comments on rare variants analyses ryo yamada kyoto university 2012/08/27 ibc2012@kobe, japan
TRANSCRIPT
![Page 1: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/1.jpg)
Comments on Rare Variants Analyses
Ryo YamadaKyoto University
2012/08/27IBC2012@Kobe, Japan
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Many difficulties to detect true signals in rare variant analyses
Type 1 error, Power-control, Various Statistics with/without Weights,Data quality, Data load, Platform variations, Missing data, Permutations, Allele freq., Rares with Commons, Replication, Neutral or not,
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Many difficulties to detect true signals in rare variant analyses
Type 1 error, Power-control, Various Statistics with/without Weights,Data quality, Data load, Platform variations, Missing data, Permutations, Allele freq., Replication, Rares with Commons integrating all variations,
So many....
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Many difficulties to detect true signals in rare variant analyses
• My discussing points– Some problems in rare variant analyses are the
unsolved problems in common variant analyses.
![Page 5: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/5.jpg)
Many difficulties to detect true signals in rare variant analyses
• My discussing points– Some problems in rare variant analyses are the
unsolved problems in common variant analyses.
![Page 6: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/6.jpg)
Many difficulties to detect true signals in rare variant analyses
• My discussing points– Some problems in rare variant analyses are the
unsolved problems in common variant analyses.
– Changes in genetic studies along with rare variant analyses• Next-generation sequencing technologies-driven
changes
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Common Variant Analyses
• Pre kit-GWAS ~2005– Exonic region-dominant
• kit-GWAS 2005 ~– Genome-wide
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Common Variant Analyses
• Pre kit-GWAS ~2005– Exonic region-dominant
• kit-GWAS 2005 ~– Genome-wide
• Exome• Whole-genome sequencing
Rare Variant Analyses
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Common Variant Analyses
• Pre kit-GWAS ~2005– Exonic region-dominant
• kit-GWAS 2005 ~– Genome-wide
• Exome• Whole-genome sequencing
Rare Variant Analyses
déjà vu
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What we can learn from SNP LD mapping
• Hypothesis-free approach• All markers vs. 1 trait
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What we can learn from SNP LD mapping
• Hypothesis-free approach• All markers vs. 1 trait
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What we can learn from SNP LD mapping
• Hypothesis-free approach• All markers vs. 1 trait
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Set of Hypotheses
• Hypothesis-free approach• All markers vs. 1 trait• Almost all hypotheses are null.– They work as negative controls.– We obtain distribution under null hypothesis.
• A few hypotheses are “positive”.
• Pick up “outliers” from “null distribution” as positive signals
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Many Positive Hypotheses
• Many hypotheses are “truly positive”.– Transctiptome, microarray-chips– False discovery rate
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Many Positive Hypotheses
• Many hypotheses are “truly positive”.– Transctiptome, microarray-chips– False discovery rate
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Many Positive Hypotheses
• Many hypotheses are “truly positive”.– Transctiptome, microarray-chips– False discovery rate
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Many Positive Hypotheses
• Many hypotheses are “truly positive”.– Transctiptome, microarray-chips– False discovery rate
• Different approach to multiple testings from GWAS
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Many Positive Hypotheses
• Many hypotheses are “truly positive”.– Transctiptome, microarray-chips– False discovery rate
• Similar approach to multiple testings in GWAS?
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Many Positive Hypotheses
• Many hypotheses are “truly positive”.– Transctiptome, microarray-chips– False discovery rate
• Similar approach in GWAS?– e-QTL and cis-effect of neighboring SNPs on gene
expression
Nature Genetics 43, 561–564 (2011)
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Both are GWAS but different
• Almost all hypotheses are null
• Many positive hypotheses
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Both are GWAS but different
• Almost all hypotheses are null– All markers vs. 1 trait
• Many positive hypotheses– All markers vs. genes (traits)
![Page 22: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/22.jpg)
Both are GWAS but different
• Almost all hypotheses are null– All markers vs. 1 trait
• Many positive hypotheses– All markers vs. genes (traits)
Many traits
![Page 23: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/23.jpg)
Both are GWAS but different
• Almost all hypotheses are null– All markers vs. 1 trait
• Many positive hypotheses– All markers vs. genes (traits)
Many traits
Positives : Neighboring and cis effectsNegatives : Remote or trans effects
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Many Positive Hypotheseswith Rare Variant Analyses
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Many Positive Hypotheseswith Rare Variant Analyses
• Distribution of statistics is like what?
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Many Positive Hypotheseswith Rare Variant Analyses
• Distribution of statistics is like what?• Strategy to detect signals should be cared.
![Page 27: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/27.jpg)
Both are GWAS but different
• Almost all hypotheses are null– All markers vs. 1 trait
• Many Positive Hypotheses– All markers vs. genes (traits)
Many traits
Positives : Neighboring and cis effectsNegatives : Remote or trans effects
![Page 28: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/28.jpg)
Same GWAS but difference
• Almost all hypotheses are null– All markers vs. 1 phenotype
• Many Positive Hypotheses– All markers vs. genes (traits)
Many traits
Positives : NeighboringNegatives : Trans / Remote genes
![Page 29: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/29.jpg)
Same GWAS but difference
• Almost all hypotheses are null– All markers vs. 1 phenotype
• Many Positive Hypotheses– All markers vs. cis-neighboring genes
Many traits
Positives : NeighboringNegatives : Trans / Remote genes
Where are many traits?
![Page 30: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/30.jpg)
Same GWAS but difference
• Almost all hypotheses are null– All markers vs. 1 phenotype
• Many Positive Hypotheses– All markers vs. cis-neighboring genes
Many traits
Positives : NeighboringNegatives : Trans / Remote genes
Where are many traits?• Biobank projects with multiple traits• EHR (Electrical Health Record)-driven genetic
studies– Very many phenotypesNature Reviews Genetics 12, 417-428 (June 2011)
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Same GWAS but difference
• Almost all hypotheses are null– All markers vs. 1 phenotype
• Many Positive Hypotheses– All markers vs. cis-neighboring genes
Many traits
Positives : NeighboringNegatives : Trans / Remote genes
Where are many traits?• Biobank projects with multiple traits• EHR (Electrical Health Record)-driven genetic
studies– Very many phenotypesNature Reviews Genetics 12, 417-428 (June 2011)
![Page 32: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/32.jpg)
Same GWAS but difference
• Almost all hypotheses are null– All markers vs. 1 phenotype
• Many Positive Hypotheses– All markers vs. cis-neighboring genes
Many traits
Positives : NeighboringNegatives : Trans / Remote genes
Where are many traits?• Physical / pathological conditions vary.• Developmental stages vary.• Cell types/ tissue types/ organs vary.
![Page 33: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/33.jpg)
Same GWAS but difference
• Almost all hypotheses are null– All markers vs. 1 phenotype
• Many Positive Hypotheses– All markers vs. cis-neighboring genes
Many traits
Positives : NeighboringNegatives : Trans / Remote genes
Where are many traits?• Physical / pathological conditions vary.• Developmental stages vary.• Cell types/ tissue types/ organs vary.
![Page 34: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/34.jpg)
Same GWAS but difference
Many traits
Positives : NeighboringNegatives : Trans / Remote genes
Where are many traits?• Physical / pathological conditions vary.• Developmental stages vary.• Cell types/ tissue types/ organs vary.
Intra-individual diversity
![Page 35: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/35.jpg)
Same GWAS but difference
Many traits
![Page 36: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/36.jpg)
Same GWAS but difference
Many traitsChange view points
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Same GWAS but difference
Many genotypes
![Page 38: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/38.jpg)
Same GWAS but difference
Many genotypes
Where are many genotypes?
![Page 39: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/39.jpg)
Same GWAS but difference
Many genotypes
Where are many genotypes?• Physical / pathological conditions vary.• Developmental stages vary.• Cell types/ tissue types/ organs vary.
![Page 40: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/40.jpg)
Same GWAS but difference
Many genotypes
Where are many genotypes?• Physical / pathological conditions vary.• Developmental stages vary.• Cell types/ tissue types/ organs vary.
Intra-individual diversityAgain
![Page 41: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/41.jpg)
Same GWAS but difference
Many genotypes
Where are many genotypes?• Physical / pathological conditions vary.• Developmental stages vary.• Cell types/ tissue types/ organs vary.
Intra-individual diversity
Next generation sequencing technology makes these possible.
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Changes by Next Generation Sequencing Technologies
• Individual cell-sequencing detects– Hereditary• Variants from parents to offsprings
– Non-hereditary but genetic• de novo mutations in gamates• Somatic mutations in fetus• Somatic mutations after birth
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Changes by Next Generation Sequencing Technologies
• Individual cell-sequencing detects– Hereditary• Variants from parents to offsprings
– Non-hereditary but genetic• de novo mutations in gamates• Somatic mutations in fetus• Somatic mutations after birth
Before birth
After birth
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Changes by Next Generation Sequencing Technologies
• Individual cell-sequencing detects– Hereditary• Variants from parents to offsprings
– Non-hereditary but genetic• de novo mutations in gamates• Somatic mutations in fetus• Somatic mutations after birth
Before birth
After birth
Hereditary ~ Genetic ~ SomaticDiscriminations are becoming vague.
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“Collapsing methods”
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“Collapsing methods”
• Patterns of possession of rare variants vary with phenotypes.
• “Collapsing methods” make the patterns into a style that can be tested easily; one-dimensional measure
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“Collapsing methods”
• Patterns of possession of rare variants vary with phenotypes.
• “Collapsing methods” make the patterns into a style that can be tested easily; one-dimensional measure
![Page 49: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/49.jpg)
“Collapsing methods”
• Patterns of possession of rare variants vary with phenotypes.
• “Collapsing methods” make the patterns into a style that can be tested easily; one-dimensional measure
• Information on functionality of variants might be used when collapse to modify the “measure”.
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“Collapsing methods”
• Patterns of possession of rare variants vary with phenotypes.
• “Collapsing methods” make the patterns into a style that can be tested easily; one-dimensional measure
• Is this problem NEW to rare variant analyses?
![Page 51: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/51.jpg)
“Collapsing methods”
• Patterns of possession of rare variants vary with phenotypes.
• “Collapsing methods” make the patterns into a style that can be tested easily; one-dimensional measure
• Is this problem NEW to rare variant analyses?
![Page 52: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/52.jpg)
“Collapsing methods”
• Patterns of possession of rare variants vary with phenotypes.
• “Collapsing methods” make the patterns into a style that can be tested easily; one-dimensional measure
• Is this problem NEW to rare variant analyses?– NO
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“Collapsing methods”
• Patterns of possession of rare variants vary with phenotypes.
• “Collapsing methods” make the patterns into a style that can be tested easily; one-dimensional value
• Is this problem NEW to rare variant analyses?– We do NOT have adequate solutions for patterns
of common variants.
Genetics September 2007 vol. 177 no. 1 535-547
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“Collapsing methods”
• Patterns of possession of rare variants vary with phenotypes.
• “Collapsing methods” make the patterns into a style that can be test easily; one-dimensional value
• Is this problem NEW to rare variant analyses?– We do NOT have adequate solutions for patterns
of common variants .
How to handle patterns of variants, BOTH common and rare, should be solved.
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Patterns of variants
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Patterns of variants
• Rephrase as “Genetic heterogeneity PER GENES”
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Notes onGenetic Heterogeneity PER GENES
• Genes vary in their size.
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Notes onGenetic Heterogeneity PER GENES
• Genes vary in their size.
![Page 59: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/59.jpg)
Notes onGenetic Heterogeneity PER GENES
• Genes vary in their size.• Number of variants vary among genes.
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Notes onGenetic Heterogeneity PER GENES
• Genes vary in their size.• Number of variants vary among genes.• Allele frequencies vary among genes.
![Page 61: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/61.jpg)
Notes onGenetic Heterogeneity PER GENES
• Genes vary in their size.• Number of variants vary among genes.• Allele frequencies vary among genes.• Haplotype frequencies vary among genes.
![Page 62: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/62.jpg)
Notes onGenetic Heterogeneity PER GENES
• Genes vary in their size.• Number of variants vary among genes.• Allele frequencies vary among genes.• Haplotype frequencies vary among genes.• Functional variations due to genetic variants
vary among genes.
![Page 63: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/63.jpg)
Unsolved Issuesin Common Variant-GWAS
on Genetic Heterogeneity PER GENES
• GWAS
![Page 64: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/64.jpg)
Unsolved Issuesin Common Variant-GWAS
on Genetic Heterogeneity PER GENES
• GWAS
![Page 65: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/65.jpg)
Unsolved Issuesin Common Variant-GWAS
on Genetic Heterogeneity PER GENES
• GWAS– Hypothesis-free approach, targetting genes evenly
![Page 66: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/66.jpg)
Unsolved Issuesin Common Variant-GWAS
on Genetic Heterogeneity PER GENES
• GWAS– Hypothesis-free approach, targetting genes evenly– But...
![Page 67: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/67.jpg)
Unsolved Issuesin Common Variant-GWAS
on Genetic Heterogeneity PER GENES
• GWAS– Hypothesis-free approach, targetting genes evenly– But...– All genes are studied UNEVENLY.
![Page 68: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/68.jpg)
Unsolved Issuesin Common Variant-GWAS
on Genetic Heterogeneity PER GENES
• GWAS– Hypothesis-free approach, targetting genes evenly– But...– All genes are studied UNEVENLY.• Genetic heterogeneity PER GENES affects on sensitivity
and specificity• HLA region and its extreme heterogeneity...
![Page 69: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/69.jpg)
Unsolved Issuesin Common Variant-GWAS
on Genetic Heterogeneity PER GENES
• GWAS– Hypothesis-free approach, targetting genes evenly– But...– All genes are studied UNEVENLY.• Genetic heterogeneity PER GENES affects on sensitivity
and specificity• HLA region and its extreme heterogeneity...
Am J Hum Genet. 2005 April; 76(4): 634–646.
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UNEVENNESS Genetic Importance
• GWAS identifies genes of “Genetic Importance” that – are Important for a phenotype,– have functional variants.
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UNEVENNESSGenetic Importance
• GWAS identifies genes of “Genetic Importance” that – are Important for a phenotype,– have functional variants.
![Page 72: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/72.jpg)
UNEVENNESSGenetic Importance
• GWAS identifies genes of “Genetic Importance” that – are Important for a phenotype,– have functional variants.
![Page 73: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/73.jpg)
UNEVENNESSGenetic Importance
• GWAS identifies genes of “Genetic Importance” that – are Important for a phenotype,– have functional variants.
![Page 74: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/74.jpg)
UNEVENNESSGenetic Importance
• Consider a pathway that is important for a phenotype.– Gene X in the pathway is functionally critical
without genetic variants.– Gene Y in the pathway has some functional roles
with genetic variants that make phenotype variations.
• Gene X is “Functionally” important.• Gene Y is “Genetically” important.
http://www.genome.jp/kegg/
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UNEVENNESSGenetic Importance
• Consider a pathway that is important for a phenotype.– Gene X in the pathway is functionally critical
without genetic variants.– Gene Y in the pathway has some functional roles
with genetic variants that make phenotype variations.
• Gene X is “Functionally” important.• Gene Y is “Genetically” important.
http://www.genome.jp/kegg/
![Page 76: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/76.jpg)
UNEVENNESSGenetic Importance
• Consider a pathway that is important for a phenotype.– Gene X in the pathway is functionally critical
without genetic variants.– Gene Y in the pathway has some functional roles
with genetic variants that make phenotype variations.
• Gene X is “Functionally” important.• Gene Y is “Genetically” important.
http://www.genome.jp/kegg/
![Page 77: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/77.jpg)
UNEVENNESSGenetic Importance
• Consider a pathway that is important for a phenotype.– Gene X in the pathway is functionally critical
without genetic variants.– Gene Y in the pathway has some functional roles
with genetic variants that make phenotype variations.
• Gene X is “Functionally” important.• Gene Y is “Genetically” important.
![Page 78: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/78.jpg)
UNEVENNESSGenetic Importance
• Consider a pathway that is important for a phenotype.– Gene X in the pathway is functionally critical
without genetic variants.– Gene Y in the pathway has some functional roles
with genetic variants that make phenotype variations.
• Gene X is “Functionally” important.• Gene Y is “Genetically” important.
![Page 79: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/79.jpg)
UNEVENNESSGenetic Importance
• Consider a pathway is important for a phenotype.– Gene X in the pathway is functionally critical
without genetic variants.– Gene Y in the pathway has some functional role
with genetic variants that make phenotype variations.
• Gene X is “Functionally” important.• Gene Y is “Genetically” important.Genetic studies work only on
“genetic” importance.
![Page 80: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/80.jpg)
• Genetic Heterogeneity PER GENES determines “Genetic Importance”
• We do NOT have adequate methods to measure genetic heterogeneity per genes.
![Page 81: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/81.jpg)
• Genetic Heterogeneity PER GENES determines “Genetic Importance”
• But,...
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• Genetic Heterogeneity PER GENES determines “Genetic Importance”
• We do NOT have adequate methods to measure genetic heterogeneity per genes.
![Page 83: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/83.jpg)
• Genetic Heterogeneity PER GENES determines “Genetic Importance”
• We do NOT have adequate methods to measure genetic heterogeneity per genes.
One-dimensional measuresMeanVariance
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• Genetic Heterogeneity PER GENES determines “Genetic Importance”
• We do NOT have adequate methods to measure genetic heterogeneity per genes.
Genetics September 2007 vol. 177 no. 1 535-547
One-dimensional measuresMeanVariance
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• Genetic Heterogeneity PER GENES determines “Genetic Importance”
• We do NOT have adequate methods to measure genetic heterogeneity per genes.
Genetics September 2007 vol. 177 no. 1 535-547
One-dimensional measuresMeanVariance
How to measure?
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Genetic Heterogeneity PER GENESFor Species
OrFor Individuals
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Genetic Heterogeneity PER GENESFor Populations
OrFor Individuals
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Genetic Heterogeneity PER GENESFor Populations
OrFor Individuals
• Heterogeneity in an absolute scale
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Genetic Heterogeneity PER GENESFor Populations
OrFor Individuals
• Heterogeneity in an absolute scale
![Page 90: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/90.jpg)
Genetic Heterogeneity PER GENESFor Populations
OrFor Individuals
• Heterogeneity in an absolute scale• Heterogeneity in a relative scale inside of
individuals
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Genetic Heterogeneity PER GENESFor Populations
OrFor Individuals
• Heterogeneity in an absolute scale• Heterogeneity in a relative scale inside of
individuals
Intra-individul genetic heterogeneity
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Intra-individul Genetic Heterogeneity
• They are the source of phenotypic heterogeneity.
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Intra-individul Genetic Heterogeneity
• They are the source of phenotypic heterogeneity.
• Individuals have to show phenotypic variations that are the basics of living creatures.
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Intra-individul Genetic Heterogeneity
• They are the source of phenotypic heterogeneity.
• Individuals have to show phenotypic variations that are the basics of living creatures.
• Individual genetic heterogeneity is the resource for the individual to realize phenotypic variations.
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Intra-individul Genetic Heterogeneity
• Individual genetic heterogeneity is the resource for the individual to realize phenotypic variations.
• Genetic heterogeneity in a gene for an individual may be relatively more important than others, depending on other genes’ heterogeneity context.
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Intra-individul Genetic Heterogeneity
• Individual genetic heterogeneity is the resource to realize phenotypic variations by the individual.
• Genetic heterogeneity in a gene for an individual may be relatively more important than others, depending on other genes’ heterogeneity context.
G x G interaction
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G x G with rare variants
• G x G approach in general– Gene set in a functional pathway– Problems with too many combinations
• Same both for common variants and rare variants– Many and scarce variants might G x G approach
less realistic.– Scarce but Many variants could open new ways to
G x G approach ??
![Page 98: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/98.jpg)
G x G with rare variants
• G x G approach in general– Gene set in a functional pathway– Problems with too many combinations
• Same both for common variants and rare variants– Many and scarce variants might G x G approach
less realistic.– Scarce but Many variants could open new ways to
G x G approach ??
![Page 99: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/99.jpg)
G x G with rare variants
• G x G approach in general– Gene set in a functional pathway– Problems with too many combinations
• Same both for common variants and rare variants– Many and scarce variants might make G x G
approach less realistic.– Scarce but Many variants could open new ways to
G x G approach ??
![Page 100: Comments on Rare Variants Analyses Ryo Yamada Kyoto University 2012/08/27 IBC2012@Kobe, Japan](https://reader035.vdocuments.mx/reader035/viewer/2022062421/56649e2b5503460f94b19951/html5/thumbnails/100.jpg)
G x G with rare variants
• G x G approach in general– Gene set in a functional pathway– Problems with too many combinations
• Same both for common variants and rare variants– Many and scarce variants might make G x G
approach less realistic.– Scarce but Many variants could open new ways to
G x G approach with new measures?????
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Summary
• Next generation sequencing enabled rare variant analyses.
• Use what next generation sequencing brought us.– Expansion of phenotypes and genotypes– Set of hypotheses and multiple testing– Measures of genetic heterogeneity– Intra-individual heterogeneities
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Thank you
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Thank you
AnnouncementSymposium and Data Analysis Hands-on Seminar
Jan. 16 – Jan. 19, 2013@ Kyoto University, Kyoto, Japan
Organized by
Marc Lathrop @ CEPHJurg Ott @ Rockefeller Univ.
Fumihiko Matsuda @ Kyoto Univ.
Details will be announced shortly.If you are interested in this seminar
or need updated timely for the details or registration, e-mail to: [email protected] (Ryo Yamada, Kyoto Univ.)