Polygenic Risk Scores
Name one reason PRS trained in a cohort of one ancestry will usually perform poorly in a group from another ancestry.
many possibilities (LD, allele freqs, gene-environment, gene-gene)
Variants in PCSK9, LDLR, and APOE represent some of the strongest GWAS signals for which trait?
LDL cholesterol
A couple undergoes carrier screening and determines they are both carriers (heterozygous) for a mutation known to cause Usher Syndrome (a Mendelian form of deafness, which follows an autosomal recessive pattern). What is the probability they will have a child affected by this disease?
25%
Describe one method for controlling for confounding effects due to ancestry when performing GWAS and self-reported ancestry labels are unknown.
use population PCs as covariates (other answers may be accepted, like LMMs)
What p-value threshold is most commonly used to determine whether a variant association with a trait reaches genome-wide significance?
p<5*10^-8
Current PRS implementations assume the effect of each SNP is additive (i.e., heterozygotes for the risk allele have half as much risk as homozygotes). Name a case where this assumption would be broken.
dominance. Other possibilities: imprinting, non-linear effects of repeats
A common nonsense variant in the gene TBC1D4 conferring an odds ratio of 10.3 for type 2 diabetes was found in which population?
Greenland
The minor allele frequency of the BLMAsh mutation implicated in Bloom Syndrome is 0.4% in Ashkenazi Jews. Assuming random mating, what do you expect the prevalence of Bloom Syndrome (an autosomal recessive disease) to be in this population?
0.004**2 = 1.6e-05
You run fine-mapping on a locus identified by GWAS and compute the following posterior inclusion probabilities (PIPs) for each variant:
rs1=90%, rs2=4%, rs3=2%, rs4=1%, rs5=1%, rs6=1%, rs=1%
Which variants will be in the 95% credible set for this locus?
rs1, rs2, rs3
What part of our genomes is primarily inherited through the maternal germline?
mitochondrial DNA
Which metrics are typically used to evaluate PRSs for quantitative and case-control, traits, respectively?
r2, auROC
A 5-SNP haplotype spanning the gene SLC16A11 is strongly associated with Type 2 Diabetes in Mexican and Hispanic populations. What population do scientists believe is the source of this unusual haplotype?
Neanderthal introgression
Red hair color is an autosomal recessive trait due to loss of function mutations in MC1R. Although it is recessive, many individuals with red hair will actually be heterozygous for two different LoF mutations, each occurring on a different chromosome copy. What term is used to describe this phenomenon?
compound heterozygote
Which three factors determine our power to detect an association for a particular variant in GWAS? (assuming the SNP shows an additive association with the trait)?
sample size, MAF, effect size
Which term corresponds to the idea that evolution is inherently a stochastic process?
genetic drift
When performing the C+T method for constructing polygenic risk scores, name at least two parameters that are often tuned?
p-value threshold, r2 threshold for LD-clumping (might accept other params related to clumping)
A top hit for height GWAS falls in the ACAN gene. What type of variant was shown to be the causal variant underlying this signal?
a protein-coding VNTR in ACAN
Which autosomal dominant disease is caused by mutations in the gene FBN1? This disease is characterized by long, slender build, and increased risk for aortic dissection. It has been hypothesized that Abraham Lincoln was affected by this disorder.
Marfan Syndrome
You are testing for association between SNP rs1 and diabetes. rs1 is bi-allelic, with alleles A and C.
You observe allele A 5000 times in cases and 4000 times in controls.
You observe allele C 2000 times in cases and 3000 times in controls.
What is the odds ratio for allele A?
(5000/4000)/(2000/3000) = 1.875
Describe an example prior on effect sizes for Bayesian PRS methods (e.g. LDPred, PRS-CS, or SBayesR)
spike and slab, mixture of normals, continuous shrinkage prior
Current PRS assume the effects of all causal variants are independent (i.e., no epistasis). Name at least one way epistasis (gene-gene or variant-variant interaction) could occur.
LPA example (eqtl + protein coding changes). other examples: Msh3 in HTT, modifier genes for CF.
A top hit for obesity and BMI GWAS falls in an intron of the gene “FTO”. Name either the causal gene(s), or causal disease mechanism, of this locus.
IRX3, IRX5. The SNP modifies a regulatory site for these genes. Expression of these genes determines the tradeoff between “white” vs. “brown” fat.
In the context of Mendelian disease, what is the definition of penetrance? Name a specific example of a Mendelian disease known to have incomplete penetrance, due either to gene-environment interaction or other factors
PKU, interaction with diet. Other answers accepted
You perform a GWAS on schizophrenia (a case/control trait) using logistic regression (logit(Y)~beta*X+...covars). How would you convert the regression coefficient beta to an odds ratio?
OR = e^beta
What is the approximate heritability of height?
80%