rare and common variants: twenty arguments g.gibson homework 3 mylène champs marine flechet mathieu...
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Rare and common variants: twenty arguments G.Gibson
Homework 3
Mylène ChampsMarine Flechet
Mathieu Stifkens
Bioinformatics - GBIO0009-1 - K.Van Steen University of Liège
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Content : Rare and common variants
IntroductionSummary
◦Rare allele model◦Infinitesimal model
Conclusion
Bioinformatics - GBIO0009-1 - K.Van Steen University of Liège
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Content : Rare and common variants
IntroductionSummary
◦Rare allele model◦Infinitesimal model
Conclusion
Bioinformatics - GBIO0009-1 - K.Van Steen University of Liège
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Introduction: Rare and common variants
◦Genome-wide association studies (GWASs) identify genetic factors that influence health and disease.
◦First model used : CDCV (Common disease Common variant) = a small number of common variants can explain the percentage of disease risk.
◦This model is not used anymore because of the “missing heritability problem”. A few loci with moderate effect cannot explain several percent of disease susceptibility.
Bioinformatics - GBIO0009-1 - K.Van Steen University of Liège
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Content : Rare and common variants
IntroductionSummary
◦Rare allele model◦Infinitesimal model
Conclusion
Bioinformatics - GBIO0009-1 - K.Van Steen University of Liège
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Summary : Rare and common variants
Rare allele model◦Presentation of the model◦Arguments « in favour »◦Arguments « against »
Bioinformatics - GBIO0009-1 - K.Van Steen University of Liège
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Summary : Rare and common variants
Rare allele model – Presentation ◦Model known as « many rare alleles of large
effect ».
◦The variance for a disease is due to rare variants (allele frequency<1%) which are highly penetrant (large effect).
◦Example: Schizophrenia = collection of many similar conditions that are attributable to rare variants.
Bioinformatics - GBIO0009-1 - K.Van Steen University of Liège
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Summary : Rare and common variants
Rare allele model – Presentation
Causal variant effects (yellow dots) may be large in a few individuals but are not common enough to represent a “hit” in a GWAS.
Bioinformatics - GBIO0009-1 - K.Van Steen University of Liège
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Summary : Rare and common variants
Rare allele model◦Presentation of the model◦Arguments « in favour »◦Arguments « against »
Bioinformatics - GBIO0009-1 - K.Van Steen University of Liège
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Summary : Rare and common variants
Rare allele model – « In favour »◦ Evolutionnary theory predicts that disease alleles should be
rare[1] ;
◦ Empirical population genetic data shows that deleterious variants are rare[1] ;
◦ Rare copy number variants contribute to several complex psychological disorders[1] ;
◦ Many rare familial disorders are due to rare alleles of large effects[1];
◦ Synthetic association may explain common variants effects[1] .
Bioinformatics - GBIO0009-1 - K.Van Steen University of Liège
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Summary : Rare and common variants
Rare allele model – « In favour »◦ Evolutionnary theory predicts that disease alleles should
be rare[1] ;
◦ Empirical population genetic data shows that deleterious variants are rare[1] ;
◦ Rare copy number variants contribute to several complex psychological disorders[1] ;
◦ Many rare familial disorders are due to rare alleles of large effects[1];
◦ Synthetic association may explain common variants effects[1] .
Bioinformatics - GBIO0009-1 - K.Van Steen University of Liège
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Summary : Rare and common variants
Evolutionnary theory predicts that disease alleles should be rare[1] :
◦Deleterious alleles are created by mutation; removed by purifying selection.
◦Rate(creation) > rate (removal)
Bioinformatics - GBIO0009-1 - K.Van Steen University of Liège
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Summary : Rare and common variants
Rare copy number variants contribute to several complex psychological disorders[1] :
◦CNVs : hemizygous deletion – local duplication;
◦Promote disease such as schyzophrenia and autism and modify its severity .
Bioinformatics - GBIO0009-1 - K.Van Steen University of Liège
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Summary : Rare and common variants
Synthetic association may explain common variants effects[1] :
Bioinformatics - GBIO0009-1 - K.Van Steen University of Liège
LD Data [2]
For common variants which do not explain much percentage of the disease susceptibility Rare variants increase this case risk.
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Summary : Rare and common variants
Rare allele model◦Presentation of the model◦Arguments « in favour »◦Arguments « against »
Bioinformatics - GBIO0009-1 - K.Van Steen University of Liège
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Summary : Rare and common variants
Rare allele model – « Against »◦ Analysis of GWAS data is not consistent with rare variants
explanations[1] ;
◦ Sibling recurrence rates are greater than would be expected by the postulated effect sizes of rare variants[1] ;
◦ Rare variants do not obviously have additive effects[1] ;
◦ Epidemiological transitions cannot be attributed to rare variants[1] ;
◦ GWAS associations are consistent across populations[1] ;
Bioinformatics - GBIO0009-1 - K.Van Steen University of Liège
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Summary : Rare and common variants
Rare allele model – « Against »◦ Analysis of GWAS data is not consistent with rare
variants explanations[1] ;
◦ Sibling recurrence rates are greater than would be expected by the postulated effect sizes of rare variants[1] ;
◦ Rare variants do not obviously have additive effects[1] ;
◦ Epidemiological transitions cannot be attributed to rare variants[1] ;
◦ GWAS associations are consistent across populations[1] ;
Bioinformatics - GBIO0009-1 - K.Van Steen University of Liège
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Summary : Rare and common variants
Analysis of GWAS data is not consistent with rare variants explanations[1]
◦ Rare variants cannot be the predominant source of heritabilily;
◦ There should be many of them with large size and effect.
Bioinformatics - GBIO0009-1 - K.Van Steen University of Liège
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Summary : Rare and common variants
Rare variants do not obviously have additive effects[1]
◦ Genetic associations are known to be additive whereas rare variants interact multiplicatively and they have dominant effect;
◦ However on the statistical side rare variants induce additivity effects.
Bioinformatics - GBIO0009-1 - K.Van Steen University of Liège
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Summary : Rare and common variants
Epidemiological transitions cannot be attributed to rare variants[1]
◦ The change of prevalence of some diseases is too fast;
◦ The model can not explain the influence of environmental variable.
Bioinformatics - GBIO0009-1 - K.Van Steen University of Liège
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Content : Rare and common variants
IntroductionSummary
◦Rare allele model◦Infinitesimal model
Conclusion
Bioinformatics - GBIO0009-1 - K.Van Steen University of Liège
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Summary : Rare and common variants
Infinitesimal model◦Presentation of the model◦Arguments « in favour »◦Arguments « against »
Bioinformatics - GBIO0009-1 - K.Van Steen University of Liège
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Summary : Rare and common variants
Infinitesimal model – Presentation◦ Known as « common » model or many common variants of small
effects.
◦ This is the model used in GWASs.
◦ Common variants are the major source of genetic variance for disease susceptibility.
◦ Hundreds or thousands of loci of small effect contribute in each case.
◦ Example : Height or BMI studies, hundred of loci have been found but they don’t explain all of the genetic variance. This problem is called the « missing heritability problem ».
Bioinformatics - GBIO0009-1 - K.Van Steen University of Liège
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Summary : Rare and common variants
Infinitesimal model – Presentation
Bioinformatics - GBIO0009-1 - K.Van Steen University of Liège
Significant “hits” of common variants with small effects. Several SNPs within a linkage disequilibrium (LD) block are associated with the trait [1].
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Summary : Rare and common variants
Infinitesimal model◦Presentation of the model◦Arguments « in favour »◦Arguments « against »
Bioinformatics - GBIO0009-1 - K.Van Steen University of Liège
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Summary : Rare and common variants
Infinitesimal model – « In favour »◦ The infinitesimal model underpins standard quantitative genetic
theory[1] ;
◦ Common variants collectively capture the majority of the genetic variance in GWASs[1] ;
◦ Variation in endophenotypes is almost certainly due to common variants[1] ;
◦ Model organism research supports common variants contributions to complex phenotypes[1] ;
◦ GWASs have successfully identified thousands of common variants[1] .
Bioinformatics - GBIO0009-1 - K.Van Steen University of Liège
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Summary : Rare and common variants
Infinitesimal model – « In favour »◦ The infinitesimal model underpins standard quantitative
genetic theory[1] ;
◦ Common variants collectively capture the majority of the genetic variance in GWASs[1] ;
◦ Variation in endophenotypes is almost certainly due to common variants[1] ;
◦ Model organism research supports common variants contributions to complex phenotypes[1] ;
◦ GWASs have successfully identified thousands of common variants[1] .
Bioinformatics - GBIO0009-1 - K.Van Steen University of Liège
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Summary : Rare and common variants
The infinitesimal model underpins standard quantitative genetic theory[1] :
◦ High heritability ;
◦ No results were against the infinitesimal model.
Bioinformatics - GBIO0009-1 - K.Van Steen University of Liège
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Summary : Rare and common variants
Common variants collectively capture the majority of the genetic variance in GWASs[1]:
Capture more of the genetic variance by using all significant SNPs;
Variance is attributed to hundreds of loci.
Bioinformatics - GBIO0009-1 - K.Van Steen University of Liège
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Summary : Rare and common variants
GWASs have successfully identified thousands of common variants[1] :
◦ Unrealistic assumptions of the effect size ;
◦ Increasing samples allows to determine more loci.
Bioinformatics - GBIO0009-1 - K.Van Steen University of Liège
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Summary : Rare and common variants
Infinitesimal model◦Presentation of the model◦Arguments « in favour »◦Arguments « against »
Bioinformatics - GBIO0009-1 - K.Van Steen University of Liège
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Summary : Rare and common variants
Infinitesimal model – « Against »◦ The QTL paradox[1] ;
◦ The abscence of blending inheritence[1] ;
◦ Demographic phenomena suggest more than one simple common-variant model[1] ;
◦ Very few common variants for disease have been functionnaly validated[1] ;
◦ What accounts for the missing heritability[1] ?
Bioinformatics - GBIO0009-1 - K.Van Steen University of Liège
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Summary : Rare and common variants
Infinitesimal model – « Against »◦ The QTL paradox[1] ;
◦ The abscence of blending inheritence[1] ;
◦ Demographic phenomena suggest more than one simple common-variant model[1] ;
◦ Very few common variants for disease have been functionnaly validated[1] ;
◦ What accounts for the missing heritability[1] ?
Bioinformatics - GBIO0009-1 - K.Van Steen University of Liège
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Summary : Rare and common variants
The QTL paradox[1]
◦ We cannot find QTLs detected in pedigrees and in experimental crosses;
◦ Explanations:-> QTLs are rare variants that only contribute in that cross.-> Each cross captures only a small fraction of genetic variance in a population.
Bioinformatics - GBIO0009-1 - K.Van Steen University of Liège
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Summary : Rare and common variants
The abscence of blending inheritence[1]
◦ The granularity in the distribution of risks and phenotypic trait variation should decrease with the crossing of two unrelated poeple;
◦ However we observe higher risks than the model predicted;
◦ For example : We can observe that in some family complex phenotype
traits are recurrent.
Bioinformatics - GBIO0009-1 - K.Van Steen University of Liège
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Summary : Rare and common variants
What accounts for the missing heritability[1] ?
◦ The model does not take into account the missing heritability problem;
◦ But the problem really exists !
Bioinformatics - GBIO0009-1 - K.Van Steen University of Liège
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Content : Rare and common variants
IntroductionSummary
◦Rare allele model◦Infinitesimal model
Conclusion
Bioinformatics - GBIO0009-1 - K.Van Steen University of Liège
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Conclusion : Rare and common variants
Which model would you choose ?
Bioinformatics - GBIO0009-1 - K.Van Steen University of Liège
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Conclusion : Rare and common variants
Which model would you choose ?
◦ Both !
◦ We should learn how to use the two models together because they both have their place in the current research.
◦ Idea : Integrate rare and common variants effects together.
Bioinformatics - GBIO0009-1 - K.Van Steen University of Liège
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Conclusion : Rare and common variants
Bioinformatics - GBIO0009-1 - K.Van Steen University of Liège
The common variants establish the background liability to a disease and this liability can be modified by the rare variants with large effects [1].
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References :
Bioinformatics - GBIO0009-1 - K.Van Steen University of Liège
[1] G. GIBSON : Rare and common variants: twenty arguments. Nat. Rev. Genet., 13(2):135145, Feb 2012.[2] Bioinformatics course – GWAS studies, K. VAN STEEN