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Genetics of Mental Disorders (Schizophrenia (Schizophrenia and C4 variants…
Genetics of Mental Disorders
Chromosomes
Chromosomes are lengths of doublestranded DNA
DNA bases are complementary between strands (meaning that A always lyies on the other side of T and G always lays on the otheside of C A&T and G&C are complementary)
4 parts of GNA base..: ATGC
Genetic code is the sequence of these bases
Humans have 23 pairs of chromosomes, including XX or
XY
One member of each pair is inherited from each parent
Meiosis
crossover formation
Members of homologous pairs exchange segments
Gamete formation
One daughter chromosome ends up in each gamete egg or sperm cell
a single strand is them passed on
Genes
Genes are stretches of DNA which provide the code from which proteins are made
.Proteins being very important, basically responsible for everything
Protein production involves
Transcription
Splicing
Translation
Gene function - transcription
DNA acts as a template to build a complementary strand of messenger RNA process called transcription
.only difference is that messenger RNA has “u” instead of “t”
Gene function – splicing
Segments of mRNA corresponding to introns are removed
. introns since not used, are removed
Gene function - translation
mRNA is translated, three bases at a time, into amino acids forming a polypeptide
. three based (called codons) form an amino acid (64 different ways to make codons, however only 23 different amino acid, therefore sometimes more than one codon can code for the same amino acitd)
Gene function – assembly
Several polypeptide subunits may be combined to form the complete protein
Also further post-processing, disulphide bonds, etc.
Gene structure
Coding regions are called exons (coding for proteins)
Non-coding introns may lie between exons
Control regions affect gene expression
(e.g. if something binds to it they can be turned on or off)
Genetic polymorphism
. every human being has a genetic code that is nearly identical to any other human being
Variations occur in genetic sequence between individuals
Variation may influence susceptibility to a disease – effects on development and/or functioning
Known variants may be used as genetic markers in mapping studies
Copy number variants (CNVs)
Copy number variation is one particular kind of gene variation between individuals
Two chromosomes (one from each parent), having the same information about the same genes
Usually two copies of each sequence – one on each of homologous pair
.
Can have deletions (meaning that then there is only one part/copy of the chromosome region instea of two)
.
Or duplications
Types of variation
Chromosomal rearrangement (bigg differences in chromosomal arrangements, deletions..)
CNV
Indel (really small deletions or insertions)
Point mutation – nonsense, frameshift, missense, splice, intronic, 3’ UTR, etc (variations in the codons)
Others, e.g. repeat sequence expansions
DNA variance in one subject
Each individual has so 3000millionen basess making up 20 thousand genes (which however only occupie around 1% of the bases/the DNA – which are coding for proteins, the rest 99% is not codign for protein)
10 thousand variations will each individual have (so an awful lot, that affect how the 20thousand geans work, and the proteins) – 2 thousand that are really rare and where the effects are not known
Genetic effects on risk
Dominant – one copy of gene affected, may be de novo (can happen when e.g. the mothers chromosome pair is rearranged into one new one for the egg)
Recessive – both copies affected (from mother and father), homozygote (where both copies of the gene have the same variant) or compound heterozygote (where both copies of the gene have a variant .. but that variant is not identical)
X-linked recessive (when there is a variant on the x-chromosome … it is always problematic, since there is only one of those (only in males))
Oligogenic/polygenic contribution (not only one variation on one gene, but many variations on many genes contributing to e.g. hight)
Evidence for genetic contribution to risk
Twin studies
Adoption studies
Replicated association of variants with disease (if genetic markers, the variance within it is over and over again associated/correlated with the disease)
Schizophrenia
High heritability
Lifetime risk of schizophrenia 1%
Identical twin concordance 50%
Risk to first degree relative 10%
Life expectancy reduced by 20 years
Societal costs in England for 2012:
£12B ($15B) (NHS budget £96B)
Schizophrenia – types of genetic risk factor
SNPs (single nucleotide polymorphisms) from GWAS (genome-wide association study) “normal”/”common” variances
CNVs (copy number variants) really rare 8duplications and delitions)
Rare sequence variants
Schizophrenia GWAS
150000 subjects (37000 cases of schizophrenia)
108 regions significant with small odds ratios (consistent hit around HLA region)
“Polygenic” effect claimed – 1000’s of
SNPs with very small OR – 1.01 (loads of other reagions that combined are also statistically significant)
Overlap of these SNPs with other diagnoses (could show a more general risk factor, not just for schizophrenia)
Schizophrenia CNVs
. much rarer .. but really significant effects on risk
C22 deletion in VCFS (around 30% risk of schizophrenia)
16p11.2 duplications
2p16.3 deletions affecting NRXN1 (one particular gene)
15q11.2 deletions
Most of these CNVs take out more than one gene.. therefore it is really hard to establish which one of those was important
Schizophrenia exome sequence study – 2016
Ggenoves et al.
12332 Swedish cases and controls
.looked at all bases that make up the exomes
Excess of “ultra-rare” (unique) variants
Concentration of genes expressed in synapses (more variance found here)
But still none individually significant
(hundrets of genes that are expressed in synapses.. that have variance, so can t say which one is important for schizophrenia)
Schizophrenia and C4 variants
C4 codes for complement component 4 (variation was found in the gene that codes for complement component 4)
In HLA region, where GWAS signal strongest
Sequencing reveals variants: C4A or C4B, long or short, different copy numbers
GWAS SNPs tag variants
Imputed variants predict C4A expression and associated with schizophrenia at p<10-20
.Found that C4A protein expression was heightened (more proteins being produced)
C4 present on dendrites, axons, at synapses
Schizophrenia patients have decreased synapse numbers
Mice lacking C4 appear to have reduced synaptic pruning
.Suggestion that glia cells might destroy synapses more in response to more C4, therefore people with schizophrenia might have more synaptic pruning and not good working synapses
Schizophrenia and SETD1A LoF variants
Exome sequence data for: 4,264 cases,
9,343 controls and 1,077 trios
10 loss of function mutations in SETD1A associated with SZ, p=3.3x10-9
SETD1A codes for a methyl transferase for histone H3 (.study found basically no individuals with the mutations that SETD1A was missing that did not have schizophrenia or an interlectual disability)
Mutations in related genes cause e.g. Wiedemann-Steiner syndrome, Kleefstra syndrome and Kabuki syndrome
Alcoholism
Evidence for genetic effect from twin and adoption studies
Linkage and association studies in progress
Genes: ALDH2, ADH1B
Acetaldehyde dehydrogenase mutation (when no acetaldehyde dehydrogenase happenes (when the alcohol is not broken down) than very unpleasant reaction – no drinking – is how some drugs work)
.
Alcohol dehydrogenase mutation (increases the function oft he enzime – also leading to flushing since the other enzyme is overworked, also causing you to not drink)
Not a direct gene variation, but a variation in metabolization
Other mental illnesses
Bipolar disorder is highly familial and there may well be specific genetic risk factors
Depression has some genetic component to risk
GWAS findings are emerging and other research is on-going for these and other diagnoses
Alzheimer's disease
Early onset – rare, Mendelian dominant (very genetic risk)
Late onset – common, moderately familial
Down’s syndrome – in middle age
All: amyloid plaques and neurofibrillary tangles
Early onset Alzheimer’s
.Varyance in three different genes:
APP (.amoloid precursive protein)
Presenilin 1
Presenilin 2
. presenilines metabolise APP
Late onset Alzheimer’s
Association studies of APOE (.the e4 of it rist for in altzheimers (three fold increase effect)
Alzheimer’s disease
Abnormal APP can form amyloid
APOE4 may interact with APP to encourage amyloid formation
Alzheimer’s disease
SORL1 – sortilin related receptor
CLU – clusterin
PICALM – clastrin assembly protein
CR1 – complement component receptor 1
BIN1 – bridging integrator 1
Can create mice models from this knowledge
Intellectual Disabilities
40% unknown aetiology
1.3-1.7:1 male excess (could relate tot he x chromosome)
Down syndrome – trisomy 21 (extra copy of chromosome 21)
Many microdeletion syndromes (little bit of a chromosome missing, very likely to have an effect on the brain)
Single gene disorders:
neurodegenerative, syndromic, nonsyndromic (only feture being inteletural disability – nonsyndromic)
Fragile X syndrome
Fragile X syndrome
Commonest specific cause of LD –
1/4000 males
CGG repeat expansion disrupts FMR1 (many more coppies of this „CGG“ sequence in chromosome)
Premutation causes only mild problems
Number of repeats can increase between generations (and only develop fragile x synfrome in e.g. the grandchildren)
.
CGG repeats increase as passed through generations
Bit at the bottom which does not “fit” with the X, is caused by the repeated CGG… which prevented the chromosome from condensing properly
Phenylketonuria
Autosomal recessive
1/10-15,000 births
Mutations in PAH coding for phenylalanine hydroxylase (if you don’t have any PAH then you have phenylalanine in your blood, which damages the brain – creating an interlectual diability over time)
500 mutations identified (therefore a biochemical test (from a blood sample) is done instead of investigating the genetic code)
Brain damage unless low phenylalanine diet
Screening with HPLC or Guthrie test (in new born babies – prevented through specific diet)
Autism
Strongly genetic with high concordance in monozygotic twins
De novo mutations contribute (meaning that the parents dont have it, but that something goes wrong in the gene copying)
Rarely due to mutations in neuroligins or MECP2
16p11.2 deletion and other CNVs
Synaptic, transcriptional and chromatin genes implicated
In practice
Clinical genetic testing services are nationally commissioned
ID, dysmorphism, etc. accepted indication for testing
Role of psychiatrist to recruit and liaise with patient and family
Can refer to clinical genetics services for testing and counselling