Genetics for Epidemiologists Lecture 4: Genetic Association Studies

1
Genetics for EpidemiologistsLecture 4 Genetic
Association Studies
National Human Genome Research Institute
U.S. Department of Health and Human
Services National Institutes of Health National
Human Genome Research Institute
National Institutes of Health
Teri A. Manolio, M.D., Ph.D.Director, Office of
Population Genomics and Senior Advisor to the
Director, NHGRI, for Population Genomics
U.S. Department of Health and Human Services
2
Topics to be Covered

• Case-control and cohort studies in genomic
  research
• Candidate gene studies
• Genome-wide association studies
• Randomized/experimental designs

3
Collins FS, Nature 2004 429475-77.
4
Desirable Characteristics of Large US Cohort Study

• Large sample size
• Full representation of US minority groups
• Broad range of ages
• Broad range of genetic backgrounds and
  environmental exposures
• Family-based recruitment for at least part of
  cohort to control for population stratification
• Broad array of clinical and laboratory data,
  regular follow up for events, additional exposure
  assessment

After Collins FS, Nature 2004 429475-77.
5
Desirable Characteristics of Large US Cohort
Study (continued)

• Technologically advanced dietary, lifestyle, and
  environmental exposure data
• Collection and storage of biological specimens
• Sophisticated data management system
• Broad access to materials and data
• Goals should not be hypothesis-limited
• Comprehensive community engagement from the
  outset
• State of the art (?dynamic) consent to allow
  multiple uses of data and regular feedback

After Collins FS, Nature 2004 429475-77.
6
Larson, G. The Complete Far Side. 2003.
7
Manolio TA et al. Nature 2006 7812-820.
8
Willett WC et al. Nature 2007 445257-258.
9
Collins FS et al. Nature 2007 445259.
10
Pros and Cons of Case-Control Studies

• Advantages
• May be the only way to study rare diseases or
  those of long latency
• Existing records can occasionally be used if risk
  factor data collected independent of disease
  status
• Can study multiple etiologic factors
  simultaneously
• May be less time-consuming and expensive
• If assumptions met, inferences are reliable

11
Pros and Cons of Case-Control Studies

• Disadvantages
• Relies on recall or records for information on
  past exposures validation can be difficult or
  impossible
• Selection of appropriate comparison group may be
  difficult
• Multiple biases may give spurious evidence of
  association between risk factor and disease
• Usually cannot study rare exposures
• Temporal relationship between exposure and
  disease can be difficult to determine

12
But, they say, This Is Genetics!(you dumb
epidemiologist) This Is Different!

• Genes are measured the same way in cases and
  controls
• Information on key exposure is easy to validate
• No recall or reporting involved
• Temporal relationship between genes and disease
  is piece of cake
• BUT, I SAY,
• Bias-free ascertainment of cases and controls is
  still major concern cases in most clinical
  series unlikely to be representative
• Assessment of risk modifiers or gene-environment
  interactions is likely to be incomplete or flawed

13
Appreciation of Weaknesses of Case-Control Studies
http//www.mainlesson.com/display.php3?authortrea
dwellbookprimerstorychickenlittle
Larson, G. The Complete Far Side. 2003.
14
Candidate Genes
15
Genetic Studies in Unrelated Individuals
(pre-2005) Candidate Gene Studies

• Goal characterize candidate genes and variants
  related to disease
• Not typically intended to find genes, generally
  begun after disease-related variants identified
• Assess generalizability of family-based
  observations (genetic heterogeneity)
• Assess importance of allelic variation at
  population level (PAR, penetrance)
• Identify modification of genetic association by
  environmental factors (GxE interaction)

16
Population Studies of Genetic Variants
Angiotensin I-Converting Enzyme (ACE)
Larsen Williams Textbook of Endocrinology, 10th
ed., 2003
17
ACE Gene Identification

• cDNA sequence determined for human testicular
  ACE, identical from residue 27 to C terminus to
  C-terminal domain of endothelial ACE (Ehlers et
  al, PNAS 1989)
• Assigned to chromosome 17q23 by in situ
  hybridization (Mattei et al, Cytogenet Cell Genet
  1989)
• Linked to elevated blood pressure in rat model of
  hypertension (Jacob et al, Cell 1991)
• Mapped to human chromosome 17q22-q24 (Jeunemaitre
  et al, Nat Genet 1992)

18
ACE Gene Polymorphisms

• Insertion/deletion polymorphism identified
  through restriction fragment length polymorphism
  (RFLP) analysis
• Two alleles results from 250-bp insertion in
  intron 16 allele frequencies 0.41 for I allele
  and 0.59 for D allele
• Accounted for 47 variance in serum ACE in 80
  subjects

ACE Genotype ACE Genotype ACE Genotype
II ID DD
ACE (µg/L) 299 (49) 392 (67) 494 (88)
Ln-ACE (µg/L) 5.7 (0.2) 6.0 (0.2) 6.2 (0.2)
Rigat et al, J Clin Invest 1990 861343-46.
19
Nature 1992 359641-44.
20
Frequency of ACE Genotypes in 1,304 MI Cases and
Controls
OR 1.34, p 0.007
104
197
200
309
390
104
Cambien et al, Nature 1992 359641-44.
21
Frequency of ACE Genotypes in 1,304 MI Cases and
Controls
Low Risk
High Risk
OR 3.2 1.7,5.9
OR 1.1 0.9,1.5
41
154
372
38
46
143
159
390
Cambien et al, Nature 1992 359641-44.
22
Age-Adjusted Odds on Hypertension by ACE ID/DD
Genotype and Sex
DD ID II P-value
Men HTN 53.1 45.8 44.4
Men OR 1.67 1.19 1.00 0.004
Women HTN 43.3 41.8 44.4
Women OR 1.01 0.80 1.00 0.15
after ODonnell C et al, Circulation 1998
971766-72.
23
Number of New, Significant Gene-Disease
Associations by Year, 1984 - 2000
Hirschhorn J et al, Genet Med 2002 445-61.
24
Of 600 Gene-Disease Associations, Only 6
Significant in gt 75 of Identified Studies
Disease/Trait Gene Polymorphism Frequency
DVT F5 Arg506Gln 0.015
Graves Disease CTLA4 Thr17Ala 0.62
Type 1 DM INS 5 VNTR 0.67
HIV/AIDS CCR5 32 bp Ins/Del 0.05-0.07
Alzheimers APOE Epsilon 2/3/4 0.16-0.24
Creutzfeldt-Jakob Disease PRNP Met129Val 0.37
Hirschhorn J et al, Genet Med 2002 445-61.
Hirschhorn J et al, Genet Med 2002 445-61.
25
Reports For and Against Associations of Variants
with Carotid Atherosclerosis
Polymorphism Present Absent Summary
ACE I/D 13 with D 1 with I 18 favors none
APOE 8 with e4, 2 with e2 9 equivocal
AGT M235T 0 8 none
AGTR1 A1166C 0 7 none
MTHFR 7 with T, 1 with non-T 8 equivocal
PON1 Q192R 3 with R 10 none
PON1 L55M 5 with L (subgroups) 1 weak
NOS3 G894T 1 with T 4 none
MMP3 -1516 5A/6A 4 with 6A 0 association
IL6 G-174C 1 with G 3 none
Manolio et al, ATVB 2004 241567-1577.
26
Summary Points Candidate Gene Studies

• Initial enthusiasm markedly damped by failure to
  replicate
• Can probably find study or story that will fit
  almost any candidate to any disease/trait
• Understanding of genome structure and function,
  and of pathophysiologic mechanisms, just too
  preliminary to project more than a handful of
  plausible candidates at present

27
Larson, G. The Complete Far Side. 2003.
28
Manolio et al., J Clin Invest 2008 1181590-605.
29
2007 The Year of GWA Studies
Pennisi E, Science 2007 3181842-43.
30
Diseases and Traits with Published GWA Studies (n
53, 5/9/08)

• Macular Degeneration
• Exfoliation Glaucoma
• Lung Cancer
• Prostate Cancer
• Breast Cancer
• Colorectal Cancer
• Neuroblastoma
• Crohns Disease
• Celiac Disease
• Gallstones
• Irritable Bowel Syndrome
• QT Prolongation
• Coronary Disease
• Stroke
• Hypertension
• Atrial Fibrillation/Flutter

• Parkinson Disease
• Amyotrophic Lat. Sclerosis
• Multiple Sclerosis
• Prog. Supranuclear Palsy
• MS Interferon-ß Response
• Alzheimers Disease
• Cognitive Ability
• Memory
• Restless Legs Syndrome
• Nicotine Dependence
• Methamphetamine Depend.
• Neuroticism
• Schizophrenia
• Bipolar Disorder
• Family Chaos
• Rheumatoid Arthritis
• Systemic Lupus Erythematosus
• Psoriasis

• HIV Viral Setpoint
• Childhood Asthma
• Type 1 Diabetes
• Type 2 Diabetes
• Diabetic Nephropathy
• End-Stage Renal Disease
• Obesity, BMI, Waist, IR
• Height
• Osteoporosis
• F-Cell Distribution
• Fetal Hgb Levels
• C-Reactive Protein
• 18 groups of Framingham Traits
• Pigmentation
• Uric Acid Levels
• Recombination Rate

31
NHGRI Catalog of GWA Studies http//www.genome.g
ov/gwastudies/
32
NHGRI Catalog of GWA Studies http//www.genome.g
ov/gwastudies/

• First author/Data/Journal/Study
• Disease/Trait
• Initial Sample Size
• Replication Sample Size
• Region
• Gene
• Strongest SNP Risk Allele
• Risk Allele Frequency in Controls
• P-value
• OR per copy 95 CI
• Platform and SNPs passing QC

33
NHGRI Catalog of GWA Studies http//www.genome.g
ov/gwastudies/

• First author/Data/Journal/Study
• Disease/Trait
• Initial Sample Size
• Replication Sample Size
• Region
• Gene
• Strongest SNP Risk Allele
• Risk Allele Frequency in Controls
• P-value
• OR per copy 95 CI
• Platform and SNPs passing QC

34
NHGRI Catalog of GWA Studies http//www.genome.g
ov/gwastudies/
35
What is a Genome-Wide Association Study?

• Method for interrogating all 10 million variable
  points across human genome
• Variation inherited in groups, or blocks, so not
  all 10 million points have to be tested
• Blocks are shorter (so need to test more points)
  the less closely people are related
• Technology now allows studies in unrelated
  persons, assuming 5,000 10,000 base pair
  lengths in common (300,000 1,000,000 markers)

36
Association of Alleles and Genotypes of rs1333049
(3049) with Myocardial Infarction
C N () C N () G N () G N () ?2 (1df) P-value
Cases 2,132 (55.4) 2,132 (55.4) 1,716 (44.6) 1,716 (44.6) 55.1 1.2 x 10-13
Controls 2,783 (47.4) 2,783 (47.4) 3,089 (52.6) 3,089 (52.6) 55.1 1.2 x 10-13
Allelic Odds Ratio 1.38 Allelic Odds Ratio 1.38 Allelic Odds Ratio 1.38 Allelic Odds Ratio 1.38 Allelic Odds Ratio 1.38 Allelic Odds Ratio 1.38 Allelic Odds Ratio 1.38 Allelic Odds Ratio 1.38





Samani N et al, N Engl J Med 2007 357443-453.
37
Association of Alleles and Genotypes of rs1333049
(3049) with Myocardial Infarction
C N () C N () G N () G N () ?2 (1df) P-value
Cases 2,132 (55.4) 2,132 (55.4) 1,716 (44.6) 1,716 (44.6) 55.1 1.2 x 10-13
Controls 2,783 (47.4) 2,783 (47.4) 3,089 (52.6) 3,089 (52.6) 55.1 1.2 x 10-13
Allelic Odds Ratio 1.38 Allelic Odds Ratio 1.38 Allelic Odds Ratio 1.38 Allelic Odds Ratio 1.38 Allelic Odds Ratio 1.38 Allelic Odds Ratio 1.38 Allelic Odds Ratio 1.38 Allelic Odds Ratio 1.38
CC N () CG N () CG N () GG N () GG N () ?2 (2df) P-value
Cases 586 (30.5) 960 (49.9) 960 (49.9) 378 (19.6) 378 (19.6) 59.7 1.1 x 10-14
Controls 676 (23.0) 1,431 (48.7) 1,431 (48.7) 829 (28.2) 829 (28.2) 59.7 1.1 x 10-14
Heterozygote Odds Ratio 1.47 Heterozygote Odds Ratio 1.47 Heterozygote Odds Ratio 1.47 Heterozygote Odds Ratio 1.47 Heterozygote Odds Ratio 1.47 Heterozygote Odds Ratio 1.47 Heterozygote Odds Ratio 1.47 Heterozygote Odds Ratio 1.47
Homozygote Odds Ratio 1.90 Homozygote Odds Ratio 1.90 Homozygote Odds Ratio 1.90 Homozygote Odds Ratio 1.90 Homozygote Odds Ratio 1.90 Homozygote Odds Ratio 1.90 Homozygote Odds Ratio 1.90 Homozygote Odds Ratio 1.90
Samani N et al, N Engl J Med 2007 357443-453.
38
Nicotine Dependence among Smokers
Bierut LJ et al, Hum Molec Genet 2007 1624-35.
39
P Values of GWA Scan for Age-Related Macular
Degeneration
Klein et al, Science 2005 308385-389.
40
Genome-Wide Scan for QTc Interval
Arking D et al, Nat Genet 2006 38644-651.
41
Genome-Wide Scan for Type 2 Diabetes in a
Scandinavian Cohort
http//www.broad.mit.edu/diabetes/scandinavs/type2
.html
42
Wellcome Trust Genome-Wide Association Study of
Seven Common Diseases
WTCCC, Nature 2007 447661-678.
43
There have been few, if any, similar bursts of
discovery in the history of medical research
Hunter DJ and Kraft P, N Engl J Med 2007
357436-439.
44
Lessons Learned from Initial GWA Studies
Signals in Previously Unsuspected Genes Signals in Previously Unsuspected Genes Signals in Previously Unsuspected Genes
Macular Degeneration CFH CFH
Coronary Disease CDKN2A/2B CDKN2A/2B
Childhood Asthma ORMDL3 ORMDL3
Type II Diabetes CDKAL1 CDKAL1
QT interval prolongation NOS1AP NOS1AP









45
Lessons Learned from Initial GWA Studies
Signals in Previously Unsuspected Genes Signals in Previously Unsuspected Genes Signals in Previously Unsuspected Genes
Macular Degeneration CFH CFH
Coronary Disease CDKN2A/2B CDKN2A/2B
Childhood Asthma ORMDL3 ORMDL3
Type II Diabetes CDKAL1 CDKAL1
QT interval prolongation NOS1AP NOS1AP
Signals in Gene Deserts Signals in Gene Deserts Signals in Gene Deserts
Prostate Cancer 8q24 8q24
Crohns Disease 5p13.1, 1q31.2, 10p21 5p13.1, 1q31.2, 10p21






46
Lessons Learned from Initial GWA Studies
Signals in Previously Unsuspected Genes Signals in Previously Unsuspected Genes Signals in Previously Unsuspected Genes
Macular Degeneration CFH CFH
Coronary Disease CDKN2A/2B CDKN2A/2B
Childhood Asthma ORMDL3 ORMDL3
Type II Diabetes CDKAL1 CDKAL1
QT interval prolongation NOS1AP NOS1AP
Signals in Gene Deserts Signals in Gene Deserts Signals in Gene Deserts
Prostate Cancer 8q24 8q24
Crohns Disease 5p13.1, 1q31.2, 10p21 5p13.1, 1q31.2, 10p21
Signals in Common Signals in Common Signals in Common
Diabetes, CHD, Melanoma, Frailty Diabetes, CHD, Melanoma, Frailty CDKN2A/2B
Prostate, Breast, Colorectal Cancer Prostate, Breast, Colorectal Cancer 8q24 region
Crohns Disease, Psoriasis Crohns Disease, Psoriasis IL23R
Crohns Disease, T1DM Crohns Disease, T1DM PTPN2
Rheumatoid Arthritis, T1DM Rheumatoid Arthritis, T1DM PTPN22
47
Unique Aspects of GWA Studies

• Permit examination of inherited genetic
  variability at unprecedented level of resolution
• Permit "agnostic" genome-wide evaluation
• Once genome measured, can be related to any trait
• Most robust associations in GWA studies have not
  been with genes previously suspected of
  association with the disease
• Some associations in regions not even known to
  harbor genes

The chief strength of the new approach also
contains its chief problem with more than
500,000 comparisons per study, the potential for
false positive results is unprecedented.
Hunter DJ and Kraft P, N Engl J Med 2007
357436-439.
48
Larson, G. The Complete Far Side. 2003.
49
Ways of Dealing with Multiple Testing

• Bonferroni correction most common, typically p lt
  10-7 or 10-8
• False discovery rate proportion of significant
  associations that are actually false positives
• False positive report probability probability
  that the null hypothesis is true, given a
  statistically significant finding
• Replication, replication, replication

50
Chanock S, Manolio T, et al, Nature 2007
447655-660.
51
Replication Strategy for Prostate Cancer Study in
CGEMS
Initial Study 1,150 cases / 1,150 controls
gt500,000 Tag SNPs
Replication Study 1 3,000 cases / 3,000 controls
24,000 SNPs
Replication Study 2 2,400 cases / 2,400 controls
1,500 SNPs
200 New ht-SNPs
Replication Study 3 2,500 cases / 2,500 controls
25-50 Loci
Hoover R, Epidemiology 2007 1813-17.
52
Replication, Replication, Replication

• Initial study Sufficient description to permit
  replication
• Sources of cases and controls
• Participation rates and flow chart of selection
• Methods for assessing affected status
• Standard Table 1 including rates of missing
  data
• Assessment of population heterogeneity
• Genotyping methods and QC metrics
• Replication study
• Similar population, similar phenotype
• Same genetic model, same SNP, same direction
• Adequately powered to detect postulated effect

Chanock S, Manolio T, et al, Nature 2007
447655-660.
53
Replication Strategy in Easton Breast Cancer Study
Stage Cases Controls SNPs
1 408 400 266,722



Easton et al, Nature 2007 4471087-93.
54
Replication Strategy in Easton Breast Cancer Study
Stage Cases Controls SNPs
1 408 400 266,722
2 3,990 3,916 13,023


Easton et al, Nature 2007 4471087-93.
55
Replication Strategy in Easton Breast Cancer Study
Stage Cases Controls SNPs
1 408 400 266,722
2 3,990 3,916 13,023
3 23,734 23,639 31

Easton et al, Nature 2007 4471087-93.
56
Replication Strategy in Easton Breast Cancer Study
Stage Cases Controls SNPs
1 408 400 266,722
2 3,990 3,916 13,023
3 23,734 23,639 31
Final 6

• ABCFS
• BCST
• COPS
• GENICA
• HBCS
• HBCP

• MEC-W
• MEC-J
• NHS
• PBCS
• RBCS
• SASBAC

• SEARCH2
• SEARCH3
• SBCP
• SBCS
• CNIOBCS
• USRT

• TBCS
• KConFab/AOCS
• KBCP
• LUMCBCS
• MCBCS
• MCCS

Easton et al, Nature 2007 4471087-93.
57
Larson, G. The Complete Far Side. 2003.
58
Replication Strategy in CGEMS Prostate Cancer
Study
Stage Cases Cases Cases Controls Controls SNPs SNPs
1 1,172 1,172 1,172 1,157 1,157 527,869 527,869







Thomas et al, Nat Genet 2008 40310-15.
59
Replication Strategy in CGEMS Prostate Cancer
Study
Stage Cases Cases Cases Controls Controls SNPs SNPs
1 1,172 1,172 1,172 1,157 1,157 527,869 527,869
2 3,941 3,941 3,941 3,964 3,964 26,958 26,958






Thomas et al, Nat Genet 2008 40310-15.
60
Replication Strategy in CGEMS Prostate Cancer
Study
Stage Cases Cases Cases Controls Controls SNPs SNPs
1 1,172 1,172 1,172 1,157 1,157 527,869 527,869
2 3,941 3,941 3,941 3,964 3,964 26,958 26,958
Selected for p lt 0.068 Selected for p lt 0.068 Selected for p lt 0.068 Selected for p lt 0.068 Selected for p lt 0.068 Selected for p lt 0.068





Thomas et al, Nat Genet 2008 40310-15.
61
Replication Strategy in CGEMS Prostate Cancer
Study
Stage Cases Cases Cases Controls Controls SNPs SNPs
1 1,172 1,172 1,172 1,157 1,157 527,869 527,869
2 3,941 3,941 3,941 3,964 3,964 26,958 26,958
Selected for p lt 0.068 Selected for p lt 0.068 Selected for p lt 0.068 Selected for p lt 0.068 Selected for p lt 0.068 Selected for p lt 0.068
SNP SNP SNP Gene Stage 12 P-value Stage 12 P-value
rs4962416 rs4962416 rs4962416 MSMB 7 x 10-13 7 x 10-13
rs10896449 rs10896449 rs10896449 11q13 2 x 10-9 2 x 10-9
rs10993994 rs10993994 rs10993994 CTBP2 2 x 10-7 2 x 10-7
rs10486567 rs10486567 rs10486567 JAZF1 2 x 10-6 2 x 10-6
Thomas et al, Nat Genet 2008 40310-15.
62
Replication Strategy in CGEMS Prostate Cancer
Study
Stage Cases Cases Cases Controls Controls SNPs SNPs
1 1,172 1,172 1,172 1,157 1,157 527,869 527,869
2 3,941 3,941 3,941 3,964 3,964 26,958 26,958
Selected for p lt 0.068 Selected for p lt 0.068 Selected for p lt 0.068 Selected for p lt 0.068 Selected for p lt 0.068 Selected for p lt 0.068
SNP SNP SNP Gene Stage 12 P-value Stage 12 P-value Initial Rank Initial Rank
rs4962416 rs4962416 rs4962416 MSMB 7 x 10-13 7 x 10-13 24,223 24,223
rs10896449 rs10896449 rs10896449 11q13 2 x 10-9 2 x 10-9
rs10993994 rs10993994 rs10993994 CTBP2 2 x 10-7 2 x 10-7
rs10486567 rs10486567 rs10486567 JAZF1 2 x 10-6 2 x 10-6
Thomas et al, Nat Genet 2008 40310-15.
63
Replication Strategy in CGEMS Prostate Cancer
Study
Stage Cases Cases Cases Controls Controls SNPs SNPs
1 1,172 1,172 1,172 1,157 1,157 527,869 527,869
2 3,941 3,941 3,941 3,964 3,964 26,958 26,958
Selected for p lt 0.068 Selected for p lt 0.068 Selected for p lt 0.068 Selected for p lt 0.068 Selected for p lt 0.068 Selected for p lt 0.068
SNP SNP SNP Gene Stage 12 P-value Stage 12 P-value Initial Rank Initial Rank
rs4962416 rs4962416 rs4962416 MSMB 7 x 10-13 7 x 10-13 24,223 24,223
rs10896449 rs10896449 rs10896449 11q13 2 x 10-9 2 x 10-9 2,439 2,439
rs10993994 rs10993994 rs10993994 CTBP2 2 x 10-7 2 x 10-7 319 319
rs10486567 rs10486567 rs10486567 JAZF1 2 x 10-6 2 x 10-6 24,407 24,407
Thomas et al, Nat Genet 2008 40310-15.
64
Replication Strategy in CGEMS Prostate Cancer
Study
Stage Cases Cases Cases Controls Controls SNPs SNPs
1 1,172 1,172 1,172 1,157 1,157 527,869 527,869
2 3,941 3,941 3,941 3,964 3,964 26,958 26,958
Selected for p lt 0.068 Selected for p lt 0.068 Selected for p lt 0.068 Selected for p lt 0.068 Selected for p lt 0.068 Selected for p lt 0.068
SNP SNP SNP Gene Stage 12 P-value Stage 12 P-value Initial Rank Initial Rank Initial P-value Initial P-value
rs4962416 rs4962416 rs4962416 MSMB 7 x 10-13 7 x 10-13 24,223 24,223 0.042 0.042
rs10896449 rs10896449 rs10896449 11q13 2 x 10-9 2 x 10-9 2,439 2,439 0.004 0.004
rs10993994 rs10993994 rs10993994 CTBP2 2 x 10-7 2 x 10-7 319 319 4 x 10-4 4 x 10-4
rs10486567 rs10486567 rs10486567 JAZF1 2 x 10-6 2 x 10-6 24,407 24,407 0.042 0.042
Thomas et al, Nat Genet 2008 40310-15.
65
Genome-wide Association and Cohort Studies
Cupples et al, BMC Med Genet 2007 8(Suppl 1)S1
Ridker et al, Clin Chem 2008 54249-55.
66
http//www.ncbi.nlm.nih.gov/sites/entrez
67
Genetic Association and Clinical Trials
7/2000
6/2006
1/2008
68
Genome-wide Association and Clinical Trials
5/2007
69
HLA DRB10701 and Transaminase Elevations
Following Ximelegatran Treatment
Kindmark et al, Pharmacogen J 2007 May 15
(on-line)
70
Genome-wide Association and Clinical Trials
5/2007
1/2008
71
Summary Points Genetic Association Studies

• Candidate gene studies enormously prone to
  spurious associations
• GWA presents new paradigm, is unconstrained by
  current imperfect understanding of genome
  structure and function
• Initial findings astoundingly positive
• Most are skimming surface of what could be
  learned
• GWA beginning to be applied to cohort studies
• Very little work in genetic association in
  clinical trials and treatment response

72
Larson, G. The Complete Far Side. 2003.
73
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