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  • testing a single SNP doesn’t work for rare variants; Need new methods for rare variantsCollapsing SNPs into a single marker to reduce d.f.
  • Combined multivariate and collapsing (CMC) method (Li & Leal 08)Weighted sum method (Madsen & Browning 09)
  • Only for rare variants
  • Multivariate analysis of variance
  • cases and controls under H0, no threshold
  • In favor of their method
  • the corresponding

Transcript

  • 1. Association Tests for Rare Variants Using Sequence Data
    GuiminGao, Wenan Chen, & Xi Gao
    Department of Biostatistics, VCU
  • 2. Introduction to Association tests: two hypotheses
    Common variant-common disease
    Common variant: Minor allele frequencies (MAF) >= 5%
    Using linkage disequilibrium(LD)
    Rare variant-common disease
    Rare variant: MAF < 1% (or 5%)
    High allelic heterogeneity: collectively by multiple rare variants with moderate to high penetrances
    Associations through LD would not be suitable
  • 3. Association tests for Common variants
    Test a single marker each time
    Cochran-Armitage’s trend test (CATT) (assuming additive (ADD))
    Power: High for additive (ADD) or Multiplicative (MUL); low recessive (REC) or Dominant (DOM)
    Genotype association test (GAT) using chi-square statistic
    Power: a little lower for ADD, higher for REC
    MAX3 = maximum of three trend test statistics across the REC, ADD, and DOM models (Freidlin et al. 2002 Hum Hered.)
    Power: lower than CATT under ADD
    higher than CATT & CAT under REC
  • 4. Association tests for Common variants
    Test for single marker (CATT, GAT, & MAX3)
    Low power when MAF <10%
    No power for rare variants with MAF<1%
    Multivariate test
    Considering a group of variants (ex. SNPs in a gene) each time
    Multiple logistic regression (or Hotelling test, Fisher’s product)
    Xij = 0, 1, 2, the count. of the minor alleles of indivi at locus j
    Power: higher than single-marker test;
    still very low due to large d.f = No. of SNPS = k
    Need new methods for rare variants
    Collapsing SNPs into a single marker to reduce d.f.
  • 5. Outline
    Introduction to association tests
    Three well-known collapsing methods for rare variants: CAST, CMC, & Weighted Sum methods
    An evaluation using GAW 17 data
    Extension to the three collapsing methods
    Future research
  • 6. Three association tests for Rare variants
    Collapsing a set of rare variants (into a single marker)
    A cohort allelic sums test (CAST) (Morgenthaler & Thilly 2007, Mutat. Res.)
    Combined Multivariate and Collapsing (CMC) (Li & Leal, 2007, AJHG)
    Division into subgroups, collapsing in each subgroup
    Weighted Sum statistic (Madsen & Browning, 2009; PloS Genet. Price et al. 2010, AJHG)
  • 7. A cohort allelic sums test (CAST)
    A group of n variants (SNPs) in a unit (ex. one gene, LD block)
    Collapsing the genotypes across the variants
    Indicator coding for individual j
    xj = 1, if rare alleles present at any of the n variants;
    xj= 0, otherwise
    Testing if the proportions of individuals with rare variants (xj = 1) in cases and controls differ
    Higher power than method testing single variant each time
    Only for rare variants
  • 8. Combined Multivariate and Collapsing (CMC) Method (Li & Leal 08)
    Consider SNPs in a unit with MAF< a threshold (0.01 or 0.05)
    Division and Collapsing
    Divided into several sub-groups based on the MAF
    Ex. Subgroups : (0, 0.001], [0.001, 0.005), [0.005, 0.01)
    SNPs are collapsed in each sub-group
    xij = 1, if indiv j has rare alleles present in the i-th subgroup;
    xij= 0, otherwise
  • 9. Combined Multivariate and Collapsing (CMC) Method (Li & Leal 08)
    Multivariate test of collapsed sub-groups
    Hotelling T2 test, MANOVA, Fisher’s product method
    Power: often higher than CAST
    Different threshold may have different power
  • 10. Weighted Sum Method (Madsen & Browning 09)
    A group of variants (SNPs) in a unit
    A weight for SNP iby the S.t.d of No. of minor alleles in the sample
    qiis the minor allele freq in controls
    Calculate a weighted genetic score for indivj
    Iij = 0, 1, 2, the count of the minor allele of indivi at locus j
    Obtain the Rank (Vj); Sum of the ranks of affected indivs
  • 11. Permutation for p-value estimation
    From observed data:
    Permutation to estimate p-value:
    Phenotype labels are permuted 1000 times, x1, …x1000
    Calculate the mean (μ) and standard deviation (σ) of 1000 xs
    Assume z ~ N(0, 1) under null hypothesis
    Obtain the p-value from N(0, 1)
    Fast, p-value ~U[0,1]
  • 12. Weighted Sum Method (Madsen & Browning 09)
    Power comparison:
    Simulations assuming genotypic relative risk is proportion to MAF at disease loci (Madsen & Browning 09)
    Weighted Sum Method (WSM) > CMC > CAST
    (WSM) > CMC may not be true in other situations
    Can be applied to rare variants & common variants
    Disadvantage:
    Give very high weights to very rare alleles (singleton), very low weights to common variants.
  • 13. An evaluation of the CMC method and Weighted sum method by using GAW 17 data
    Both methods are powerful (based on the authors’ simulation)
    Our evaluation based on simulated datasets from GAW 17
    GAW 17 data:
    a subset of genes with real sequence data available in the 1000 genome project
    Simulated phenotypes
    Unrelated individuals, families
    Dataset of 697 unrelated individuals
    24487 SNPs in 3205 genes from 22 autosomal chromosomes
    Only test for the 2196 genes with non-synonymous SNPs
  • 14. GAW 17 dataset of unrelated individuals
    Four phenotypes: Q1, Q2, Q4 and disease status.
    Q1, Q2, and Q4 are quantitative traits
    Q1 associated with 39 SNP in 9 genes,
    Q2 associated with 72 SNPs in 13 genes
    Q4: not related to any genes
    Disease status is a binary trait: affected or unaffected, associated with 37 genes
    200 simulated phenotype replicates
    Only one replicate of genotype data (original data)
  • 15. Transforming Phenotypes
    • Methods: case-control design
    • 16. Transform Q1, Q2, Q4 into binary traits
    • 17. Splitting at the top 30% percentile of the distributions
  • Criteria for evaluation of Tests
    Familywise error rate (FWER)
    2196 genes with non-synonymous SNPs, 2196 tests
    2196 null hypotheses Hj0: gene not associated with the trait
    Q1 associated in 9 genes, 9 null hypotheses are not true.
    (2196-9) null hypotheses are true
    FWER = Pr(reject at least one true null hypothesis) = Nf/200
    Nf: No. of replicates, at least one true hypothesis are rejected
    Average Power
    Mean of power for all the 9 genes that affect the phenotypes
    Evaluating power: Q1, Q2, Disease
    Evaluate FWER: Q4
  • 18. Distribution of MAF in the GAW 17 dataset
    Figure 1. Distribution of MAF of 24487 SNPs in GAW 17
  • 19. Figure 1. Group SNPs based on MAFs for CMC
    Similar to Madsen & Browning (2009)
    0 - 0.01
    0.01 - 0.1
    >=0.1
  • 20. Table 1: Average power
  • 21. Table 2: FWER (nominal α = 0.05)
    • CMC has FWER inflation
    • 22. Population stratification or admixture,
    Samples from Asian, Europe,…
    • Relatedness among samples
    • 23. Similar results in Power and FWER were reported at GAW 17
  • Variable-Threshold Approach (Price et al 2010)
    Given a threshold T, calculate a score for indivj
    Iij = 0, 1, 2, the count of the minor allele of indivi at locus j
    Calculate the sum of score for cases:
    Calculate Z(T) = V(T)/Var(V(T))
    Find T to maximize Z(T), Zmax = max (Z(T))
    Permutation to estimate p-value for Zmax
    Power: >CMC; Extended to quantitative traits
  • 24. A weighted approach (Price et al 2010)
    Calculate a weighted score for indivj
    Iij = 0, 1, 2
    Calculate the sum of score for cases
    Possible weight
    Power: similar to the weighted sum method (Madsen & Browning 09)
  • 25. A weighted approach (Price et al 2010)
    Calculate the sum of score for cases
    Iij = 0, 1, 2
    Calculate weight by the prediction of functional effects
    PolyPhen-2 is used to predict damaging effects of missense mutations with probabilistic scores.
    Probabilistic scores as weights may reduce the noise of non-functional variants.
    Higher Power than other methods
  • 26. A data-adaptive sum test (Han & Pan 2010, Hum Hered)
    Logistic model
    xij = 0, 1, 2, the count of the minor allele of indivi at locus j
    Effect on opposite directions
    If j <0, with p-value < threshold (0.1), change xij into 2-xij
    Permutation to estimate p-value
  • 27. Conclusion
    Collapsing methods have higher power than single-marker test
    For genome-wide data analysis, collapsing methods don’t have much power after multiple testing adjusting
    Weighted sum methods are promising, need prior information from biological data
  • 28. Future research
    Modifying the weighted sum method (in progress)
    Very high weights to very rare variants
    Smoothing weights w’ = 0.5w +0.5 (average of all w)
  • 29. Thank you