Topic 10: giant case study Flashcards
why is height a complex trait?
includes many bioligcal and environmental factors
what are the biological factors of height?
- pathogenesis often involves several tissues (pituitary, liver, bones, growth plate)
- signalling pathways have many members (thyroid hormone, growth hormone)
- effects of genetic changes may be buffered (growth potential, catch-up growth)
what are the environemntal factors of height?
- many influences (infections, protein malnutrition, socio-economic factors)
- exposure often hard to measure (many are not even known)
- effect of exposure differs with age (infant v. adolescent v. adult)
how does the heratibility of height differ between infants and adolescents?
infant: 0.2-0.5
adolescent: 0.7-0.9
how is growth assessed in clinic?
using growth charts that take into accoutn the height of the mother and the father to get an estimate of what the child’s height should be, with the middle line being the 50th percentile and going from 97th to 3rd percentile which would still tehcnically be considered normal, as long as the child stays within the same line throughout development
what is catch-up growth?
when a child has some sort of abnormaility with its growth but then you change something/fix something and the child then quickly goes back to its normal growth trajectory
protein malnutrion leads to ______
irreversibel growth retardation, where you can never “take back those inches” even if they go back to eating properly
what does improper body proportions in child with stunted growth hint at?
problem with thyroid (hypothyroidism leading to goider)
what are the broad classifications of bone/growth disorders?
- epiphyseal abnormility (small secondary epiphyseal)
- metaphyseal abnormality ( unequal metaphysis edge)
- diaphyseal abnormaity ( bigger diaphysis)
- spnodylo-abnormalitiy (smaller vertabrae)
what key features can be seen on a hand and leg x-ray of a person with achondroplasia?
- small hand (generally looks like that of a 8 yr old)
- immature epipheaseal plate at the wrist
- in leg, no clear seperation bwn epiphysis and growth plate
how are the body proportions in a person with achondroplasia?
in legs specifically
shorter thigh than leg
what is the genetic cause of achondroplasia?
mutation of FGFR3, leading to a gain of function in the growth plates (constitutive activation)
what symptoms are seen in a person with achondroplasia?
- obesity, sleep apnea, recurrent ear infections
- spinal curvature, bowed legs, arthritis
- narrowing of lower spinal canal (spinal stenosis)
can achondroplasia be inherited?
80% de novo, 20% inherited
what does FGF3R do?
and what happen when it is mutated?
it is a receptor tyrosine kinase that leads to activation of the MAPK pathway, leading to chondrocyte differentitation, and activation of STAT, leading to inhibition if chorndrocyte proliferation
what is the most common mutation in FGF3R?
Gly380Arg (in TM domain)
what does Vosoritide do?
it is a c-type natriuretic peptide that inhibits FGFR3 downstream of signalling (at level of Raf1), stimulating chorndrocyte proliferation and differentiation.
for achondroplasia
what vosoritide showed to work in its clinical trial?
yes, and when they saw such a big difference between placebo and therapy, they began giving the therapy to the placebo group where they saw big improvment like seen in the other group.
what is the genetic cause of Morqio A syndrome?
N-acetylgalactosamine 6-sulfatase (AR) (GALNS)
what can be seen in x-rays of a person with Moroqio A syndrome?
- fish-shaped and light/weak spin
- in hand, disorganized epiphyseal plates at bottom of hands and no wrost bones/no epiphysis
what does GALNS do?
removes sulfate from keratan sulfate, where deficiency leads to accumulation of keratan sulfate in lysosomes
what symptoms and features are seen in patients with Morquio A syndrome?
- enlarged skull, platyspondyly and dorsolumbar kyphosis
- epiphyseal irregularity, widened metaphyses
- cloudy cornea, thin tooth enamel, multiple cavities, heart valve abnormalities, mild liver enlargement
- atlanto-axial instability (hypoplasia of odontoid process)
- joint pain, early onset arthritis
what does Vimizim therapy do?
IV infusion to relapce GALNS, leading to sustained imporvemtn in distance walked
what x-ray features can be seen in people who have multiple epiphyseal dysplasia?
immature wrist bones and problems in the hip
what is the genetic cause of multiple epiphyseal dysplasia?
COMP (catilage oligomeric matrix protein), which normally activates TGF-BR, which when mutated leads to lack of proliferation/differentiation of chorndrocytes and structural integrity of cartilage/tendons/ligaments
so similar to achondroplasia but worse
what can be seen on the x-rays of a personw ith Osteogenesis Imperfecta Type 1?
multiple healing fractures
what is the genetic cause of osteogenesis imperfecta type 1?
COL1A1, leading to defects in type 1 collagen synthesis, processing, transport
what are symptoms of osteogenesis imperfecta type 1?
- bone fracture after minor trauma
- bowing of legs + pther deformities
- short strature
what is the recombination rule of thumb?
families
- Typically, one recombination event occurs in each chromosome arm per generation
- Two loci that are 1 centimorgan (cM) apart have a 1% chance of being separated by recombination in a single generation (1cM is about 1 million bases)
what is the recombination rule of thumb?
populations
- Recombination often occurs in the same small region of the genome (“hotspots”)
- Results from chromatin structure and specific “fragile” DNA sequences (trinucleotide repeats)
what is the rationale for tag SNP-based association studies?
- statistical tests detect association (not causation)
- SNPs may be genetically indistinguishable or “linked” to each other as a result of biological processes
what is a key consideration when doing population studies?
need to make sure cultural origins are the same between all groups that are being testing in order to make sure that the genetic differences seen are due to disease and not place of origin
what are the different disease association statistical tests/models?
- additional
- dominant
- recessive
what are trait association studies done in GWAS?
modelled using linear regression can determine effect (slope of line) from background noise (correlation) and report significance of association (P-value)
only significant when above the line (smaller p-value than normal)
what gene was associated with adult height (GWAS)?
european origin
HMGA2 is a non-histone chromosomal high-mobility group (HMG) protein
what did the GIANT consortium find?
Genetic Investigation of ANthropometric Traits
- 83 SNPs in coding
- rest in non-coding
- most located in or near: GH, GHR, IGF1, …
- many genes regulating skeletal developemnt (TGF-b, hedgehog), chondrocyte development, and extracellualr matrix formation
what types of genes are generally found in GWAS studies?
generally genes that may be more common and have smaller effect size.
what type of study is used to find rare coding SNPs with high effect size, uncommon coding SNP with modest effects, and common SNPs with low effect size?
- rare: linkage studies
- uncommon: whole exome sequencing
- common: GWAS or whole exome sequencing
what is the first step in interpretating a GWAS study?
and how can it be done
First steps include discovering which types of
cells have enhancers or promoter that contain
the SNP and then seeing whether the SNP
affects expression of nearby genes – this can
be done using collections of tissues collected
from different people (GTeX Consortium)
why is it that association studies have multiple testing?
since genotyping platforms perform hundreds of thousands of independent tests, significance threshold is reduced to avoid making a false discovery (Type I errors)
what is allelic spectrum?
describes relationship between effect size and allele frequency of associated variants, and can alos consider functional properties of effector alleles (coding vs non-coding)
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what genes are associated with BMI?
FTO
how do we interpret GWAS studies?
- first find where the gene is expressed
- then do functional assessments
what is genetic fine mapping?
in GWAS, we get a noisy result where it is hard to find the true “signal,” meaning that the true signal may be missed. Then fine mapping allows us to find the actual causative variants, reducing the number of SNPs that cna be used for functional studies
why use fine-maping in a GWAS study?
- to find causal genes (effector transcripts) – causative coding variants/regulatory variants
- to link variant with a functional or regulatory pathway – experimental validation, disease pathogenesis
- to understand genetic architecture – type of variant, compare across traits/populations, devlop models
what is a conditional analysis in GWAS?
condition on a lead SNP and test whether there are any other SNPs that remain significantly associated
what did a conditional analysis for BMI allow us to find?
secondary signals in MC4R
what are the challenges in identifying causal variants in a trait-associated locus?
- the variant (SNP) with the strongest statistical association in the region is frequently (usually) not the causal variant
- most approaches search for a single causal variant; however, the phenotype may result from the combined effects of several variants
- regions in tight linkage disequilibrium (LD) are often inherited as haplotype blocks without recombination – so the study population does not have sufficient combinatorial complexity to dissect the effects of individual variants
what are some considerations when selecting the best candidates in GWAS studies?
based on convergence of actual or predicted effects of genetic variants: coding variant, variants in regulatory elements
what does colocalization tests tell us?
tests whether genetic associations of two traits at a specific locus are explained by the same variants or distinct variants
what do eQTLs tell us?
Expression quantitative trait loci
link SNPs to genes
what are 3 situations that can lead to this transcriptional change to phenotype seen?
can be either
causality: causal variant to transcription to phenotype
pleiotropy: causal variant leading to both transcriptional change and phenotype
linkage: causal variant 1 leading to transcriptional change which is linked to another causal variant which leads to phenotype
what is the massivley parallel reporter assay (MPRA) workflow?
it measures the effect of thousands of variants on transcriptional (enhancer) activity in the lab:
region selection, barcode amplication, analyze fequncy of candidates
what does FTO do?
2-oxyglutarate and Fe(II) dependent nucleic acid demethylase (DNA & RNA)
which type of fat does FTO generally affect?
predominantly effects subcutaneous fat (not visceral fat or fat distribution)
what does FTO loss of function lead to?
syndrome with postnatal growth retardation, microcephaly, severe psychomotor delay, and death before age 30 months
what are the steps n a study aimed at identofying a mechanistic basis for the association between the FTO locus and obesity in humans?
- Step 1: Identify potential regulatory elements and target cell types
- Step 2: Identify candidate effector transcripts in chromatin region
- Step 3: Assess gene expression in people carrying the risk variant
- Step 4: Demonstrate link between candidate effector transcript and adipocyte differentiation and function
- Step 5a. Study effects of lead variant on gene expression (I) (establish whether it changes effector gene expression)
- Step 5b. Study effects of lead variant on gene expression (II) (establish whether it changes adipocyte function)
