Genome-wide analysis of expression quantitative trait loci ... · Genome-wide analysis of...
Transcript of Genome-wide analysis of expression quantitative trait loci ... · Genome-wide analysis of...
![Page 1: Genome-wide analysis of expression quantitative trait loci ... · Genome-wide analysis of expression quantitative trait loci in breast cancer Author: Nicholas Knoblauch Subject: TCGA](https://reader034.fdocuments.net/reader034/viewer/2022052013/6029ba74bc059b791b49d6d3/html5/thumbnails/1.jpg)
Genome-‐wide analysis of expressionquanMtaMve trait loci in breast
cancerNicholas KnoblauchResearch Assistant II
Beck LabDepartment of Pathology, Beth Israel Deaconess
Medical Center & Harvard Medical School
![Page 2: Genome-wide analysis of expression quantitative trait loci ... · Genome-wide analysis of expression quantitative trait loci in breast cancer Author: Nicholas Knoblauch Subject: TCGA](https://reader034.fdocuments.net/reader034/viewer/2022052013/6029ba74bc059b791b49d6d3/html5/thumbnails/2.jpg)
IntroducMon
Genotype Phenotype
![Page 3: Genome-wide analysis of expression quantitative trait loci ... · Genome-wide analysis of expression quantitative trait loci in breast cancer Author: Nicholas Knoblauch Subject: TCGA](https://reader034.fdocuments.net/reader034/viewer/2022052013/6029ba74bc059b791b49d6d3/html5/thumbnails/3.jpg)
IntroducMon
(Germline) Genotype
(Breast Cancer)Phenotype
![Page 4: Genome-wide analysis of expression quantitative trait loci ... · Genome-wide analysis of expression quantitative trait loci in breast cancer Author: Nicholas Knoblauch Subject: TCGA](https://reader034.fdocuments.net/reader034/viewer/2022052013/6029ba74bc059b791b49d6d3/html5/thumbnails/4.jpg)
Genotype Phenotype
![Page 5: Genome-wide analysis of expression quantitative trait loci ... · Genome-wide analysis of expression quantitative trait loci in breast cancer Author: Nicholas Knoblauch Subject: TCGA](https://reader034.fdocuments.net/reader034/viewer/2022052013/6029ba74bc059b791b49d6d3/html5/thumbnails/5.jpg)
Breast Cancer GWAS
• A number of SNPs are associated withincreased risk of Breast cancer–~50 in GWAS catalog
• How do we infer the mechanism of these riskalleles?– How do we study the funcMonal consequences ofvariaMon at these loci?
![Page 6: Genome-wide analysis of expression quantitative trait loci ... · Genome-wide analysis of expression quantitative trait loci in breast cancer Author: Nicholas Knoblauch Subject: TCGA](https://reader034.fdocuments.net/reader034/viewer/2022052013/6029ba74bc059b791b49d6d3/html5/thumbnails/6.jpg)
Gene Expression as a phenotype
• Easy to measure tensof thousands offeaturessimultaneously
• FacilitatesinvesMgaMon offuncMonal theconsequences ofgeneMc variance
![Page 7: Genome-wide analysis of expression quantitative trait loci ... · Genome-wide analysis of expression quantitative trait loci in breast cancer Author: Nicholas Knoblauch Subject: TCGA](https://reader034.fdocuments.net/reader034/viewer/2022052013/6029ba74bc059b791b49d6d3/html5/thumbnails/7.jpg)
Germline Genotype
eQTLAnalysis
ER status
Tumor Gene
Expression
![Page 8: Genome-wide analysis of expression quantitative trait loci ... · Genome-wide analysis of expression quantitative trait loci in breast cancer Author: Nicholas Knoblauch Subject: TCGA](https://reader034.fdocuments.net/reader034/viewer/2022052013/6029ba74bc059b791b49d6d3/html5/thumbnails/8.jpg)
Data
• 382 TCGA invasive breast cancer cases• Germline SNP data from Affymetrix 6.0 SNP• Expression from Agilent G4502A 244k Array• Imputed SNP data
– ~8 million SNPs
![Page 9: Genome-wide analysis of expression quantitative trait loci ... · Genome-wide analysis of expression quantitative trait loci in breast cancer Author: Nicholas Knoblauch Subject: TCGA](https://reader034.fdocuments.net/reader034/viewer/2022052013/6029ba74bc059b791b49d6d3/html5/thumbnails/9.jpg)
~1M SNPs ~8M SNPs• ImputaMon
– EsMmate genotype for ungenotyped markers using agenotyped reference panel
– BEAGLE • Infers haplotypes for unrelated individuals
– minimac• Low memory footprint • Implements MaCH algorithm
– 906600 SNPs – 1000G (Nov 2010) for imputaMon
![Page 10: Genome-wide analysis of expression quantitative trait loci ... · Genome-wide analysis of expression quantitative trait loci in breast cancer Author: Nicholas Knoblauch Subject: TCGA](https://reader034.fdocuments.net/reader034/viewer/2022052013/6029ba74bc059b791b49d6d3/html5/thumbnails/10.jpg)
--------------
EIGENSTRAT Analysis (PC1 vs. PC2)
Genetically estimated
White 577
Asian 42
Black 46
Total 665
![Page 11: Genome-wide analysis of expression quantitative trait loci ... · Genome-wide analysis of expression quantitative trait loci in breast cancer Author: Nicholas Knoblauch Subject: TCGA](https://reader034.fdocuments.net/reader034/viewer/2022052013/6029ba74bc059b791b49d6d3/html5/thumbnails/11.jpg)
Linear Model
g =α +γ x +βs +ε • Parameters for intercept,genotype andcovariate (ER status)
• MatrixEQTL– Tests each SNP-‐transcript pair– “Ultra-‐fast”
• ~2 days with 70GB RAM
![Page 12: Genome-wide analysis of expression quantitative trait loci ... · Genome-wide analysis of expression quantitative trait loci in breast cancer Author: Nicholas Knoblauch Subject: TCGA](https://reader034.fdocuments.net/reader034/viewer/2022052013/6029ba74bc059b791b49d6d3/html5/thumbnails/12.jpg)
Results
• Of ~8 million SNPs:–~140,000 SNP are eQTL–None of 51 known breast cancer riskalleles were detected as eQTL at thegiven significance threshold
![Page 13: Genome-wide analysis of expression quantitative trait loci ... · Genome-wide analysis of expression quantitative trait loci in breast cancer Author: Nicholas Knoblauch Subject: TCGA](https://reader034.fdocuments.net/reader034/viewer/2022052013/6029ba74bc059b791b49d6d3/html5/thumbnails/13.jpg)
Risk Alleles and eQTL
Not Risk Allele
Is a Risk Allele
Not eQTL 7880425 53
Is an eQTL 138138 0
Χ2=0.1901, p=0.6628
![Page 14: Genome-wide analysis of expression quantitative trait loci ... · Genome-wide analysis of expression quantitative trait loci in breast cancer Author: Nicholas Knoblauch Subject: TCGA](https://reader034.fdocuments.net/reader034/viewer/2022052013/6029ba74bc059b791b49d6d3/html5/thumbnails/14.jpg)
eQTL Network
• Loci -‐> Transcripts• In-‐degree• Out-‐degree• ConnecMvity
![Page 15: Genome-wide analysis of expression quantitative trait loci ... · Genome-wide analysis of expression quantitative trait loci in breast cancer Author: Nicholas Knoblauch Subject: TCGA](https://reader034.fdocuments.net/reader034/viewer/2022052013/6029ba74bc059b791b49d6d3/html5/thumbnails/15.jpg)
In-‐Degree DistribuMon
![Page 16: Genome-wide analysis of expression quantitative trait loci ... · Genome-wide analysis of expression quantitative trait loci in breast cancer Author: Nicholas Knoblauch Subject: TCGA](https://reader034.fdocuments.net/reader034/viewer/2022052013/6029ba74bc059b791b49d6d3/html5/thumbnails/16.jpg)
Out-‐Degree DistribuMon
![Page 17: Genome-wide analysis of expression quantitative trait loci ... · Genome-wide analysis of expression quantitative trait loci in breast cancer Author: Nicholas Knoblauch Subject: TCGA](https://reader034.fdocuments.net/reader034/viewer/2022052013/6029ba74bc059b791b49d6d3/html5/thumbnails/17.jpg)
QTs with highest in-‐degree
Gene In-‐degree Descrip;on
TSSK1B 4446 tesMs-‐specific serine kinase
CYB5A 3142 Cytochrome b5 type A
DPF3 2794 Zinc Finger Protein
PRL 2354 ProlacMn
MEN1 2156 mulMple endocrine neoplasia
CSH1 2120 chorionic somatomammotropinhormone 1 (placentallactogen)
![Page 18: Genome-wide analysis of expression quantitative trait loci ... · Genome-wide analysis of expression quantitative trait loci in breast cancer Author: Nicholas Knoblauch Subject: TCGA](https://reader034.fdocuments.net/reader034/viewer/2022052013/6029ba74bc059b791b49d6d3/html5/thumbnails/18.jpg)
![Page 19: Genome-wide analysis of expression quantitative trait loci ... · Genome-wide analysis of expression quantitative trait loci in breast cancer Author: Nicholas Knoblauch Subject: TCGA](https://reader034.fdocuments.net/reader034/viewer/2022052013/6029ba74bc059b791b49d6d3/html5/thumbnails/19.jpg)
“ER-‐dimorphic” eQTL• 32 eQTL with opposite t-‐staMsMc in ER+ andER-‐ cases.
Gene Descrip;on
CD5L inhibitor of apoptosis
C19orf6(membralin) Tumor-‐associatedprotein
MUC4 inhibitor of apoptosis
SPATA19 Spermiogenesis
IGF1R anM-‐apoptoMc agent byenhancing cell survival
H2AFB3 Atypical histone H2Awhich can replaceconvenMonal H2A insome nucleosomes
![Page 20: Genome-wide analysis of expression quantitative trait loci ... · Genome-wide analysis of expression quantitative trait loci in breast cancer Author: Nicholas Knoblauch Subject: TCGA](https://reader034.fdocuments.net/reader034/viewer/2022052013/6029ba74bc059b791b49d6d3/html5/thumbnails/20.jpg)
Conclusions
• Of 1,253,331,753,741 SNP-‐transcript interacMons, 375,127 eQTL were found
• Risk allele status does not predict eQTL status• ER status can interact with direcMon of eQTL• Germline genotype can lend insight intoBreast cancer phenotype
![Page 21: Genome-wide analysis of expression quantitative trait loci ... · Genome-wide analysis of expression quantitative trait loci in breast cancer Author: Nicholas Knoblauch Subject: TCGA](https://reader034.fdocuments.net/reader034/viewer/2022052013/6029ba74bc059b791b49d6d3/html5/thumbnails/21.jpg)
Acknowledgements
• AdiM Hazra• Pete Kra?• John Quackenbush• Constance Chen
• Andrew Beck