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Scientific Foundations > Neurogenetics > Flashcards

Neurogenetics Flashcards

1
Q

What is DNA made up of and what are the three main componenets?

A

Repeating nucleotide units made up of:
▪️ Phosphate group
▪️ Sugar
▪️ Nitrogenous base (ATGC)

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2
Q

How identical is the genetic code between people?

A

99.9%

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3
Q

What is genetic variation?

A

Differences in our DNA sequence

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4
Q

What are SNPs?

A

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

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5
Q

When are SNPs typically benign?

A

▪️ 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

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6
Q

What are Mendelian diseases?

A

▪️ 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)

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7
Q

What are the main examples of Mendelian diseases in neuropsychiatry?

A

▪️ Huntington’s disease
▪️ Familial Alzheimer’s disease
▪️ Motor Neurones Disease/FTD
▪️ Fragile X syndrome
▪️ Tuberous Sclerosis
▪️ Spinocerebellar ataxia

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8
Q

What are the majority of psychiatric and behavioural disorders?

A

Complex diseases

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9
Q

What are complex diseases?

A

▪️ 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

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10
Q

How do Mendelian forms of a disease typically differ from their complex counterparts?

A

Generally more severe and earlier onset of symptoms (e.g., Alzheimer’s)

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11
Q

What are the main types of large chromosome-level changes to DNA?

A

▪️ Deletion (e.g., 22q11.2 = VCFS, increased risk of SCZ and autism)
▪️ Duplication (e.g., trisomy 21 = DS, double APP = EOAD)
▪️ Rearrangement

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12
Q

What are the main types of smaller genetic mutations?

A

▪️ Deletion (e.g., PSEN1 and AD)
▪️ Duplications (e.g., CAG expansion in HD)
▪️ SNP substitutions (e.g., PSEN1 and AD)

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13
Q

How might a SNP substitution cause disease?

A

▪️ Changes coding of protein (missense mutation)
▪️ Changes processing of mRNA which changes protein
▪️ Changes regulation of gene expression

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14
Q

How many missense mutations in PSEN1 can cause AD?

A

~93

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15
Q

What is a dominant disease?

A

▪️ Only needs ONE mutant allele to get the disease
▪️ 50% chance of passing disease on
▪️ Never “skips” a generation

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16
Q

What is a recessive disease?

A

▪️ Needs TWO mutant alleles to get the disease
▪️ 25% chance of passing disease on
▪️ 50% will be carriers (one mutant allele) - asymptomatic

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17
Q

How common are SNPs?

A

▪️ Very!
▪️ ~10 million in human genome
▪️ Once every 300 nucleotides

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18
Q

What is the Hardy Weinberg equation for SNP frequency?

A

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

19
Q

What is heritability?

A

The proportion of phenotypic variance attributable to additive genetic factors

2(rmz - rdz)

20
Q

What is an MAF?

A

Minor Allele Frequency

21
Q

What is a GRR?

A

Genotype Relative Risk

22
Q

What are the main types of heritability?

A

▪️ 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)

23
Q

What factors contribute to genetic risk in a population?

A

▪️ Number of risk alleles
▪️ Frequency of each risk allele (major or minor)
▪️ Effect size of risk allele
▪️ Interaction between alleles (additive or multiplicative)

24
Q

Why are diseases such as SCZ, influenced by multiple genes, not diagnosed as continuous traits?

A

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)

25
Q

How can we identify rare alleles that cause Mendelian disease (high effects)?

A

▪️ Linkage analysis
▪️ Candidate gene analysis

26
Q

What can linkage analysis be used for?

A

▪️ Identifying genes for monogenic diseases
▪️ Identifying large genomic regions containing susceptibility genes

27
Q

How does linkage analysis work?

A

▪️ SNPs throughout genome as markers to tag the genotypes of those with and without disease within a family
▪️ If tag genotype is physically close to the disease SNP, it will always be inherited by those with disease
▪️ Relies on recombination between chromosomes and alleles being inherited together

28
Q

What are linked alleles?

A

Alleles that are inherited together more than 50% of the time (more than chance/expected)

(Often syntenic genes - on the same chromosome)

29
Q

What are the main problems with linkage analysis?

A

▪️ Relies on large pedigrees from one family, especially to find very rare, low GRR genes
▪️ Smaller pedigrees may be heterogeneous (different genetic causes)
▪️ Incomplete penetrance?
▪️ Complex inheritance patterns
▪️ Marker linked with disease usually still along way away so may not find faulty gene

30
Q

What can be used now to solve the problems with linkage analysis?

A

Genome Wide Association Studies

(can measure more precisely too)

31
Q

What is a GWAS?

A

A technique that compares differences in the frequencies of specific alleles between diseased individuals and healthy controls from the population

Can be:
▪️ Case controlled
▪️ Family based
▪️ Quantitative trait study

32
Q

Associated alleles can….

A

▪️ Directly influence risk
▪️ Be in linkage disequilibrium with the disease-causing allele (detecting susceptibility polymorphisms by proxy)

33
Q

What is imputation?

A

Using statistics to calculate genotypes at “all” loci, filling in the gaps of SNPs that aren’t actually measures

34
Q

What are the main limitations of GWAS?

A

▪️ Not good for rare variants (<5%)
▪️ Multiple testing with large number of SNPs can identify more than is significant (FP)
▪️ Advances in power means previously significant variants may not be anymore
▪️ Problems with diagnosis (e.g., pleiotropy)

35
Q

What is pleiotropy?

A

One gene causes different phenotypes (e.g., TREM2 in AD)

(Equally one phenotypes may be caused by different combinations of genes)

36
Q

What are the main benefits of GWAS?

A

▪️ Very large studies - detect small effect size variants
▪️ Compare populations
▪️ Inform molecular pathways underlying disease
▪️ Focus for treatment?

37
Q

What does a negative OR suggest about a variant?

A

It is protective for disease

38
Q

How do we report the effect size of an associated SNP?

A

▪️ Odds ratio
▪️ Forest plot

39
Q

Why might the frequency of alleles vary across populations (ethnicities)?

A

▪️ Depending on when they arose in evolutionary history
▪️ Maintenance and representation in populations through time

40
Q

What techniques can we used to identify variants with small effect sizes?

A

▪️ GWAS
▪️ Sequencing analysis

41
Q

What techniques can we use to identify rare variants with small effect sizes?

A

▪️ Sequencing analysis
▪️ Possibly GWAS imputation if large enough sample size

42
Q

What are the two main methods of sequencing analysis?

A

Next Generation Sequencing:
▪️ Whole exome sequencing (only the genome for the coding sequence)
▪️ Whole genome sequencing (both coding and non-coding)

43
Q

What are the main issues with next generation sequencing?

A

▪️ Enormous multiple testing issue (millions of SNPs)
▪️ Complex data analysis

BUT very good for rare variants with small ES

44
Q

How can we improve the number of identified risk genes, filling in the “missing” heritability?

A

▪️ Improve power of studies (larger sample sizes to detect small effects)
▪️ More genetic markers (currently looking at proxy SNPs but we need to find direct association with causative variants)
▪️ Better phenotyping of psychiatric disorders (endophenotypes?)
▪️ Identify other types of common genetic variants (not just SNPs!)

Scientific Foundations (27 decks)

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