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FRAMINGHAM HEARTFRAMINGHAM HEART
STUDYSTUDY
A history of medical science
from CV risk factors to genetics
Presenter DisclosurePresenter Disclosure
InformationsInformations
• Name of the speaker:Name of the speaker:
Alexandru Andritoiu
• Potential conflicts of interest to report:Potential conflicts of interest to report:
Speaker for:
Pfizer, Astra-Zeneca, Servier, Abbot, Sanofi-Aventis,
KRKA, Ozone, Shering-Plough,
Novartis,Zentiva,Antibiotice Iasi, Terapia-Rambaxy
HistoryHistory
• Cardiovascular disease (CVD) is the
leading cause of death and serious illness
in the United States.
• In 19481948, the Framingham Heart Study -
under the direction of the National HeartNational Heart
Institute (now known as the NationalInstitute (now known as the National
Heart, Lung, and Blood Institute or NHLBIHeart, Lung, and Blood Institute or NHLBI)
- embarked on an ambitious project in
health research.
BackgroundBackground
• The study, nearly six decades later and now
known as the “Framingham Heart Study” (FHS), is
the longest running, multigenerational longitudinal
study in medical history (Butler, 1999).
• It has helped identify several “risk factors” and
their cumulative influence on the manifestation of
CVD.
• The term ‘risk factorrisk factor’ was coined by Framingham
investigators (Kannel et al 1961)
PARTICIPATING INSTITUTIONS
• Framingham Heart
Study
• Boston University
School of Medicine
• National Heart, Lung,
and Blood Institute
• Boston University College of
Arts & Sciences
• Framingham Heart Study
Genetics Lab
• Boston University School of
Public Health
• National Center for
Biotechnology Information
Dr. Thomas Royle (Roy) DawberDr. Thomas Royle (Roy) Dawber
Ann N Y Acad SciAnn N Y Acad Sci 1963, 1071963, 107::539-556539-556
Dawber TR, Meadors GF, Moore FEJ: Epidemiological approaches to heart disease: the
Framingham Study. Am J Public Health 1951, 41:279-286. 
Dawber TR, Kannel WB, Revotskie N, Stokes JI, Kagan A, Gordon T: Some factors
associated with the development of coronary heart disease; six years' follow-up experience in the
Framingham Study. Am J Public Health 1959, 49:1349-1356. 
The objective of the FraminghamThe objective of the Framingham
Heart StudyHeart Study
to identify the common factors or
characteristics that contribute to CVD by
following its development over a long
period of time in a large group of
participants who had not yet developed
overt symptoms of CVD or suffered a
heart attack or stroke.
MethodsMethods
The researchers recruited 5,209 men and
women between the ages of 30 and 62
from the town of Framingham,
Massachusetts
The CohortsThe Cohorts
• Since 1948,1948, the subjects have continued to return to the
study every two years for a detailed medical history,
physical examination, and laboratory tests, and in 1971,
the Study enrolled a second generation - 5,124 of the
original participants' adult children and their spouses - to
participate in similar examinations.
• In 19941994, the need to establish a new study reflecting a
more diverse community of Framingham was
recognized, and the first Omni cohort of the Framingham
Heart Study was enrolled.
• In April 2002April 2002 the Study entered a new phase, the
enrollment of a third generation of participants, the
grandchildren of the Original Cohort.
• In 20032003, a second group of Omni participants was
enrolled.
The concept of CVD risk factorsThe concept of CVD risk factors
has become an integral part of the modern
medical curriculum and has led to the
development of effective treatment and
preventive strategies in clinical practice.
Identifying major CVD risk factorsIdentifying major CVD risk factors
• high blood pressure,
• high blood cholesterol,
• smoking,
• obesity,
• diabetes,
• and physical inactivity
• valuable information on the effects of related
factors such as blood triglyceride and HDL
cholesterol levels, age, gender, and psychosocial
issues.
RESEARCH MILESTONES (1)
• 1960 Cigarette smoking found to increase the risk of
heart disease
• 1961 Cholesterol level, blood pressure, and
electrocardiogram abnormalities found to increase the
risk of heart disease
• 1967 Physical activity found to reduce the risk of heart
disease and obesity to increase the risk of heart disease
• 1970 High blood pressure found to increase the risk of
stroke
• 1970 Atrial fibrillation increases stroke risk 5-fold
• 1976 Menopause found to increase the risk of heart
disease
• 1978 Psychosocial factors found to affect heart disease
RESEARCH MILESTONES (2)
• 1988 High levels of HDL cholesterol found to reduce risk
of death
• 1994 Enlarged left ventricle (one of two lower chambers
of the heart) shown to increase the risk of stroke
• 1996 Progression from hypertension to heart failure
described
• 1998 Framingham Heart Study researchers identify that
atrial fibrillation is associated with an increased risk of
all-cause mortality.
• 1998 Development of simple coronary disease prediction
algorithm involving risk factor categories to allow
physicians to predict multivariate coronary heart disease
risk in patients without overt CHD factor categories to
allow physicians to predict multivariate coronary heart
disease risk in patients without overt CHD
RESEARCH MILESTONES (3)
• 1999 Lifetime risk at age 40 years of developing coronary heart
disease is one in two for men and one in three for women
• 2001 High-normal blood pressure is associated with an increased
risk of cardiovascular disease, emphasizing the need to determine
whether lowering high-normal blood pressure can reduce the risk of
cardiovascular disease.
• 2002 Lifetime risk of developing high blood pressure in middle-aged
adults is 9 in 10.
• 2002 Obesity is a risk factor for heart failure.
• 2004 Serum aldosterone levels predict future risk of hypertension in
non-hypertensive individuals.
• 2005 Lifetime risk of becoming overweight exceeds 70 percent, that
for obesity approximates 1 in 2.
• 2006 The National Heart, Lung and Blood Institute (NHLBI) of the
National Institutes of Health announces a new genome-wide
association study at the Framingham Heart Study in collaboration
with Boston University School of Medicine to be known as the
SHARe project (SNP Health Association Resource).
RESEARCH MILESTONES (4)
• 2007 Based on evaluation of a densely interconnected
social network of 12,067 people assessed as part of the
Framingham Heart Study, network phenomena appear
to be relevant to the biologic and behavioral trait of
obesity, and obesity appears to spread through social
ties.
• 2008 Based on analysis of a social network of 12,067
people participating in the Framingham Heart Study
(FHS), researchers discover that social networks exert
key influences on decision to quit smoking.
• 2008 Discovery by Framingham Heart Study and
publication of four risk factors that raise probability of
developing precursor of heart failure; new 30-year risk
estimates developed for serious cardiac events.
RESEARCH MILESTONES (5)
• 2009 Framingham Heart Study cited by the American
Heart Association among the top 10 cardiovascular
research achievements of 2009, "Genome-wide
Association Study of Blood Pressure and Hypertension:
Genome-wide association study identifies eight loci
associated with blood pressure".
• 2009 A new genetic variant associated with increased
susceptibility for atrial fibrillation, a prominent risk factor
for stroke and heart failure, is reported in two studies
based on data from the Framingham Heart Study.
• 2009 Framingham Heart Study researchers find parental
dementia may lead to poor memory in middle-aged
adults.
• 2009 Framingham Heart Study researchers find high
leptin levels may protect against Alzheimer's disease
and dementia
RESEARCH MILESTONES (6)
• 2010 Sleep apnea tied to increased risk of
stroke
• 2010 Framingham Heart Study researchers
identify additional genes that may play a role in
Alzheimer's disease
• 2010 Framingham Heart Study finds fat around
the abdomen associated with smaller, older
brains in middle-aged adults
• 2010 Framingham Heart Study finds genes link
puberty timing and body fat in women
RESEARCH MILESTONES (7)
• 2010 Having first-degree relative with atrial
fibrillation associated with increased risk for this
disorder
• 2009-2010 Framingham Heart Study
researchers contribute to discovering hundreds
of new genes underlying major heart disease
risk factors—body mass index, blood
cholesterol, cigarette smoking, blood pressure
and glucose/diabetes
• 2010 First definitive evidence that occurrence of
stroke by age 65 years in a parent increased risk
of stroke in offspring by 3-fold
RISK SCORE PROFILE
• Atrial Fibrillation (AF) (10-year risk)
• Cardiovascular Disease (30-year risk)
• Congestive Heart Failure
• Coronary Heart Disease (10-year risk)
• Coronary Heart Disease (2-year risk)
• Diabetes Risk Score
• General Cardiovascular Disease
• Hard Coronary Heart Disease and
calculator (10-year risk)
• Hypertension Risk Score
• Intermittent Claudication
• Recurring Coronary Heart Disease
• Stroke
• Stroke after Atrial Fibrillation
• Stroke or Death after Atrial
Fibrillation
The Framingham Heart Study,The Framingham Heart Study,
on its way to becoming the goldon its way to becoming the gold
standard for Cardiovascularstandard for Cardiovascular
Genetic Epidemiology?Genetic Epidemiology?
Cashell E Jaquish - BMC Medical Genetics 2007; 8:63
The participants in the Framingham StudyThe participants in the Framingham Study
are readily divided into three groupsare readily divided into three groups
• Gen 1 (5209 p):Gen 1 (5209 p): those recruited in 1948 as part
of the Original Cohort
• Gen 2Gen 2 (5124 p):(5124 p): those recruited in 1971 as part
of the Offspring Cohort
• Gen 3 (4095 p):Gen 3 (4095 p): those recruited in 2002 as part
of the third Generation Cohort.
• The Family Structure FileFamily Structure File contains information
for biologically related Framingham participants.
• A total of 1538 families1538 families are present
• Framingham SHAR(SNP Health
Association Resource) includes data on
more than 9300 participants spanning three
generations, including more than 900
families, who had their DNA tested for
550 000 genetic variations (single
nucleotide polymorphisms [SNPs]).
• "As one of the most comprehensive studies ever
undertaken, the Framingham Heart Study will
play a vital role in laying the foundation for this
vast data set to help researchers link genes and
disease.“
• Analyzing individual-level data with computer
programs, researchers will be able to search for
new connections between genetic variations and
phenotypes such as high cholesterol.
Dr Elizabeth Nabel - Director of the National Heart, Lung, and Blood Institute
Dr Christopher O'Donnell, associate director of the Framingham Heart
Study and scientific director of Framingham SHARe
• "This important study will take genetic research
in the Framingham study to the next level -
accelerating discoveries on the causes,
prevention, and treatment of major chronic
diseases"
• "Using the latest technology, researchers will be
able to obtain more information about the
connection between unique genetic variations in
DNA and cardiovascular disease risk factors as
well as the genetic basis for heart attack, stroke,
and other chronic diseases."
Nabel EG, 2006
• The genome-wide association studies at
Framingham represent unparalleled opportunities
as well as challenges.
• The challenges include bioinformatics, logistical,
and ethical concerns.
• However, the extensive genotypic and phenotypic
characterizations of Framingham participants
represent unique steps in the goal of achieving
medical care that is predictive, preemptive and
personalized
Nabel EG, 2006
• "This is certainly going to be a valuable resource
for the cardiovascular genomics community.
• Having a large, exceptionally well-characterized
cohort followed for decades with genomewide
SNP/variant coverage is far better than waiting
for years for prospective studies to accrue.
• It's terrific that the NHLBI made this possible."
Dr Eric Topol (Scripps Translational Science Institute, San Diego, CA
Cardiovascular risk between parents and offspring in relation to quintiles
of major risk factors: systolic blood pressure, body mass index, total to
high density lipoprotein-cholesterol, diabetes and smoking.
Lloyd-Jones et al. 2004
Association of known polymorphisms inAssociation of known polymorphisms in
candidate genes with cardiovascular risk factorscandidate genes with cardiovascular risk factors
• the association between two polymorphisms in
the estrogen receptor-β gene with left ventricular
mass and wall thickness in women with
hypertension (Peter et al., 2005);
• L162 polymorphisms of the peroxisome
proliferator-activated receptor alpha (PPARA)
and plasma lipids (Tai et al., 2002);
• ATP-binding cassette transporter -1 (ABCA1;
polymorphisms with HDL concentrations
(Brousseau et al., 2001)
In 2015…In 2015…
,,In conclusion, GWAS have reported on many SNP associationsIn conclusion, GWAS have reported on many SNP associations
with various traits and diseases. Although these numbers are quitewith various traits and diseases. Although these numbers are quite
impressive, we still have to carry out a lot of additional research toimpressive, we still have to carry out a lot of additional research to
find the mechanisms underlying diseases and to build a bridge to afind the mechanisms underlying diseases and to build a bridge to a
clinical setting,,clinical setting,,
Medical possibilities are unlimited;
possibilities are limited only for patients

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All About Framingham Heart Study

  • 1. FRAMINGHAM HEARTFRAMINGHAM HEART STUDYSTUDY A history of medical science from CV risk factors to genetics
  • 2. Presenter DisclosurePresenter Disclosure InformationsInformations • Name of the speaker:Name of the speaker: Alexandru Andritoiu • Potential conflicts of interest to report:Potential conflicts of interest to report: Speaker for: Pfizer, Astra-Zeneca, Servier, Abbot, Sanofi-Aventis, KRKA, Ozone, Shering-Plough, Novartis,Zentiva,Antibiotice Iasi, Terapia-Rambaxy
  • 3. HistoryHistory • Cardiovascular disease (CVD) is the leading cause of death and serious illness in the United States. • In 19481948, the Framingham Heart Study - under the direction of the National HeartNational Heart Institute (now known as the NationalInstitute (now known as the National Heart, Lung, and Blood Institute or NHLBIHeart, Lung, and Blood Institute or NHLBI) - embarked on an ambitious project in health research.
  • 4. BackgroundBackground • The study, nearly six decades later and now known as the “Framingham Heart Study” (FHS), is the longest running, multigenerational longitudinal study in medical history (Butler, 1999). • It has helped identify several “risk factors” and their cumulative influence on the manifestation of CVD. • The term ‘risk factorrisk factor’ was coined by Framingham investigators (Kannel et al 1961)
  • 5. PARTICIPATING INSTITUTIONS • Framingham Heart Study • Boston University School of Medicine • National Heart, Lung, and Blood Institute • Boston University College of Arts & Sciences • Framingham Heart Study Genetics Lab • Boston University School of Public Health • National Center for Biotechnology Information
  • 6. Dr. Thomas Royle (Roy) DawberDr. Thomas Royle (Roy) Dawber Ann N Y Acad SciAnn N Y Acad Sci 1963, 1071963, 107::539-556539-556 Dawber TR, Meadors GF, Moore FEJ: Epidemiological approaches to heart disease: the Framingham Study. Am J Public Health 1951, 41:279-286.  Dawber TR, Kannel WB, Revotskie N, Stokes JI, Kagan A, Gordon T: Some factors associated with the development of coronary heart disease; six years' follow-up experience in the Framingham Study. Am J Public Health 1959, 49:1349-1356. 
  • 7.
  • 8. The objective of the FraminghamThe objective of the Framingham Heart StudyHeart Study to identify the common factors or characteristics that contribute to CVD by following its development over a long period of time in a large group of participants who had not yet developed overt symptoms of CVD or suffered a heart attack or stroke.
  • 9. MethodsMethods The researchers recruited 5,209 men and women between the ages of 30 and 62 from the town of Framingham, Massachusetts
  • 10. The CohortsThe Cohorts • Since 1948,1948, the subjects have continued to return to the study every two years for a detailed medical history, physical examination, and laboratory tests, and in 1971, the Study enrolled a second generation - 5,124 of the original participants' adult children and their spouses - to participate in similar examinations. • In 19941994, the need to establish a new study reflecting a more diverse community of Framingham was recognized, and the first Omni cohort of the Framingham Heart Study was enrolled. • In April 2002April 2002 the Study entered a new phase, the enrollment of a third generation of participants, the grandchildren of the Original Cohort. • In 20032003, a second group of Omni participants was enrolled.
  • 11.
  • 12.
  • 13. The concept of CVD risk factorsThe concept of CVD risk factors has become an integral part of the modern medical curriculum and has led to the development of effective treatment and preventive strategies in clinical practice.
  • 14.
  • 15.
  • 16. Identifying major CVD risk factorsIdentifying major CVD risk factors • high blood pressure, • high blood cholesterol, • smoking, • obesity, • diabetes, • and physical inactivity • valuable information on the effects of related factors such as blood triglyceride and HDL cholesterol levels, age, gender, and psychosocial issues.
  • 17.
  • 18. RESEARCH MILESTONES (1) • 1960 Cigarette smoking found to increase the risk of heart disease • 1961 Cholesterol level, blood pressure, and electrocardiogram abnormalities found to increase the risk of heart disease • 1967 Physical activity found to reduce the risk of heart disease and obesity to increase the risk of heart disease • 1970 High blood pressure found to increase the risk of stroke • 1970 Atrial fibrillation increases stroke risk 5-fold • 1976 Menopause found to increase the risk of heart disease • 1978 Psychosocial factors found to affect heart disease
  • 19. RESEARCH MILESTONES (2) • 1988 High levels of HDL cholesterol found to reduce risk of death • 1994 Enlarged left ventricle (one of two lower chambers of the heart) shown to increase the risk of stroke • 1996 Progression from hypertension to heart failure described • 1998 Framingham Heart Study researchers identify that atrial fibrillation is associated with an increased risk of all-cause mortality. • 1998 Development of simple coronary disease prediction algorithm involving risk factor categories to allow physicians to predict multivariate coronary heart disease risk in patients without overt CHD factor categories to allow physicians to predict multivariate coronary heart disease risk in patients without overt CHD
  • 20. RESEARCH MILESTONES (3) • 1999 Lifetime risk at age 40 years of developing coronary heart disease is one in two for men and one in three for women • 2001 High-normal blood pressure is associated with an increased risk of cardiovascular disease, emphasizing the need to determine whether lowering high-normal blood pressure can reduce the risk of cardiovascular disease. • 2002 Lifetime risk of developing high blood pressure in middle-aged adults is 9 in 10. • 2002 Obesity is a risk factor for heart failure. • 2004 Serum aldosterone levels predict future risk of hypertension in non-hypertensive individuals. • 2005 Lifetime risk of becoming overweight exceeds 70 percent, that for obesity approximates 1 in 2. • 2006 The National Heart, Lung and Blood Institute (NHLBI) of the National Institutes of Health announces a new genome-wide association study at the Framingham Heart Study in collaboration with Boston University School of Medicine to be known as the SHARe project (SNP Health Association Resource).
  • 21. RESEARCH MILESTONES (4) • 2007 Based on evaluation of a densely interconnected social network of 12,067 people assessed as part of the Framingham Heart Study, network phenomena appear to be relevant to the biologic and behavioral trait of obesity, and obesity appears to spread through social ties. • 2008 Based on analysis of a social network of 12,067 people participating in the Framingham Heart Study (FHS), researchers discover that social networks exert key influences on decision to quit smoking. • 2008 Discovery by Framingham Heart Study and publication of four risk factors that raise probability of developing precursor of heart failure; new 30-year risk estimates developed for serious cardiac events.
  • 22. RESEARCH MILESTONES (5) • 2009 Framingham Heart Study cited by the American Heart Association among the top 10 cardiovascular research achievements of 2009, "Genome-wide Association Study of Blood Pressure and Hypertension: Genome-wide association study identifies eight loci associated with blood pressure". • 2009 A new genetic variant associated with increased susceptibility for atrial fibrillation, a prominent risk factor for stroke and heart failure, is reported in two studies based on data from the Framingham Heart Study. • 2009 Framingham Heart Study researchers find parental dementia may lead to poor memory in middle-aged adults. • 2009 Framingham Heart Study researchers find high leptin levels may protect against Alzheimer's disease and dementia
  • 23. RESEARCH MILESTONES (6) • 2010 Sleep apnea tied to increased risk of stroke • 2010 Framingham Heart Study researchers identify additional genes that may play a role in Alzheimer's disease • 2010 Framingham Heart Study finds fat around the abdomen associated with smaller, older brains in middle-aged adults • 2010 Framingham Heart Study finds genes link puberty timing and body fat in women
  • 24. RESEARCH MILESTONES (7) • 2010 Having first-degree relative with atrial fibrillation associated with increased risk for this disorder • 2009-2010 Framingham Heart Study researchers contribute to discovering hundreds of new genes underlying major heart disease risk factors—body mass index, blood cholesterol, cigarette smoking, blood pressure and glucose/diabetes • 2010 First definitive evidence that occurrence of stroke by age 65 years in a parent increased risk of stroke in offspring by 3-fold
  • 25.
  • 26.
  • 27.
  • 28.
  • 29.
  • 30.
  • 31.
  • 32.
  • 33.
  • 34.
  • 35.
  • 36.
  • 37. RISK SCORE PROFILE • Atrial Fibrillation (AF) (10-year risk) • Cardiovascular Disease (30-year risk) • Congestive Heart Failure • Coronary Heart Disease (10-year risk) • Coronary Heart Disease (2-year risk) • Diabetes Risk Score • General Cardiovascular Disease • Hard Coronary Heart Disease and calculator (10-year risk) • Hypertension Risk Score • Intermittent Claudication • Recurring Coronary Heart Disease • Stroke • Stroke after Atrial Fibrillation • Stroke or Death after Atrial Fibrillation
  • 38.
  • 39.
  • 40. The Framingham Heart Study,The Framingham Heart Study, on its way to becoming the goldon its way to becoming the gold standard for Cardiovascularstandard for Cardiovascular Genetic Epidemiology?Genetic Epidemiology? Cashell E Jaquish - BMC Medical Genetics 2007; 8:63
  • 41.
  • 42. The participants in the Framingham StudyThe participants in the Framingham Study are readily divided into three groupsare readily divided into three groups • Gen 1 (5209 p):Gen 1 (5209 p): those recruited in 1948 as part of the Original Cohort • Gen 2Gen 2 (5124 p):(5124 p): those recruited in 1971 as part of the Offspring Cohort • Gen 3 (4095 p):Gen 3 (4095 p): those recruited in 2002 as part of the third Generation Cohort. • The Family Structure FileFamily Structure File contains information for biologically related Framingham participants. • A total of 1538 families1538 families are present
  • 43. • Framingham SHAR(SNP Health Association Resource) includes data on more than 9300 participants spanning three generations, including more than 900 families, who had their DNA tested for 550 000 genetic variations (single nucleotide polymorphisms [SNPs]).
  • 44. • "As one of the most comprehensive studies ever undertaken, the Framingham Heart Study will play a vital role in laying the foundation for this vast data set to help researchers link genes and disease.“ • Analyzing individual-level data with computer programs, researchers will be able to search for new connections between genetic variations and phenotypes such as high cholesterol. Dr Elizabeth Nabel - Director of the National Heart, Lung, and Blood Institute Dr Christopher O'Donnell, associate director of the Framingham Heart Study and scientific director of Framingham SHARe
  • 45. • "This important study will take genetic research in the Framingham study to the next level - accelerating discoveries on the causes, prevention, and treatment of major chronic diseases" • "Using the latest technology, researchers will be able to obtain more information about the connection between unique genetic variations in DNA and cardiovascular disease risk factors as well as the genetic basis for heart attack, stroke, and other chronic diseases." Nabel EG, 2006
  • 46. • The genome-wide association studies at Framingham represent unparalleled opportunities as well as challenges. • The challenges include bioinformatics, logistical, and ethical concerns. • However, the extensive genotypic and phenotypic characterizations of Framingham participants represent unique steps in the goal of achieving medical care that is predictive, preemptive and personalized Nabel EG, 2006
  • 47. • "This is certainly going to be a valuable resource for the cardiovascular genomics community. • Having a large, exceptionally well-characterized cohort followed for decades with genomewide SNP/variant coverage is far better than waiting for years for prospective studies to accrue. • It's terrific that the NHLBI made this possible." Dr Eric Topol (Scripps Translational Science Institute, San Diego, CA
  • 48.
  • 49. Cardiovascular risk between parents and offspring in relation to quintiles of major risk factors: systolic blood pressure, body mass index, total to high density lipoprotein-cholesterol, diabetes and smoking. Lloyd-Jones et al. 2004
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  • 51. Association of known polymorphisms inAssociation of known polymorphisms in candidate genes with cardiovascular risk factorscandidate genes with cardiovascular risk factors • the association between two polymorphisms in the estrogen receptor-β gene with left ventricular mass and wall thickness in women with hypertension (Peter et al., 2005); • L162 polymorphisms of the peroxisome proliferator-activated receptor alpha (PPARA) and plasma lipids (Tai et al., 2002); • ATP-binding cassette transporter -1 (ABCA1; polymorphisms with HDL concentrations (Brousseau et al., 2001)
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  • 66. ,,In conclusion, GWAS have reported on many SNP associationsIn conclusion, GWAS have reported on many SNP associations with various traits and diseases. Although these numbers are quitewith various traits and diseases. Although these numbers are quite impressive, we still have to carry out a lot of additional research toimpressive, we still have to carry out a lot of additional research to find the mechanisms underlying diseases and to build a bridge to afind the mechanisms underlying diseases and to build a bridge to a clinical setting,,clinical setting,,
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  • 76. Medical possibilities are unlimited; possibilities are limited only for patients