QTL Studies- Past, Present and Future. David Evans
|
|
- Maude Pitts
- 5 years ago
- Views:
Transcription
1 QTL Studies Past, Present and Future David Evans
2 Genetic studies of complex diseases have not met anticipated success Glazier et al, Science (2002) 298:
3 Korstanje & Pagan (2002) Nat Genet Korstanje & Pagan (2002) Nat Genet
4 Reasons for Failure? BUT Not much success in mapping complex diseases / traits! Individual environment Linkage Marker Linkage Gene 1 disequilibrium Linkage Association Complex Phenotype Mode of inheritance Gene 2 Gene 3 Common environment Polygenic background Weiss & Terwilliger (2000) Nat Genet
5 LD Patterns and Allelic Association Type 1 diabetes and Insulin VNTR Alzheimers and ApoE4 Bennett & Todd, Ann Rev Genet, 1996 Pattern of LD unpredictable Extent of common genetic variation unknown Roses, Nature 2000
6 Genomewide Association? Risch & Merikangas, Science 1996
7 Multiple Rare Variant Hypothesis? GWA assumes that common variants underlie common diseases
8 Enabling Genomewide Association Studies HAPlotype MAP High throughput genotyping Large cohorts ALSPAC
9 Wellcome Trust Case Control Consortium
10 Wellcome Trust CaseControl Consortium GenomeWide Association Across Major Human Diseases DESIGN Collaboration amongst 26 UK disease investigators 2000 cases each from 9 diseases 1000 cases from 4 diseases GENOTYPING Affymetrix 500k SNPs Illumina Human NS_12 SNP chip CASES 1. Type 1 Diabetes 2. Type 2 Diabetes 3. Crohn s Disease 4. Coronary Heart Disease 5. Hypertension 6. Bipolar Disorder 7. Rheumatoid Arthritis 8. Malaria 9. Tuberculosis 10. Ankylosing Spondylitis 11. Grave s Disease 12.Breast Cancer 13.Multiple Sclerosis CONTROLS 1. UK Controls A (1, BC) 2. UK Controls B (1,500 NBS) 3. Gambian controls (2000)
11
12 Ankylosing Spondylitis Autoimmune arthritis resulting in fusion of vertebrae Prevalence of 0.4% in Caucasians. More common in men. Often associated with psoriasis, IBD and uveitis Ed Sullivan, Mike Atherton
13 Ankylosing Spondylitis GWAS WTCCC (2007) Nat Genet IL23R ARTS1
14 Successes MSMB JAZF1 CTBP2 HNF1B 10q21 PTPN2 FAM92B NKX23 IFIH1 CTLA4 KCNJ11 ERBB3 TCF2 WFS1 TCF7L2 Common genes = common etiology? Some in gene deserts Large relative risks does not = success 11q13 NCF4 CD25 SLC30A8 Drug targets 2q35 LSP1 3des. NUDT11 PHOX2B IRGM PTPN22 KIAAA 035D PPARG HHEX MAPKI3 SLC22A3 BSN IL2RA IGF2BP2 TNRC9 KLK3 ATG16L1 18p11 CDKAL1 2q36 8q24 LMTK2 8q24 5p13 12q24 FTO 6q251 IL21 IL23R FGFR2 8q24 SMAD7 NOD2 IL23R INS 9p21 FTO GCKR 9p21 IL2 PTPN22 ARTS GALP LOXL1 ORMDL Breast ca Prostate ca Colorectal ca Crohn s Dis IBD T1D T2D Obesity Triglycerides CAD Coeliac Dis Rheumatoid A Ankylosing S Alzheimer Dis Glaucoma Asthma
15 What About Quantitative Traits? 1 Gene 3 Genotypes 3 Phenotypes 2 Genes 9 Genotypes 5 Phenotypes 3 Genes 27 Genotypes 7 Phenotypes 4 Genes 81 Genotypes 9 Phenotypes Quantitative genetics theory suggests that quantitative traits are the result of many variants of small effect Unselected samples Central Limit Theorem Normal Distribution The corollary is that very large sample sizes will be needed to detect these variants in UNSELECTED samples
16
17 FTSO WTCCC T2D Scan FTO FTO produces a moderate signal in WTCCC T2D scan But, no signal in an American T2D scan? American cases and controls matched on BMI
18 Replication is critical!!! FTO
19 Height The Archetypal Polygenic Dizygotic Twins Trait Monozygotic Twins Twin, family and adoption studies suggest that, within a population, 90% of variation in height is due to genetic variation Twins separated at birth Borjeson, Acta Paed, 1976
20 GWA of Height A 1914 Cases (WTCCC T2D) B 4892 Cases (DGI) C 6788 Cases (WTCCC HT) D 8668 Cases (WTCCC CAD) E Cases (EPIC) F Cases (WTCCC UKBS) Weedon et al. (in press) Nat Genet Large numbers are needed to detect QTLs!!! Significant results Other loci? Collaboration is the name of the game!!!
21 A: 1,900 B: 5,000 C: 7,200 D: 9,100 E: 12,600 F: 14,000 Some real hits sit in the bottom of the distribution Weedon et al. (in press) Nat Genet Some hits initially look interesting but then go away
22 Hedgehog signaling, cell cycle, and extracellular matrix genes overrepresented Candidate gene Monogenic Knockout mouse Details* ZBTB38 Transcription factor. CDK6 Yes Involved in the control of the cell cycle. HMGA2 Yes Yes Chromatin architectural factors GDF5 Yes Yes Involved in bone formation LCORL May act as transcription activator LOC Not known EFEMP1 Yes Extracellular matrix C6orf106 Not known PTCH1 Yes Yes Hedgehog signalling SPAG17 Not known SOCS2 Yes Regulates cytokine signal transduction HHIP Hedgehog signaling ZNF678 Transcription factor DLEU7 Not known SCMH1 Yes Polycomb protein ADAMTSL3 Extracellular matrix IHH Yes Yes Hedgehog signaling ANAPC13 Cell cycle ACAN Yes Yes Extracellular matrix DYM Yes Not known Weedon et al. (in press) Nat Genet
23 The combined impact of the 20 SNPS with a P < 5 x 10 7 The 20 SNPs explain only ~3% of the variation of height Lots more genes to find but extremely large numbers needed Weedon et al. (in press) Nat Genet
24 Height Linkage Regions Perola et al, Plos Genetics, 2007; data available at Weedon et al.; unpublished data
25 Perola et al, Plos Genetics, 2007; data available at Weedon et al.; unpublished data
26 What s Going On? Loci identified by GWAs don t have linkage peaks over them Linkage analysis lacks power? Areas identified by linkage don t have significant assocation hits over them Type I error? Power? BUT what if linkage analysis and association analysis identify different types of loci?
27 What next? Genomewide Sequencing Functional Studies Animal models Other ethnic groups Epigenetics Fine mapping Initial Genome Wide Scans More genes Transcriptomics Mendelian Randomisation Genomic Profiling CNVs
28 Distribution of MAFs in HapMap Genomewide panels and HapMap biased towards common variants Common variants don t tag rare variants well
29 Complex Disease Tree??????????????? High hanging fruit??? ARTS1 TCF7L2 FTO IL23R PPARG Low hanging fruit WFS1 TCF2 HLAB27 SEMA5A Rotten Fruit
30 Methods of gene hunting rare, monogenic (linkage) Effect Size? common, complex (association) Frequency
31 Genomewide Sequencing Sequence individuals genomes Will identify rare variants But will we have enough power? Evans et al. (2008) EJHG
32 Genomic Profiling The idea of using genetic information to inform diagnosis Predictive testing in the case of monogenic diseases has been used for years (1300+ tests available) (e.g. Phenylketonuria) Not possible in complex diseases as effects of an individual variant is so small BUT if we consider several predisposing genetic and environmental factors, can we predict disease?
33 Genomic Profiling (from Janssens et al AJHG) => Give up and go home? (from Yang et al AJHG)
34 Ankylosing Spondylitis POSTERIOR PROBABILITY OF DISEASE D+/B27+ D+/B27 D+/B27+,ARTS1+,IL23+ D+/B27/ARTS1/IL23R PRIOR DISEASE PROBABILITY (Brown & Evans, in prep) Prevalence of B27+, ARTS1+,IL23R+ is 2.4% Prevalence of B27, ARTS1, IL23R is 19%
35 Using Genetics to Inform Classical Epidemiology
36 Observational Studies Fanciful claims often made from observational studies In a casecontrol study, a group of diseased individuals are recruited (Cases); A group of individuals without disease are gathered (Controls); Both groups are then measured retrospectively on an exposure of interest; A test of association is performed Example: Obesity (Exposure) and Coronary Heart Disease (Outcome) CHD Control Obesity Yes No Odds of obesity in cases: 200/100 = Odds of obesity in controls: 50/250 = 0.2 Odds Ratio: 2/0.2 = 10
37 Confounding Classic limitations to observational science Reverse Causation Bias
38 Randomized Control Trials Individuals free from exposure and disease Randomization Treatment Group Control Group Measure Outcome Measure Outcome Randomization controls for confounding Reverse causation impossible Gold standard for assessing causality
39 Mendelian Randomization RCTs not always ethical or possible Fortunately nature has provided us with a natural randomized control trial! Mendel s law of independent assortment states that inheritance of a trait is independent (randomized) with respect to other traits Therefore individuals are randomly assigned to three groups based on their genotype (AA, Aa, aa) independent of outcome Assessing the relationship between genotype, environmental risk factor and disease informs us on causality
40 Mendelian Randomization Genetic Variant (FTO) Confounding Variables (smoking, diet etc.) β FTOObesity Modifiable Environmental Exposure (Obesity) β ObesityCHD Disease (Coronary Heart Disease) If obesity causes CHD then the relationship between FTO and CHD should be estimated by the product of β FTOObesity and β ObesityCHD
41 Mendelian Randomization Genetic Variant (FTO) Confounding Variables (smoking, diet etc.) β FTOObesity Modifiable Environmental Exposure (Obesity) β ObesityCHD Disease (Coronary Heart Disease) If CHD causes obesity then β FTOCHD should be zero.
42 Mendelian Randomization Genetic Variant (FTO) Confounding Variables (smoking, diet etc.) β FTOObesity Modifiable Environmental Exposure (Obesity) Disease (Coronary Heart Disease) If the relationship between Obesity and CHD is purely correlational (i.e. due to confounding) then β FTOCHD should be 0
43 Mendelian Randomization Genetic Variant (FTO) Confounding Variables (smoking, diet etc.) Modifiable Environmental Exposure (Obesity) Disease (Coronary Heart Disease) Genotype is associated with the environmental exposure of interest Genotype is NOT associated with confounders Genotype is only related to its outcome via its association with the modifiable environmental exposure
44 Mendelian Randomization Mendelian Randomization is a way of using a genetic variant(s) to make causal inferences about (modifiable) environmental risk factors for disease and health related outcomes Environmental exposures (e.g. Obesity) can be modified! Genetic factors cannot (at least for the moment ) Still a relatively new approach that has problems (i.e. finding genetic proxies for environmental exposures multiple instruments?) but a LOT of scope for development
45 Could SEM be used to enhance MR? Genetic Variant (FTO) Confounding Variables (smoking, diet etc.) Modifiable Environmental Exposure (Obesity) Disease (Coronary Heart Disease) Genetic Variant (MC4R) Genetic Variant (?)
Thinking big: Finding more and (more) genes influencing glycaemic and anthropometric traits. Mark McCarthy, Oxford
Thinking big: Finding more and (more) genes influencing glycaemic and anthropometric traits Mark McCarthy, Oxford Slow progress in finding multifactorial genes Glazier et al, Science, 2002 Why? biological
More informationIntroduction to linkage and family based designs to study the genetic epidemiology of complex traits. Harold Snieder
Introduction to linkage and family based designs to study the genetic epidemiology of complex traits Harold Snieder Overview of presentation Designs: population vs. family based Mendelian vs. complex diseases/traits
More informationIntroduction to the Genetics of Complex Disease
Introduction to the Genetics of Complex Disease Jeremiah M. Scharf, MD, PhD Departments of Neurology, Psychiatry and Center for Human Genetic Research Massachusetts General Hospital Breakthroughs in Genome
More informationCS2220 Introduction to Computational Biology
CS2220 Introduction to Computational Biology WEEK 8: GENOME-WIDE ASSOCIATION STUDIES (GWAS) 1 Dr. Mengling FENG Institute for Infocomm Research Massachusetts Institute of Technology mfeng@mit.edu PLANS
More informationIntroduction to Genetics and Genomics
2016 Introduction to enetics and enomics 3. ssociation Studies ggibson.gt@gmail.com http://www.cig.gatech.edu Outline eneral overview of association studies Sample results hree steps to WS: primary scan,
More informationMining the Human Phenome Using Allelic Scores That Index Biological Intermediates
That Index Biological Intermediates The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters. Citation Published Version Accessed Citable
More informationGWAS of HCC Proposed Statistical Approach Mendelian Randomization and Mediation Analysis. Chris Amos Manal Hassan Lewis Roberts Donghui Li
GWAS of HCC Proposed Statistical Approach Mendelian Randomization and Mediation Analysis Chris Amos Manal Hassan Lewis Roberts Donghui Li Overall Design of GWAS Study Aim 1 (DISCOVERY PHASE): To genotype
More informationQuantitative genetics: traits controlled by alleles at many loci
Quantitative genetics: traits controlled by alleles at many loci Human phenotypic adaptations and diseases commonly involve the effects of many genes, each will small effect Quantitative genetics allows
More informationOver the past year, the capacity to perform
BRIEF REPORT Adiposity-Related Heterogeneity in Patterns of Type 2 Diabetes Susceptibility Observed in Genome-Wide Association Data Nicholas J. Timpson, 1,2 Cecilia M. Lindgren, 1,3 Michael N. Weedon,
More informationGenetics and Pharmacogenetics in Human Complex Disorders (Example of Bipolar Disorder)
Genetics and Pharmacogenetics in Human Complex Disorders (Example of Bipolar Disorder) September 14, 2012 Chun Xu M.D, M.Sc, Ph.D. Assistant professor Texas Tech University Health Sciences Center Paul
More informationEffects of environment and genetic interactions on chronic metabolic diseases
22 1 2010 1 Chinese Bulletin of Life Sciences Vol. 22, No. 1 Jan., 2010 1004-0374(2010)01-0001-06 ( 200031) 2 2 20 2 2 2 R151; R589; R587.1; R363.16 A Effects of environment and genetic interactions on
More informationAn Introduction to Quantitative Genetics I. Heather A Lawson Advanced Genetics Spring2018
An Introduction to Quantitative Genetics I Heather A Lawson Advanced Genetics Spring2018 Outline What is Quantitative Genetics? Genotypic Values and Genetic Effects Heritability Linkage Disequilibrium
More informationMULTIFACTORIAL DISEASES. MG L-10 July 7 th 2014
MULTIFACTORIAL DISEASES MG L-10 July 7 th 2014 Genetic Diseases Unifactorial Chromosomal Multifactorial AD Numerical AR Structural X-linked Microdeletions Mitochondrial Spectrum of Alterations in DNA Sequence
More informationGenes, Genes, Everywhere! The key to a cure for IBD
Genes, Genes, Everywhere! The key to a cure for IBD Dermot McGovern MD, PhD, FRCP Director, Translational Medicine Professor of Medicine Joshua L and Lisa Z Greer Endowed Chair in IBD Genetics F. Widjaja
More informationBST227 Introduction to Statistical Genetics. Lecture 4: Introduction to linkage and association analysis
BST227 Introduction to Statistical Genetics Lecture 4: Introduction to linkage and association analysis 1 Housekeeping Homework #1 due today Homework #2 posted (due Monday) Lab at 5:30PM today (FXB G13)
More informationLarge-scale identity-by-descent mapping discovers rare haplotypes of large effect. Suyash Shringarpure 23andMe, Inc. ASHG 2017
Large-scale identity-by-descent mapping discovers rare haplotypes of large effect Suyash Shringarpure 23andMe, Inc. ASHG 2017 1 Why care about rare variants of large effect? Months from randomization 2
More informationGenetics of Pediatric Inflammatory Bowel Disease
Genetics of Pediatric Inflammatory Bowel Disease Judith Kelsen MD Assistant Professor of Pediatrics Division of Gastroenterology, Hepatology, and Nutrition IBD Education Day 2/9/2014 Objectives Brief overview
More informationDan Koller, Ph.D. Medical and Molecular Genetics
Design of Genetic Studies Dan Koller, Ph.D. Research Assistant Professor Medical and Molecular Genetics Genetics and Medicine Over the past decade, advances from genetics have permeated medicine Identification
More informationResults. Introduction
(2009) 10, S95 S120 & 2009 Macmillan Publishers Limited All rights reserved 1466-4879/09 $32.00 www.nature.com/gene ORIGINAL ARTICLE Analysis of 55 autoimmune disease and type II diabetes loci: further
More informationDuring the hyperinsulinemic-euglycemic clamp [1], a priming dose of human insulin (Novolin,
ESM Methods Hyperinsulinemic-euglycemic clamp procedure During the hyperinsulinemic-euglycemic clamp [1], a priming dose of human insulin (Novolin, Clayton, NC) was followed by a constant rate (60 mu m
More informationA genome-wide association study identifies vitiligo
A genome-wide association study identifies vitiligo susceptibility loci at MHC and 6q27 Supplementary Materials Index Supplementary Figure 1 The principal components analysis (PCA) of 2,546 GWAS samples
More informationGenetics of common disorders with complex inheritance Bettina Blaumeiser MD PhD
Genetics of common disorders with complex inheritance Bettina Blaumeiser MD PhD Medical Genetics University Hospital & University of Antwerp Programme Day 6: Genetics of common disorders with complex inheritance
More informationMendelian Randomization
Mendelian Randomization Drawback with observational studies Risk factor X Y Outcome Risk factor X? Y Outcome C (Unobserved) Confounders The power of genetics Intermediate phenotype (risk factor) Genetic
More informationFTO Polymorphisms Are Associated with Obesity But Not with Diabetes in East Asian Populations: A Meta analysis
BIOMEDICAL AND ENVIRONMENTAL SCIENCES 22, 449 457 (2009) www.besjournal.com FTO Polymorphisms Are Associated with Obesity But Not with Diabetes in East Asian Populations: A Meta analysis BO XI #, + AND
More informationOverview of the Synthetic Derivative
Overview of the Synthetic Derivative April 22, 2009 Melissa Basford, MBA Program Manager, BioVU and Synthetic Derivative What is BioVU? A biobank intended to support a broad view of biology Currently contains
More informationAdditional Disclosure
Additional Disclosure The Genetics of Prostate Cancer: Clinical Implications William J. Catalona, MD Collaborator with decode genetics, Inc. Non-paid consultant with no financial interest or support Northwestern
More informationGenetics and Genomics in Medicine Chapter 8 Questions
Genetics and Genomics in Medicine Chapter 8 Questions Linkage Analysis Question Question 8.1 Affected members of the pedigree above have an autosomal dominant disorder, and cytogenetic analyses using conventional
More informationOur Stage 1 genotype scan was performed using Illumina Human1 Beadarrays, which have a
Supplementary Note Analysis of Stage 1 GWAS and design of the Stage 2 iselect array Our Stage 1 genotype scan was performed using Illumina Human1 Beadarrays, which have a gene-centric design, and Illumina
More informationTopic (Final-03): Immunologic Tolerance and Autoimmunity-Part II
Topic (Final-03): Immunologic Tolerance and Autoimmunity-Part II MECHANISMS OF AUTOIMMUNITY The possibility that an individual s immune system may react against autologous antigens and cause tissue injury
More informationImaging Genetics: Heritability, Linkage & Association
Imaging Genetics: Heritability, Linkage & Association David C. Glahn, PhD Olin Neuropsychiatry Research Center & Department of Psychiatry, Yale University July 17, 2011 Memory Activation & APOE ε4 Risk
More informationAn expanded view of complex traits: from polygenic to omnigenic
BIRS 2017 An expanded view of complex traits: from polygenic to omnigenic How does human genetic variation drive variation in complex traits/disease risk? Yang I Li Stanford University Evan Boyle Jonathan
More informationBST227: Introduction to Statistical Genetics
BST227: Introduction to Statistical Genetics Lecture 11: Heritability from summary statistics & epigenetic enrichments Guest Lecturer: Caleb Lareau Success of GWAS EBI Human GWAS Catalog As of this morning
More informationWhite Paper Guidelines on Vetting Genetic Associations
White Paper 23-03 Guidelines on Vetting Genetic Associations Authors: Andro Hsu Brian Naughton Shirley Wu Created: November 14, 2007 Revised: February 14, 2008 Revised: June 10, 2010 (see end of document
More informationGenetic Meta-Analysis and Mendelian Randomization
Genetic Meta-Analysis and Mendelian Randomization George Davey Smith MRC Centre for Causal Analyses in Translational Epidemiology, University of Bristol RCT vs Observational Meta- Analysis: fundamental
More informationSpecial Report. Genome-wide association studies and musculoskeletal diseases. Future Rheumatology
Genome-wide association studies and musculoskeletal diseases Patrick Danoy & Matthew A Brown Author for correspondence: Diamantina Institute of Cancer, Immunology and Metabolic Medicine, The University
More informationDoes prenatal alcohol exposure affect neurodevelopment? Attempts to give causal answers
Does prenatal alcohol exposure affect neurodevelopment? Attempts to give causal answers Luisa Zuccolo l.zuccolo@bristol.ac.uk MRC IEU, School of Social and Community Medicine Background Prenatal alcohol
More informationEditorial Type 2 Diabetes and More Gene Panel: A Predictive Genomics Approach for a Polygenic Disease
Cronicon OPEN ACCESS EC DIABETES AND METABOLIC RESEARCH Editorial Type 2 Diabetes and More Gene Panel: A Predictive Genomics Approach for a Polygenic Disease Amr TM Saeb* University Diabetes Center, College
More informationHeritability and genetic correlations explained by common SNPs for MetS traits. Shashaank Vattikuti, Juen Guo and Carson Chow LBM/NIDDK
Heritability and genetic correlations explained by common SNPs for MetS traits Shashaank Vattikuti, Juen Guo and Carson Chow LBM/NIDDK The Genomewide Association Study. Manolio TA. N Engl J Med 2010;363:166-176.
More informationGenome-wide association studies (case/control and family-based) Heather J. Cordell, Institute of Genetic Medicine Newcastle University, UK
Genome-wide association studies (case/control and family-based) Heather J. Cordell, Institute of Genetic Medicine Newcastle University, UK GWAS For the last 8 years, genome-wide association studies (GWAS)
More informationCordoba 01/02/2008. Slides Professor Pierre LEFEBVRE
Cordoba 01/02/2008 Slides Professor Pierre LEFEBVRE Clinical Research in Type 2 Diabetes : Current Status and Future Approaches Pierre Lefèbvre* University of Liège Belgium Granada, Spain, February 2008
More informationARTICLE Genetic Risk Factors for Type 2 Diabetes: A Trans-Regulatory Genetic Architecture?
ARTICLE Genetic Risk Factors for Type 2 Diabetes: A Trans-Regulatory Genetic Architecture? Steven C. Elbein, 1,7,8 Eric R. Gamazon, 2,7 Swapan K. Das, 1 Neda Rasouli, 3,4 Philip A. Kern, 5,6 and Nancy
More informationTransferability of Type 2 Diabetes Implicated Loci in Multi-Ethnic Cohorts from Southeast Asia
Transferability of Type 2 Diabetes Implicated Loci in Multi-Ethnic Cohorts from Southeast Asia Xueling Sim 1, Rick Twee-Hee Ong 1,2,3, Chen Suo 1, Wan-Ting Tay 4, Jianjun Liu 3, Daniel Peng-Keat Ng 5,
More informationHeritability enrichment of differentially expressed genes. Hilary Finucane PGC Statistical Analysis Call January 26, 2016
Heritability enrichment of differentially expressed genes Hilary Finucane PGC Statistical Analysis Call January 26, 2016 1 Functional genomics + GWAS gives insight into disease relevant tissues Trynka
More informationOverlap of disease susceptibility loci for rheumatoid arthritis and juvenile idiopathic arthritis
Additional data are published online only. To view these fi les please visit the journal online (http://ard.bmj.com) 1 arc-eu, Stopford Building, The University of Manchester, Manchester, UK 2 Haywood
More informationThe genetic architecture of type 2 diabetes appears
ORIGINAL ARTICLE A 100K Genome-Wide Association Scan for Diabetes and Related Traits in the Framingham Heart Study Replication and Integration With Other Genome-Wide Datasets Jose C. Florez, 1,2,3 Alisa
More informationMRC Integrative Epidemiology Unit (IEU) at the University of Bristol. George Davey Smith
MRC Integrative Epidemiology Unit (IEU) at the University of Bristol George Davey Smith The making of a University Unit MRC Centre for Causal Analyses in Translational Epidemiology 2007 to 2013 Interdisciplinary
More informationGenetic association analysis incorporating intermediate phenotypes information for complex diseases
University of Iowa Iowa Research Online Theses and Dissertations Fall 2011 Genetic association analysis incorporating intermediate phenotypes information for complex diseases Yafang Li University of Iowa
More informationGenome-wide Association Analysis Applied to Asthma-Susceptibility Gene. McCaw, Z., Wu, W., Hsiao, S., McKhann, A., Tracy, S.
Genome-wide Association Analysis Applied to Asthma-Susceptibility Gene McCaw, Z., Wu, W., Hsiao, S., McKhann, A., Tracy, S. December 17, 2014 1 Introduction Asthma is a chronic respiratory disease affecting
More informationIS IT GENETIC? How do genes, environment and chance interact to specify a complex trait such as intelligence?
1 IS IT GENETIC? How do genes, environment and chance interact to specify a complex trait such as intelligence? Single-gene (monogenic) traits Phenotypic variation is typically discrete (often comparing
More informationMultifactorial Inheritance. Prof. Dr. Nedime Serakinci
Multifactorial Inheritance Prof. Dr. Nedime Serakinci GENETICS I. Importance of genetics. Genetic terminology. I. Mendelian Genetics, Mendel s Laws (Law of Segregation, Law of Independent Assortment).
More informationMultifactorial Inheritance
S e s s i o n 6 Medical Genetics Multifactorial Inheritance and Population Genetics J a v a d J a m s h i d i F a s a U n i v e r s i t y o f M e d i c a l S c i e n c e s, Novemb e r 2 0 1 7 Multifactorial
More informationSummary & general discussion
Summary & general discussion 160 chapter 8 The aim of this thesis was to identify genetic and environmental risk factors for behavioral problems, in particular Attention Problems (AP) and Attention Deficit
More informationSupplemental Table 1 Age and gender-specific cut-points used for MHO.
Supplemental Table 1 Age and gender-specific cut-points used for MHO. Age SBP (mmhg) DBP (mmhg) HDL-C (mmol/l) TG (mmol/l) FG (mmol/l) Boys 6-11 90th * 90th * 1.03 1.24 5.6 12 121 76 1.13 1.44 5.6 13 123
More informationGenetics and the Path Towards Targeted Therapies in Systemic Lupus
Genetics and the Path Towards Targeted Therapies in Systemic Lupus Emily Baechler Gillespie, Ph.D. University of Minnesota Department of Medicine Division of Rheumatic and Autoimmune Diseases Disclosures
More informationOn Missing Data and Genotyping Errors in Association Studies
On Missing Data and Genotyping Errors in Association Studies Department of Biostatistics Johns Hopkins Bloomberg School of Public Health May 16, 2008 Specific Aims of our R01 1 Develop and evaluate new
More informationDOES THE BRCAX GENE EXIST? FUTURE OUTLOOK
CHAPTER 6 DOES THE BRCAX GENE EXIST? FUTURE OUTLOOK Genetic research aimed at the identification of new breast cancer susceptibility genes is at an interesting crossroad. On the one hand, the existence
More informationSupplementary Online Content
Supplementary Online Content Lyall DM, Celis-Morales C, Ward J, et al. Association of body mass index with cardiometabolic disease in the UK Biobank: a mendelian randomization study. JAMA Cardiol. Published
More informationFTO gene variants are strongly associated with type 2 diabetes in South Asian Indians
Diabetologia (2009) 52:247 252 DOI 10.1007/s00125-008-1186-6 SHORT COMMUNICATION FTO gene variants are strongly associated with type 2 diabetes in South Asian Indians C. S. Yajnik & C. S. Janipalli & S.
More informationSNPrints: Defining SNP signatures for prediction of onset in complex diseases
SNPrints: Defining SNP signatures for prediction of onset in complex diseases Linda Liu, Biomedical Informatics, Stanford University Daniel Newburger, Biomedical Informatics, Stanford University Grace
More informationThe genetics of complex traits Amazing progress (much by ppl in this room)
The genetics of complex traits Amazing progress (much by ppl in this room) Nick Martin Queensland Institute of Medical Research Brisbane Boulder workshop March 11, 2016 Genetic Epidemiology: Stages of
More informationGenome- Wide Association Studies of Human Growth Traits
Drivers of Growth Gillman MW, Gluckman PD, Rosenfeld RG (eds): Recent Advances in Growth Research: Nutritional, Molecular and Endocrine Perspectives. Nestlé Nutr Inst Workshop Ser, vol 71, pp 29 38, (DOI:
More informationExample HLA-B and abacavir. Roujeau 2014
Example HLA-B and abacavir Roujeau 2014 FDA requires testing for abacavir Treatment with abacavir is generally well tolerated, but 5% of the patients experience hypersensitivity reactions that can be life
More informationTutorial on Genome-Wide Association Studies
Tutorial on Genome-Wide Association Studies Assistant Professor Institute for Computational Biology Department of Epidemiology and Biostatistics Case Western Reserve University Acknowledgements Dana Crawford
More informationFor more information about how to cite these materials visit
Author(s): Kerby Shedden, Ph.D., 2010 License: Unless otherwise noted, this material is made available under the terms of the Creative Commons Attribution Share Alike 3.0 License: http://creativecommons.org/licenses/by-sa/3.0/
More informationMissing Heritablility How to Analyze Your Own Genome Fall 2013
Missing Heritablility 02-223 How to Analyze Your Own Genome Fall 2013 Heritability Heritability: the propor>on of observed varia>on in a par>cular trait (as height) that can be agributed to inherited gene>c
More informationGenomic approach for drug target discovery and validation
Genomic approach for drug target discovery and validation Hong-Hee Won, Ph.D. SAIHST, SKKU wonhh@skku.edu Well-known example of genetic findings triggering drug development Genetics Mendelian randomisation
More informationNew Enhancements: GWAS Workflows with SVS
New Enhancements: GWAS Workflows with SVS August 9 th, 2017 Gabe Rudy VP Product & Engineering 20 most promising Biotech Technology Providers Top 10 Analytics Solution Providers Hype Cycle for Life sciences
More information26 th International Workshop on Methodology for Human Genomic Studies: the Advanced course
26 th International Workshop on Methodology for Human Genomic Studies: the Advanced course Ben Neale (co-director) Goncalo Abecasis(co-director) Jeff Barrett David Evans Pak Sham Lindon Eaves Mike Neale
More informationCommon variants in WFS1 confer risk of type 2 diabetes
Europe PMC Funders Group Author Manuscript Published in final edited form as: Nat Genet. 2007 August ; 39(8): 951 953. doi:10.1038/ng2067. Common variants in WFS1 confer risk of type 2 diabetes Manjinder
More informationThe Genetic Epidemiology of Rheumatoid Arthritis. Lindsey A. Criswell AURA meeting, 2016
The Genetic Epidemiology of Rheumatoid Arthritis Lindsey A. Criswell AURA meeting, 2016 Overview Recent successes in gene identification genome wide association studies (GWAS) clues to etiologic pathways
More informationSUPPLEMENTARY DATA. 1. Characteristics of individual studies
1. Characteristics of individual studies 1.1. RISC (Relationship between Insulin Sensitivity and Cardiovascular disease) The RISC study is based on unrelated individuals of European descent, aged 30 60
More informationComponents of heritability in an Icelandic cohort
Components of heritability in an Icelandic cohort Noah Zaitlen Harvard School of Public Health Conflict of Interest Disclosure Four of the authors (Helgason, Gudbjartsson, Kong, Stefansson) are shareholders
More informationMetabolomics for Characterizing the Human Exposome: The need for a unified and high-throughput way to ascertain environmental exposures
Metabolomics for Characterizing the Human Exposome: The need for a unified and high-throughput way to ascertain environmental exposures Chirag J Patel 5/28/2015 Center for Biomedical Informatics Harvard
More informationGENOME-WIDE ASSOCIATION STUDIES
GENOME-WIDE ASSOCIATION STUDIES SUCCESSES AND PITFALLS IBT 2012 Human Genetics & Molecular Medicine Zané Lombard IDENTIFYING DISEASE GENES??? Nature, 15 Feb 2001 Science, 16 Feb 2001 IDENTIFYING DISEASE
More informationNature Genetics: doi: /ng Supplementary Figure 1
Supplementary Figure 1 Illustrative example of ptdt using height The expected value of a child s polygenic risk score (PRS) for a trait is the average of maternal and paternal PRS values. For example,
More informationLecture 20. Disease Genetics
Lecture 20. Disease Genetics Michael Schatz April 12 2018 JHU 600.749: Applied Comparative Genomics Part 1: Pre-genome Era Sickle Cell Anaemia Sickle-cell anaemia (SCA) is an abnormality in the oxygen-carrying
More informationIntroduction of Genome wide Complex Trait Analysis (GCTA) Presenter: Yue Ming Chen Location: Stat Gen Workshop Date: 6/7/2013
Introduction of Genome wide Complex Trait Analysis (GCTA) resenter: ue Ming Chen Location: Stat Gen Workshop Date: 6/7/013 Outline Brief review of quantitative genetics Overview of GCTA Ideas Main functions
More informationSupplementary Online Content
Supplementary Online Content Lotta LA, Stewart ID, Sharp SJ, et al. Association of genetically enhanced lipoprotein lipase mediated lipolysis and low-density lipoprotein cholesterol lowering alleles with
More informationNature Genetics: doi: /ng Supplementary Figure 1
Supplementary Figure 1 Replicability of blood eqtl effects in ileal biopsies from the RISK study. eqtls detected in the vicinity of SNPs associated with IBD tend to show concordant effect size and direction
More informationSupplementary Figure 1: Attenuation of association signals after conditioning for the lead SNP. a) attenuation of association signal at the 9p22.
Supplementary Figure 1: Attenuation of association signals after conditioning for the lead SNP. a) attenuation of association signal at the 9p22.32 PCOS locus after conditioning for the lead SNP rs10993397;
More informationReplication of 13 genome-wide association (GWA)-validated risk variants for type 2 diabetes in Pakistani populations
Diabetologia (2011) 54:1368 1374 DOI 10.1007/s00125-011-2063-2 ARTICLE Replication of 13 genome-wide association (GWA)-validated risk variants for type 2 diabetes in Pakistani populations S. D. Rees &
More informationSupplementary Online Content
Supplementary Online Content Hartwig FP, Borges MC, Lessa Horta B, Bowden J, Davey Smith G. Inflammatory biomarkers and risk of schizophrenia: a 2-sample mendelian randomization study. JAMA Psychiatry.
More informationMendelian & Complex Traits. Quantitative Imaging Genomics. Genetics Terminology 2. Genetics Terminology 1. Human Genome. Genetics Terminology 3
Mendelian & Complex Traits Quantitative Imaging Genomics David C. Glahn, PhD Olin Neuropsychiatry Research Center & Department of Psychiatry, Yale University July, 010 Mendelian Trait A trait influenced
More informationAssessing Accuracy of Genotype Imputation in American Indians
Assessing Accuracy of Genotype Imputation in American Indians Alka Malhotra*, Sayuko Kobes, Clifton Bogardus, William C. Knowler, Leslie J. Baier, Robert L. Hanson Phoenix Epidemiology and Clinical Research
More informationHuman population sub-structure and genetic association studies
Human population sub-structure and genetic association studies Stephanie A. Santorico, Ph.D. Department of Mathematical & Statistical Sciences Stephanie.Santorico@ucdenver.edu Global Similarity Map from
More informationGenetic predisposition to obesity leads to increased risk of type 2 diabetes
Diabetologia (2011) 54:776 782 DOI 10.1007/s00125-011-2044-5 ARTICLE Genetic predisposition to obesity leads to increased risk of type 2 diabetes S. Li & J. H. Zhao & J. Luan & C. Langenberg & R. N. Luben
More informationRole of Genomics in Selection of Beef Cattle for Healthfulness Characteristics
Role of Genomics in Selection of Beef Cattle for Healthfulness Characteristics Dorian Garrick dorian@iastate.edu Iowa State University & National Beef Cattle Evaluation Consortium Selection and Prediction
More informationThe Risk of Anti-selection in Protection Business from Advances in Statistical Genetics
The Risk of Anti-selection in Protection Business from Advances in Statistical Genetics Richard Russell, PhD Lead Health Data Scientist Stephen Courquin Head of UK Actuarial Research Peter Banthorpe SVP,
More informationGenetics of COPD Prof. Ian P Hall
Genetics of COPD 1 Prof. Ian P. Hall Dean, Faculty of Medicine and Health Sciences The University of Nottingham Medical School Ian.Hall@nottingham.ac.uk Chronic obstructive pulmonary disease (COPD) 900,000
More informationEXAMINATION OF THE CONTRIBUTION OF DIFFERENCES IN DISEASE ARCHITECTURE AND EPISTASIS TO TYPE 2 DIABETES RISK IN AFRICAN AMERICANS JACOB MILES KEATON
EXAMINATION OF THE CONTRIBUTION OF DIFFERENCES IN DISEASE ARCHITECTURE AND EPISTASIS TO TYPE 2 DIABETES RISK IN AFRICAN AMERICANS BY JACOB MILES KEATON A Dissertation Submitted to the Graduate Faculty
More informationUse and Interpreta,on of LD Score Regression. Brendan Bulik- Sullivan PGC Stat Analysis Call
Use and Interpreta,on of LD Score Regression Brendan Bulik- Sullivan bulik@broadins,tute.org PGC Stat Analysis Call Outline of Talk Intui,on, Theory, Results LD Score regression intercept: dis,nguishing
More informationSupplementary Appendix
Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Ference BA, Robinson JG, Brook RD, et al. Variation in PCSK9
More informationBest (but oft-forgotten) practices: the design, analysis, and interpretation of Mendelian randomization studies 1
AJCN. First published ahead of print March 9, 2016 as doi: 10.3945/ajcn.115.118216. Statistical Commentary Best (but oft-forgotten) practices: the design, analysis, and interpretation of Mendelian randomization
More informationMOLECULAR EPIDEMIOLOGY Afiono Agung Prasetyo Faculty of Medicine Sebelas Maret University Indonesia
MOLECULAR EPIDEMIOLOGY GENERAL EPIDEMIOLOGY General epidemiology is the scientific basis of public health Descriptive epidemiology: distribution of disease in populations Incidence and prevalence rates
More informationWhat Do We Know About Individual Variability and Its
What Do We Know About Individual Variability and Its Contribution to Disease? Nathaniel Rothman, MD, MPH, MHS Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics,
More informationDivision of Public Health Sciences, Department of Biostatistics, Wake Forest University Health Sciences, Winston-Salem, NC, USA; 2
(2009) 10, S5 S15 & 2009 Macmillan Publishers Limited All rights reserved 1466-4879/09 $32.00 www.nature.com/gene ORIGINAL ARTICLE WM Brown 1, JJ Pierce 1, JE Hilner 2, LH Perdue 1, K Lohman 1,LLu 1, PIW
More informationGenome-wide association study identifies variants in TMPRSS6 associated with hemoglobin levels.
Supplementary Online Material Genome-wide association study identifies variants in TMPRSS6 associated with hemoglobin levels. John C Chambers, Weihua Zhang, Yun Li, Joban Sehmi, Mark N Wass, Delilah Zabaneh,
More informationNutritional Epidemiology in the Genomic Age. Saroja Voruganti, PhD Assistant Professor Department of Nutrition and UNC Nutrition Research Institute
Nutritional Epidemiology in the Genomic Age Saroja Voruganti, PhD Assistant Professor Department of Nutrition and UNC Nutrition Research Institute Learning objectives Types of genetic association approaches
More informationComplex Multifactorial Genetic Diseases
Complex Multifactorial Genetic Diseases Nicola J Camp, University of Utah, Utah, USA Aruna Bansal, University of Utah, Utah, USA Secondary article Article Contents. Introduction. Continuous Variation.
More information