SZ in 1970, then 289 adopted away offspring, 196 adopted before 5 years. control adoptees matched using tight controls. adoptive fams studied for 2 days. 10 index offspring had psychosis, 1 control.
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what else was found in tianari et als adoption study?
126 matched pairs found strong interaction between disturbance & dysfunctional family environment
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what did Wahlberg find?
reviewed tianaris - reported more detailed analyses of these data, finding interaction between communication disturbance in the adopting family environment and thought disorder in genetically at risk children
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what are genome wide association studies?
theory free hunting for alleles associated w/ mental illness using case control design but large number of genes creating risk of type 1 error (false pos). very strict p requirement - means studies will be unlikely to detect true effects unless large
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what did the international SZ consortium do?
relaxed stat rules to identify rules w/ modest associations w/ SZ & created sum scores for polygenic assoc. accounted for about 30% of variance in liability to SZ & similar to bipolar.
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what did the psych genonomics consortium find?
more recent studies link SZ genes to bipolar, depression, autism & intellectual disabilities
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how does heritibality differ in GWAS studies?
always comes out lower than hertiability calculared from more classical methods
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what are copy number variants?
in addition to variations in sequence (SNP's), indivs have variation in genomic structure.CNV's involving loss/gain of up to severalM base pairs of DNA sequence estimated to constitue upwards of 5% of human genome
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what do CNV's show in general?
higher penetrance (more severe phenotype) than duplications and larger CNV's often have higher penetrance and/or more clinical feaures of smaller ones
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how are CNV's inherited?
mutations during meiosis. rare ones assoc. w/ SZ, autism and severe intellectual impairment
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what is deletion syndrome? (diGeorge, velo-cardio-facial-syndrome)
caused by deletion of small piece of chromosome 22. prevalence = 1:4000. symptoms highly variable- congenital heart disease, defects in palate, learning difficulties, mild differences in facial features, recurrent infections
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what did murphy et al find about deletion syndrome?
15/50 ps w/ VCFS were psychotic, 12 meeting criteria for DSM SZ. 6 met criteria for MDD w/o psychotic features
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what did bassett conclude about gwas studies?
on basis of then published gwas studies, these deletions were only present in 0.9-1% of SZ cases - suggested this may be an underestimate
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student of Rudin. advocated the sterilisation of not only mentally ill people but their relatives too. forced to move from Germany to US as was half Jewish

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what were Kallmans family history studies?

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