Association of Human DNA Variation with Complex Traits

1
Association of Human DNA Variation with Complex
Traits
David R. Cox M.D., Ph.D. Chief Scientific
Officer Perlegen Sciences Inc. david_cox_at_perlegen
.com
2
Genes, through the proteins they encode, interact
with challenges from the environment
3
Whole-Genome Patterns of Common Human DNA
Variation Have Been Characterized
18 February 2005
..February, 2005
27 October 2005
..October, 2005
4
Genetic Association
Cases- drug toxicity
Controls- no toxicity
40 Green and 60 red
50 Green and 50 red
If a segment of the genome is associated with
toxicity, cases will have a different SNP allele
frequency than controls.
5
Lessons Learned From SNP Association Studies To
Date
SNP associations can lead to novel biological
insights It is not possible to predict the
fraction of variation of a complex trait
determined by a SNP prior to performing an
association study The majority of SNP
associations account for a small fraction trait
variability
6
Questions That Remain Unanswered

• What is the relative role of common versus rare
• genetic variation in complex human traits?
• What is the relative role of population specific
• versus global genetic variation in complex human
• traits?
• Which segments of the human genome play the
• most important role in human phenotype variation?
• Will genetic associations of modest effect have
• clinical utility?

7
How will Genetic Knowledge Impact Health
Outcomes and the Practice of Medicine?
8
Automobiles
Not formalized on large scale
Mass produced
Mass customized
Personalized
Individualize to small degree
Timing
Pre-1900
1900-1920
1920-1940
1940-present
Basically never
Organization example

• None

• Rolls-Royce

• Ford

• General Motors

• Rolls Royce

• -

• Individuals

• Rolls, CS Royce, FH

• Henry Ford

• Alfred Sloan

Key person

• -

• Ad-hoc methods

• Job-shop

• Line

• Multiple-line

Method of production

• -

• Non-motorized vehicle

• Silver Spirit

• Model-T

• Pontiac

Product example
Visual
While mass customization developed soon after
mass production, personalization never occurred
in auto industry
9
Clothing
Not formalized on large scale
Individualized to small degree
Mass produced
Mass customized
Personalized
Timing
Pre-history
Pre-1850
1850-1940
1940-present
2000 (but it didnt work out)
Organization example

• None

• Bespoke tailor

• US Army

• Major retailer

• Levi Jeans Co.
• IC3D

• None

• Davies Son (1803)

• Alexander, M (1850)

• OBrien, R Shelton, WC (1941)

Key person
Product example

• Levis personalized jeans

• None

• Bespoke suit

• Civil War uniform

• 1950 shirt

Visual
As with automobiles, apparel became mass
customized relatively quickly but has also never
become personalized on large scale
10
Medicine
Genetic knowledge will reclassify disease based
on biological causality Individuals will receive
group assignments based on this
information
11
What is the right phenotype to study?
12
A Genome-Wide Association Study of Breast Cancer
Douglas F Easton, Alison M Dunning, Karen Pooley,
Paul DP Pharoah, Dennis Ballinger, Deborah
Thompson, D Gareth Evans, Diana Eccles, Nazneen
Rahman, Michael R Stratton, Julian Peto, Olivia
Fletcher, David R. Cox, Bruce AJ Ponder, The
Breast Cancer Association Consortium
13
Low Frequency Germline Gene Mutations Associated
with Increased Breast Cancer Risk
High risk BRCA1, BRCA2 Two-fold
risk
CHEK2, ATM, BRIP1, and PALB2
14
Study Design
15
Breast Cancer Association Consortium
CNIO, Madrid Roger Milne Gloria Ribas Ana
Gonzalez Javier Benitez SASBAC Per Hall, Sara
Wedren, JJ Liu, Low Yin Lin Copenhagen BCS Stig
Bojesen, Borge Nordestgaard Leiden BCS Rob
Tollenaaer, C.E. Jacobi, J.G.M. Klijn, Peter
Devilee Rotterdam BCS Hanne Meijers-Hiejboer,
André Unterlinden Sheffield BCS Angie
Cox Helsinki BCS Heli Nevanlinna Kuopio BCS
Arto Mannermaa, Veli-Matti Kosma, Vesa Kataja,
Jaana Hartikainen GENICA Hiltrud
BrauchHannover BCS Thilo Dörk Polish BCS
Montse Garcia-Closas
kConFab/AOCS Georgia Chenevix-Trench, Mandy
Spurdle, Jonathan Beesley, Xiaoqin Chen ABCFS
John Hopper, Margaret McCredie, Melissa Southey,
Graham Giles MCCS Graham Giles, Melissa Southey,
John Hopper, Chris Schroen Nurses Health Study
David Hunter, Sue Hankinson, David Cox Mayo
Clinic BCS Fergus Couch, Ellen Goode, Janet
Olson US Radiologic Technologists Study Alice
Sigurdson, Jeff Struewing Multi-ethnic Cohort
Chris Haiman Thailand/IARC Paul Brennan Soeul
Breast Cancer Study Daehee Kang Taiwan Breast
Cancer Study Chen-Yang Shen
16
Observed numbers of associations after stage 2
by level of significance, before and after
adjustment for population stratification, and
expected numbers under the null hypothesis of no
association
1Adjusted for inflation of the test statistic by
the genomic control method
17
Five SNPs Selected for Stage 3 With Strong
Evidence of Association
2 Minor allele frequency in Search (UK) study.
Combined allele frequency from three Asian
studies in italics
18
Results for Five Loci from 22 Studies (21,668
cases/ 20,973 controls)
19
Odds Ratios for Carcinoma in situ vs Controls
20
Additive Genetic Variance Predicts A Subset of
the Population At Increased Risk For An Adverse
Response To Treatment
4 4
2 2
3 3
5 5
1 1
1
1
2
2
3
3
4
4
5
5
21
Risk Stratifier
High risk
Risk
Low risk
22
A High Proportion of Women in the General
Population Carry the FGFR2 Breast Cancer Risk
Allele
Copies of FGFR2 Risk Allele 2
1 0 14 47
39 10.5 6.7 5.5
Frequency In UK Population
Breast cancer Risk by age 70
23
American Cancer Society Guidelinesfor Breast
Screening with MRI as anAdjunct to Mammography
Debbie Saslow, PhD Carla Boetes, MD, PhD Wylie
Burke, MD, PhD Steven Harms, MD Martin O.
Leach, PhD Constance D. Lehman, MD, PhD
Elizabeth Morris, MD Etta Pisano,MD Mitchell
Schnall, MD, PhD Stephen Sener, MD Robert A.
Smith, PhD Ellen Warner,MD Martin Yaffe, PhD
Kimberly S. Andrews Christy A. Russell, MD (for
the American Cancer Society Breast Cancer
Advisory Group)
ABSTRACT New evidence on breast Magnetic
Resonance Imaging (MRI) screening has become
available since the American Cancer Society (ACS)
last issued guidelines for the early detection of
breast cancer in 2003. A guideline panel has
reviewed this evidence and developed new
recommendations for women at different defined
levels of risk. Screening MRI is recommended for
women with an approximately 2025 or greater
lifetime risk of breast cancer, including women
with a strong family history of breast or ovarian
cancer and women who were treated for Hodgkin
disease. There are several risk subgroups for
which the available data are insufficient to
recommend for or against screening, including
women with a personal history of breast cancer,
carcinoma in situ, atypical hyperplasia, and
extremely dense breasts on mammography. Diagnostic
uses of MRI were not considered to be within the
scope of this review.
CA Cancer J Clin 2007577589.
24
(No Transcript)
25
(No Transcript)
26
The Missing Piece
An international network collecting long
term treatment outcomes for a wide range of
disorders Genetic association analysis using
data collected by such a network would provide an
important scientific body of knowledge that could
be used to improve treatment efficacy and
to reduce adverse treatment events in individual
patients
27
Prohibiting Genetic Discrimination
Kathy L. Hudson Ph.D.
28
(No Transcript)
29
(No Transcript)
30
The Enhancing Drug Safety and Innovation Act of
2007

• Passed the US Senate with a vote of 93 to 1.
• Requires the FDA to link electronic health care
• database to answer questions about the safety of
• drugs on the market.
• Gives FDA the authority to require a drug
• company to conduct any post-approval study
• necessary to answer a question that the FDAs
• own surveillance system will not answer

31
Conclusions Rosiglitazone was associated with a
significant increase in the risk of myocardial
infarction and with an increase in the risk of
death from cardiovascular causes that had
borderline significance. Our study was limited by
a lack of access to original source data, which
would have enabled time-to-event analysis.
Despite these limitations, patients and providers
should consider the potential for serious adverse
cardiovascular effects of treatment with
rosiglitazone for type 2 diabetes.
Online May 21, 2007 N ENGL J MED
10.1056/NEJMoa072761
32
Conclusions
Genetic knowledge can be used in conjunction
with other risk factors to help individual
patients and their physicans to choose between
exisitng treatment options, thereby maximizing
treatment efficacy and minimizing adverse
events Large scale outcome studies, performed
as an intergral component of the healthcare
system, will be essential for the short
term application of genetic knowledge to human
health outcomes.