Transcript Rare and common variants: twenty arguments G.Gibson

Rare and common
variants: twenty
arguments
G.Gibson
Homework 3
Mylène Champs
Marine Flechet
Mathieu Stifkens
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Content :
Rare and common variants
Introduction
 Summary

◦ Rare allele model
◦ Infinitesimal model

Conclusion
Bioinformatics - GBIO0009-1 - K.Van Steen
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Content :
Rare and common variants
Introduction
 Summary

◦ Rare allele model
◦ Infinitesimal model

Conclusion
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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.
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Content :
Rare and common variants
Introduction
 Summary

◦ Rare allele model
◦ Infinitesimal model

Conclusion
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Summary :

Rare and common variants
Rare allele model
◦ Presentation of the model
◦ Arguments « in favour »
◦ Arguments « against »
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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.
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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.
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Summary :

Rare and common variants
Rare allele model
◦ Presentation of the model
◦ Arguments « in favour »
◦ Arguments « against »
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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] .
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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] .
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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)
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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 .
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Summary

:
Rare and common variants
Synthetic association may explain common variants
effects[1] :
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 »
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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] ;
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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] ;
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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.
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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.
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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.
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Content :
Rare and common variants
Introduction
 Summary

◦ 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 »
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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 ».
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Summary :

Rare and common variants
Infinitesimal model – Presentation
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 »
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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] .
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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] .
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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.
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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.
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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.
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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
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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
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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
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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.
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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.
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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 !
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Content :
Rare and common variants
Introduction
 Summary

◦ 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 ?
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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.
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Conclusion :
Rare and common variants
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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Thank you for your attention !
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References :
[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
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Do you have any question(s) ?
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