Refrigerator mothers and beyond

The aetiology of autism

Genetics

Genetics of autism

• Large number of chromosome abnormalities associated with autism, familial clustering of autism is well above the normal population prevalence, twin-based studies• Hereditability around 90% (Schizophrenia and major depression around 40-

50%• Not simple genetic transmission Autisms rather than autism• Evidence from twin studies suggest an MZ to DZ concordance rate of 60%• The rate amongst siblings of an autistic proband is ~3%

• Genome: 6 billion bits of information from father and mother. We have 99% similarity with only 1% difference• Only a small section codes for genes, the other ‘dark matter’ relating to how

genes are expressed into proteins• Suggested that there may be up to 1,000 genes involved in autism. Genes act

in an additive way (synergistic) along with the environment to produce the final phenotype

Evolution

• Twin studies have suggested that autism has high heritability. This occurs in the context of environmental risks and gene-environment interplay.

• Autistic traits could have been subject to positive selection pressure, because the benefits of a solitary single-minded obsessive focus

• Such individuals might have successfully traded products or their building and fixing skills. Thus acquiring resources and increasing their reproductive fitness, which could have maintained autism alleles in the gene pool

Studying the genetics of autism

• ‘Guided missiles’ represent experiments where there is a clear hypothesis about the role of a particular region of the chromosome or specific candidate genes

• ‘Carpet bombs’ represent studies whereby the whole genome is looked at all at once, looking for genes/chromosomal regions that are associated with ASD. These are ‘genome-wide’ linkage or association studie

ExamplesChromosome Genes Function

2 HOX Early growth and development

7 AUTS1MET

Speech and languageImmune function, cerebellar growth

5 CDH9,10 Proteins

15 Genetic errors cause Angelman and Prader-Willi syndromes

17 GABA pathways genes Serotonin transport

How might genetic variation occur?

Issue % of people with ASD Notes

Locus heterogeneity Up to 1,000 genes implicated

Rare mutations 5% Minor allele frequency

Chromosomal abnormalities

5%

Rare copy variations 10%

De novo mutations Eg deletion, duplication, nonsense codes that occur in germline (especially paternal) and could be causal in simplex cases

FamiliesCause of ASD Points

Might be due to ‘de novo’ changes in DNA sequence (eg rare sequence variant or a copy number variant)

Simplex family Multiplex family

Only 1 member of extended family has a diagnosis of ASD

More than one member of extended family has a diagnosis, or several members have very high levels of autistic traits

Might be due to ‘de novo’ changes in DNA sequence (eg rare sequence variant or a copy number variant)

Might never have a formal diagnosis

One off-change during formation of gametesCan account for nearly 10% of all people diagnosed with ASD

Specific genetic variations passed down through generations

Theme: Neural development

Role of genes in neural growth, patterning and formation of synapses

Altered calcium signalling amongst mechanisms through which genes manifest themselves

Neuroimaging shows altered connectivity and atypical wiring

This class of genes are involved in developing atypical patterns of neural connectivity

Theme: Social behaviour

Genes influence social behaviour in animals eg oxytocin-vasopressin system and maternal behaviour in rodents

Oxytocin administration in humans results in increased trust among strangers in lab

Atypicalities of social behaviour in ASD

Oxytocin receptor gene, OXTR, is one of the few candidate genes associated with ASD

Theme: Exposure to testosterone

Exposure to prenatal testosterone is related to the development of autistic traits in general population

Primary clue has been that ASD is associated with a strong sex difference, affecting nearly seven times as many males to females

Recent studies found evidence that genes related to sex hormone function are associated with ASD and/or autistic traits in the general population