Genetics of ASD Flashcards
What is the heritability of ASD?
Has a high heritability - 80%. Sandin et al. (2017) - entire population monitored at different levels of their health, included more than 7 million people. Lots of siblings with different level of relationship (e.g. sibling vs. identical twins) - therefore can look at heritability. Found strong role of genetics.
What are chromosomal (cytogenetic) abnormalities in ASD?
Abnormality can be in the number of chromosomes (aneuploidy), a deletion or duplication of part of a chromosome, or translocation of part of a chromosome to another.
What chromosomal abnormalities are responsible for some syndromic form of autism?
Fragile X syndrome: part of the X chromosome is missing - probably why boys are more affected than girls.
22q13 deletion syndrome: deletions or rearrangements on the q terminal end of chromosome 2.. The SHANK3 gene is often but not always missing in patients with 22q13.3 deletion syndrome. Gene involved in synaptic communication.
What are polymorphisms and mutations in ASD?
No 2 people share exactly the same genome (except MZ twins). DNA sequence variants called polymorphisms or allelic variants. Some polymorphisms may be beneficial or harmful. There are very rare single nucleotide variations that are harmful and called mutations. Mutations in the SHANK3 gene have been implicated in some forms of ASD.
What are copy number variation in ASD?
Between the extremes of chromosomal abnormalities and SNP, copy number variation is an intermediate type of genetic variation. CVS’s are a feature of the normal genome, but there is increasing evidence that they are also genetic risk factors for ASD.
What is the Mendelian model of inheritance of ASD?
Dominant, recessive, or X-linked mutations responsible for syndromic forms of autism, e.g. Fragile X, Rett, MECP2 duplication, Tuberous Sclerosis Complex, PTEN, Macrocephaly, Timothy syndrome.
What is the Non-Mendelian model of inheritance of ASD?
No gene either necessary of sufficient to cause disorder. The ‘genetic architecture’ of ASD is still unclear. Much of the heritability comes from genetic variants that are common in the population. Each genetic variant adds only a small increase to risk in the individual.
What are risk alleles in ASD?
De novo CNVs (not inherited) and SNVs/indels. Rare CNVs (inherited) and SNVs. Common SNPs.
What are De Novo CNVs and SNVs in ASD?
Genes that have shown to be affected:
- CHD8 (encodes enzyme essential during foetal development)
- SYNGAP1 (encodes protein in NMDA receptor-mediated synaptic plasticity and membrane insertion of AMPA receptors)
- DYRK1A (changes functioning of the protein)
- SCN2A (encodes the alpha subunit of the voltage-sodium channel)
What are rare CNVs and SNVs in ASD?
Genes that have been shown to be affected:
- CNTNAP2 (encodes neurexin, protein involved in formation of synapses)
- NHE9 or SLC9A9
- AMT (encodes an enzyme involved in biochemical reactions)
- PEX7 (involved in transport of proteins)
- CC2D1A (encodes transcription factor that represses HTR1A gene transcription in neuronal cells)
- BCKDK (encodes enzyme involve in the degradation of valine, leucine, and isoleucine)
What are mutations in syndromic and non-syndromic autism?
Have something in common - always dealing with synaptic transmission. In many cases, the two overlap on the level of similar type of mechanics - synaptic conductivity/mechanism of proteins and synapses.
What did Gandal et al. 2015 investigate?
Gene expression in the cortex of 700 post-mortem partners with ASD, SCZ, BD, MDD, or AAS compared to brains of 293 matched healthy controls. Looked at the overlap between genetic variation between disorders. Greatest overlap was schizophrenia and bipolar disorder, and then surprisingly, schizophrenia and ASD.
What did Gandal et al. 2015 find?
Difference between autism and schizo is in the places they are expressed. To characterise the biological pathways involved, weighted gene co-expression network analysis was performed. Several shared and disorder specific co-expression modules were identified. Genes are called ‘hub’ genes, because they co-express with other gene within the module. To do with many things, including stress responses and microglia. Genes linked to neuronal firing were down-regulated in ASD, and to a lesser extent in SCZ and BD. An astrocyte-related module was up-regulated in ASD and to a less extent in BD and SCZ. This suggests that changes in brain cell communication play a role in all three conditions.
What do the modules that Gandal et al. 2015 outlined represent?
Module CD11 related to microglial markers was up-regulated specifically in ASD, suggesting that microglia play a critical role regulating synaptic function during neurodevelopment. Module CD2 upregulation in MDD suggests a link between inflammation and dysregulation of the hypothalamic-pituitary (HPA) axis, which is consistent with current models of MDD pathophysiology
What are differences between schizophrenia and autism?
In ASD synaptic abnormalities have been reported, but GWAS show no hint of association in the MHC locus, suggesting that ASD synaptic pruning defects are likely not caused by the C4 locus. C4 not involved in the genesis of autism. Most probably, the abnormalities of synaptic pruning in ASD are linked to up-regulation of microglia
