Unit 5: Schizophrenia

MOOC Summaries - Introduction to Human Behavioral Genetics - Schizophrenia

Unit 5: Schizophrenia

“What Is Schizophrenia?… The Epidemiology of Schizophrenia… Twin and Adoption Studies… What We Have Learned About Environmental Risk From Twin and Adoption Studies…Identifying Risk Alleles – The Positional Cloning Strategy… Identifying Risk Alleles – The GWAS Strategy – UPDATED… Identifying Risk Alleles – Rare Variants And CNVs – UPDATED… Supplemental – Genetics, Race & Ancestry… ” 
(Source)

Summaries

  • Module A: What Is Schizophrenia?
  • Module B: The Epidemiology of Schizophrenia
  • Module C: Twin and Adoption Studies of Schizophrenia
  • Module D: What We Have Learned About Environmental Risk From Twin and Adoption Studies
  • Module E: Identifying Schizophrenia Risk Alleles - The Positional Cloning Strategy
  • Module F: Identifying Schizophrenia Risk Alleles - The GWAS Strategy - UPDATED
  • Module G: Identifying Schizophrenia Risk Alleles – Rare Variants And CNVs - UPDATED
  • Module H: Supplemental - Genetics, Race & Ancestry

Module A: What Is Schizophrenia?

  • Schizophrenia is a disorder of thought (and not of mood), and has nothing to do with multiple personalities.
    • Positive symptoms (presence of something normally absent) – Thought disorder: illogical thought processes, delusions (false beliefs), paranoia, hallucinations, hear voices and movement disorder;
    • Negative symptoms (disrupted normal responses) – Inappropriate effect  (hard time experiencing pleasure, demotivated) and deterioration of social behaviour, poor hygiene and health;
    • Cognitive symptoms – Working memory, attention etc impaired.
  • It is an important psychiatric phenotype, but not a neurodegenerative disorder.
    • It is one of the leading cause of disability according to the World Health Organization;
    • No cure;
    • Roughly 10% of the people with schizophrenia will commit suicide;
    • Life expectancy shortened by 12-15 years.
    • Majority of individuals with schizophrenia are unemployed, with maybe around 20% being homeless across many Western countries
  • In the past, it was thought that it was caused by the parents communicated their children; behavioral genetics research changed that view.
  • The chance that a randomly selected individual will develop schizophrenia sometime during his or her life is about 1%, with variable age of onset and differences between male and female.
Chop Chop MOOCs’ summary of https://class.coursera.org/behavioralgenetics-002/lecture/view?lecture_id=53

Module B: The Epidemiology of Schizophrenia

  • Epidemiology is the science that studies the distribution of disease in the population.
  • Four features of the distribution of schizophrenia:
    • Sex;
    • Social class/urbanicity;
    • Worldwide distribution/Immigration;
    • Fertility;
  • Examples of studies:
    • Men who develop schizophrenia tend to develop it a little bit earlier than women, they also tend to have more severe forms;
    • The rate of schizophrenia was much higher in the inner city of Chicago, and got progressively less common in to the suburbs (usually wealthier) – but could be correlation not causation, and in effect could be an effect;
    • Seems to be roughly equally distributed across the whole world (WHO study);
    • Individuals who migrate have a higher rate of schizophrenia than individuals who do not (again not clear if it is correlation, cause or effect);
    • Individuals with schizophrenia have reduced fertility but not physically infertile – they reproduce at about 40% of the general population.
  • Puzzle: if it is heritable but has obvious disadvantages, why is it still so common (in fact it has been maintained at about 1% of the population)?
Chop Chop MOOCs’ summary of https://class.coursera.org/behavioralgenetics-002/lecture/view?lecture_id=55

Module C: Twin and Adoption Studies of Schizophrenia

  • Majority of the time, genetically identical teams are discordant for schizophrenia.
  • Where they are concordant, MZ twins concordance is consistently greater than DZ for schizophrenia.
  • Even though it is heritable, the environment is very important; this is corroborated by twins and adoption studies.
  • Risk of developing schizophrenia, that lifetime morbid risk, increases exponentially with your degree of relationship with an individual with schizophrenia e.g. zero degrees are MZ twins (~50%), first degree (~9-10%), second degree (~4-5%), third degree (~2%), and no relation/general public (~1%).
  • These percentages are similar to other non-psychiatric disorders (e.g. bipolar, insulin dependent late onset diabetes);
  • This must be because the contribution comes from multiple genes (and even multiple factors) – compare to autosomal dominant disorder such as Hungtington Disease, which have a more linear relationship with the degrees of relationship.
  • These multiple contribution means that studies on heritability focus a multi-factorial threshold model i.e. whether one has a large number of the factors that are above a certain value, where we try to understand the heritability of the underlying liability (which corroborates with the empirical risk).
  • Schizophrenia appears to be highly heritable and that is characteristic of neurodevelopment disorders such as ADHD, autism, intellectual disability, learning disabilities etc.
Chop Chop MOOCs’ summary of https://class.coursera.org/behavioralgenetics-002/lecture/view?lecture_id=57

Module D: What We Have Learned About Environmental Risk From Twin and Adoption Studies

  • Shared environment (e.g. social class, neighbourhood, way parents raise children) may not be as important for schizophrenia because
    • typically families do not have multiple members suffering from schizophrenia;
    • adoption studies of the offspring of adopted parents with schizophrenia do not show elevated risk of schizophrenia in those offspring;
    • studies of offspring of twins show they are discordant for schizophrenia.
  • Non-share environment important (because if concordance in MZ twins is only 50%, then there has to be factors dues to the non-shared environment).
    • On average individuals who develop schizophrenia have somewhat larger ventricles than individuals who do not (some brain pathology going on?), and large ventricles are associated with:
      • Low birth weight is associated with developing schizophrenia (e.g. in MZ twins, the smaller twin at birth is more likely to do so);
      • Obstetrical complications i.e. prenatal or perinatal deprivation of oxygen, Rh incompatibility, placental disruption etc;
      • Maternal conditions (e.g. severe malnutrition, exposure to influenza etc).
  • Appears that a major reason of these non-shared environment factors happens very early in the child’s development that disrupt the normal course of neurodevelopment; in schizophrenia, there seems to be some lesion in the brain, and the increased ventricle size is a marker of this.
Chop Chop MOOCs’ summary of https://class.coursera.org/behavioralgenetics-002/lecture/view?lecture_id=59

Module E: Identifying Schizophrenia Risk Alleles – The Positional Cloning Strategy

  • Now that the human genome was sequenced, how can genetic variants that underlie disease be found?
  • Positional Cloning strategy:
    • Determine a disease or trait was heritable;
    • Find the chromosomal regions where the risk alleles might be;
    • Identify the variants or mutations.
  • This was proposed because it had worked for Mendelian traits, which scientists had been very successful in mapping (e.g. for cystic fibrosis, Huntington’s disease, PKU etc).
  • Started to use it for more complex diseases but seems to be less successful.
  • Detailed step-by-step explanation as it was used for schizophrenia research – – they did not scan everything but only those genes within regions that are likely candidates.
  • Problem was the results were not statistically significant at a level that was better that chance.
  • Two major potential reasons that positional cloning strategy did not seem to work:
    • They did not pick the right candidates (though unlikely in the schizophrenia case);
    • The sample wasn’t large enough.
Chop Chop MOOCs’ summary of  https://class.coursera.org/behavioralgenetics-002/lecture/view?lecture_id=61

Module F: Identifying Schizophrenia Risk Alleles – The GWAS Strategy – UPDATED

  • Genome-Wide Association Study (GWAS): survey whole genomes for association.
    • Compare: Candidate gene study/Positional cloning strategy targets specific genes.
  • Step-by-step explanation of GWAS, including the use of Manhattan plots.
  • Pattern emerges (for schizophrenia):
    • identified risk alleles are typically quite common;
    • each have very small effects but implicate certain pathways.
    • the risk alleles could account for 5-7% of variance – most of heritability missing as heritability is 50-80%.
  • Missing heritability also observed in BMI, height, total cholesterol etc and could be due to:
    • smaller effects that need even large samples
    • other genetic variants (next Module);
    • other reasons (e.g. GxE)?
Chop Chop MOOCs’ summary of  https://class.coursera.org/behavioralgenetics-002/lecture/view?lecture_id=151

Module G: Identifying Schizophrenia Risk Alleles – Rare Variants And CNVs – UPDATED

  • GWAS can detect risks/variants that are relatively common but will miss out on:
    • Rare variants (frequencies < 1%);
    • Structural variants (e.g. Copy Number Variants – CNVs).
  • Rare variants – schizophrenia frequency increases as a function of the father’s age but not the mother’s age – suggests rare variants are at play.
  • There are also other medical (genetic) and behavioral disorders where paternal age has an effect.
    • Compared to women, men produce more mutations in their gametes with age.
  • Structural variants also linked to schizophrenia risk e.g. velo-cardiofacial syndrome where there is deletion of genetic materials and these are equally like to come from the mother or father.
  • In summary, for schizophrenia:
    • Moderate to strong heritability;
    • Polygenic;
    • GWAS results indicate common variants have small effect;
    • Rare variants have moderate effect;
    • Much of heritability still missing.
Chop Chop MOOCs’ summary of  https://class.coursera.org/behavioralgenetics-002/lecture/view?lecture_id=153

Module H: Supplemental – Genetics, Race & Ancestry

  • Common genetic variants exist in all human populations groups but at different frequencies.
  • For these common genetic variants, the variance largely exists within instead of between populations.
  • Genetic differences largely due to chance and selection for local conditions.
  • Genetic similarity between two individuals is related to the geographic proximity of their ancestors.
  • Genetic differences across population groups are continuous instead of discrete; the former suggests it is better to think in terms of ancestry, and the latter indication the idea of race should be rejected).
  • Ancestral genetic differences matter in rare Mendelian (i.e. single gene) disorders; common diseases – thanks to GWAS studies – also differ across groups; these are however medical genotypes and there are no convincing genetic examples for behavioral phenotypes.
Chop Chop MOOCs’ summary of  https://class.coursera.org/behavioralgenetics-002/lecture/view?lecture_id=155

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