2 Neuroscience2.9 Genetics
2.9.5 Molecular and genetic heterogeneity, phenotype genotype correspondence, endophenotypes and biotypes
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Written by Resident Doctor Committee · Published
Genotype and phenotype
Genotype-phenotype correspondence describes how reliably genes predict traits. It is loose in psychiatry: one variant can give different outcomes, and one diagnosis can have different causes.
Common disorders involve many variants of small effect, so polygenic scores predict little for an individual.
Forms of heterogeneity
Form | Meaning | Example |
|---|---|---|
Allelic | Different mutations within one gene give one disorder | Nonsense, missense or frameshift variants in one gene |
Locus | Mutations at different loci (different genes) give one phenotype | Familial early-onset Alzheimer's disease from APP, PSEN1 or PSEN2 |
Molecular | Different molecular mechanisms converge on one clinical picture | Copy number change or polygenic liability causing intellectual disability with psychosis |
Phenotypic | One variant gives a range of outcomes | 22q11.2 deletion causing developmental, psychiatric or physical problems |
Copy number variants in schizophrenia
People with schizophrenia carry an excess of rare, gene-disrupting copy number variants compared with controls.
These variants are often de novo and cluster in synaptic signalling genes. They also raise the risk of developmental delay, autism and epilepsy.
Endophenotypes and biotypes
An endophenotype is a measurable, heritable liability trait that is relatively independent of acute illness and detectable in unaffected relatives.
Candidate endophenotypes include working memory, P300, mismatch negativity, prepulse inhibition and smooth pursuit eye tracking.
Biotypes group people across diagnoses by biological profile, using cognition, physiology, imaging or molecular data.
An endophenotype needs evidence of inherited liability, whereas a biotype is derived from measurements alone.