“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… ”
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.
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)?
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.
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.
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);
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;
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.
