Neurogenetics Flashcards
What is DNA made up of and what are the three main componenets?
Repeating nucleotide units made up of:
▪️ Phosphate group
▪️ Sugar
▪️ Nitrogenous base (ATGC)
How identical is the genetic code between people?
99.9%
What is genetic variation?
Differences in our DNA sequence
What are SNPs?
Single nucleotide polymorphisms - the most common type of variation that can lead to differences in DNA sequence (typically not deleterious/mutation)
E.g., a G swapped for a T
When are SNPs typically benign?
▪️ Between genes (non-coding areas)
▪️ Within genes but don’t change protein coding regions
▪️ Within genes and change protein sequence, but small effect and possibly advantageous to protein function
What are Mendelian diseases?
▪️ Direct relationship between gene and disease
▪️ Single gene disorder - change in DNA/gene will definitely lead to disease
▪️ Recognisable heritable patterns
▪️ Much less common (but much more significant effect)
What are the main examples of Mendelian diseases in neuropsychiatry?
▪️ Huntington’s disease
▪️ Familial Alzheimer’s disease
▪️ Motor Neurones Disease/FTD
▪️ Fragile X syndrome
▪️ Tuberous Sclerosis
▪️ Spinocerebellar ataxia
What are the majority of psychiatric and behavioural disorders?
Complex diseases
What are complex diseases?
▪️ Gene = increased risk but does not cause disease directly
▪️ May observe familial pattern but less clear
▪️ Disease is due to interaction between multiple genes or genes + environment
How do Mendelian forms of a disease typically differ from their complex counterparts?
Generally more severe and earlier onset of symptoms (e.g., Alzheimer’s)
What are the main types of large chromosome-level changes to DNA?
▪️ Deletion (e.g., 22q11.2 = VCFS, increased risk of SCZ and autism)
▪️ Duplication (e.g., trisomy 21 = DS, double APP = EOAD)
▪️ Rearrangement
What are the main types of smaller genetic mutations?
▪️ Deletion (e.g., PSEN1 and AD)
▪️ Duplications (e.g., CAG expansion in HD)
▪️ SNP substitutions (e.g., PSEN1 and AD)
How might a SNP substitution cause disease?
▪️ Changes coding of protein (missense mutation)
▪️ Changes processing of mRNA which changes protein
▪️ Changes regulation of gene expression
How many missense mutations in PSEN1 can cause AD?
~93
What is a dominant disease?
▪️ Only needs ONE mutant allele to get the disease
▪️ 50% chance of passing disease on
▪️ Never “skips” a generation
What is a recessive disease?
▪️ Needs TWO mutant alleles to get the disease
▪️ 25% chance of passing disease on
▪️ 50% will be carriers (one mutant allele) - asymptomatic
How common are SNPs?
▪️ Very!
▪️ ~10 million in human genome
▪️ Once every 300 nucleotides
What is the Hardy Weinberg equation for SNP frequency?
p2 + 2pq + q2 = 1
p = frequency of “A” allele
q = frequency of “a” allele
p2 = probability of homozygous AA
2pq = probability of heterozygous Aa
q2 = probability of homozygous aa
What is heritability?
The proportion of phenotypic variance attributable to additive genetic factors
2(rmz - rdz)
What is an MAF?
Minor Allele Frequency
What is a GRR?
Genotype Relative Risk
What are the main types of heritability?
▪️ Rare high risk mutations with clear impact (few highly penetrant genes)
▪️ Common low-risk genetic variants (MAF >2%, GRR = 1-2)
▪️ Rare moderate-risk genetic variants (MAF <2%, GRR = 2-50)
▪️ Rare low-risk genetic (MAF <2%, GRR = 1-2)
What factors contribute to genetic risk in a population?
▪️ Number of risk alleles
▪️ Frequency of each risk allele (major or minor)
▪️ Effect size of risk allele
▪️ Interaction between alleles (additive or multiplicative)
Why are diseases such as SCZ, influenced by multiple genes, not diagnosed as continuous traits?
Liability threshold model - certain threshold must be exceeded before disease occurs/is recognised
E.g., relatives have shifted distribution of trait reflecting increased liability (move distribution curve to the right)
