Are People Physically Inactive Because of Their Genes?

Introduction

To understand whether genes can influence physical activity, let’s begin by making a distinction between physical

inactivity and level of physical activity. Physical inactivity is a construct of great importance for a proper

understanding of the relationships between behavior and risks for a number of diseases and even premature death.

Indeed, a sedentary lifestyle, which is dominated by physical inactivity, has been recognized as a major risk factor

for hypertension, coronary heart disease, stroke, type 2 diabetes, obesity and other conditions. The other important

concept, level of physical activity, reflects the variation in activity from a small amount of light exercise performed

occasionally to a large amount executed every day. Research has clearly shown that an active lifestyle, with even a

moderate amount of physical activity almost every day, is quite beneficial in terms of prevention of cardiovascular

events, type 2 diabetes and premature death. 

Human variation in degree of physical inactivity or amount of physical activity in a typical day is quite large. For

instance, physical inactivity is the way of life in quadraplegic individuals, is almost complete in people who are

bedridden for some reasons or who have lost some of their mobility because of disease or senescence, and is

pervasive in people who have a sedentary occupation. For instance, the amount of energy expended at rest in the

reclining or sitting position is about 1500 kcal per day in a 165 lb young adult male, but energy expenditure for

physical activity of any kind may range from as low as about 100 kcal (for a bedridden patient) to almost 300 kcal

or so for a couch potato, very sedentary individual. In contrast, the range

of energy expenditure associated with physical activity is much larger for

people who engage in voluntary regular exercise. Thus, a young male may

typically expend a total of 400 to 500 kcal when he exercises for about 30

min at moderate intensity, while a professional cyclist with the same body

mass competing in very demanding races (such as the Tour de France) may

expend as many as 6,000 kcal per day.

Even though this enormous range of physical activity level (and related

energy expenditure) is best represented by a more or less normal

distribution, it is useful for a number of purposes to categorize people in

two activity phenotype groups: the physically inactive (or sedentary) group

and the physically active group. It is also relevant for research and perhaps

clinical purposes to use a third category, based on the distinction between

those who are physically active and those who are engaging in very

demanding exercise programs. However, for the purpose of this review and

considering the dearth of data on the topic in general, we will focus only

on the former: the physical inactivity and moderate level of physical

activity phenotypes (as measured behavioral traits).

The fundamental question that we will address is whether human genetic

variation contributes to the observation that there are individuals who are

Series 7, No. 2 June 2006

Published quarterly by the

President’s Council on

Physical Fitness and Sports

Washington, D.C.

H

Guest Authors:

Claude Bouchard, PhD, and

Tuomo Rankinen, PhD.

Human Genomics Laboratory,

Pennington Biomedical

Research Center, Baton Rouge, LA

H

Co-edited by:

Dr. Deborah Young, University of

Maryland, Dr. Robert P. Pangrazi,

Arizona State University, and

Dr. Barbara Ainsworth,

San Diego State University

President’s Council on Physical Fitness and Sports

ResearchDi est
reliably physically inactive and others who readily

adopt and maintain a physically active lifestyle 

Challenging the common dogma 

Research on the determinants of a sedentary lifestyle

or level of physical activity is typically rooted in

paradigms that incorporate social factors, economic

circumstances, time constraint, equipment and

facilities, education level, etc. Despite the fact that it

is never stated as such, the behaviorists engaged in

this field of research assume by and large that

biology has little to do with human variation in

physical activity level or the adoption of a physically

inactive lifestyle. To oversimplify, the underlying

assumption is that individuals are born with a blank

slate (to borrow from Steven Pinker’s excellent

book)1, with an almost infinite ability to learn and

adopt desirable behavior. For quite some time, we

have expressed the view that these research

paradigms needed to be broadened and enriched to

include biological determinants, including genetic

factors and epigenetic (see glossary) events as well.

Unfortunately, the interest in the biological basis of

physical activity does not have a long history as

revealed by two recent papers published on the

topic2,3.

Several lines of evidence can be invoked to support

the hypothesis that biology plays a role among the

determinants of physical inactivity and physical

activity levels. 

• First, current models that do not incorporate 

biological influences account for only a moderate

fraction of the variance in physical activity levels 

and do not discriminate fully between sedentary 

and physically active people.

• Second, most people who begin to exercise with 

the goal of becoming more physically active 

revert to a sedentary lifestyle. Low adherence 

rates diminish the public health value of regular 

physical activity and the preventive and 

therapeutic potential of regular exercise. 

• Third, there are family lines with high rates of 

sedentary behavior as opposed to others in which 

all members are quite active as shown by a whole

series of twin and family studies. 

• Fourth, the heritability coefficients (quantitative 

indicators of the contribution of genetic 

inheritance to human variation in a trait) for 

physical activity level and sedentarism are 

statistically significant and meaningful from a 

behavioral perspective. 

• Fifth, the genome-wide screening studies in 

animal models and in one human study have 

identified several regions on chromosomes that 

appear to harbor genes and DNA sequence 

variants that contribute to variation in activity 

levels among individuals. 

• Sixth, a few genes exhibiting DNA sequence 

differences among people have already been 

associated with human variation in activity level 

or physical inactivity. 

• Seventh, there is highly suggestive evidence from

animal studies that maternal nutritional status and

other in utero or perinatal factors cause 

alterations (epigenetic events) in the levels of 

gene expression without altering DNA sequence,

thus setting the stage for stable changes in 

physiology.

Reviewing the evidence for these seven lines of

evidence is beyond the scope of this brief statement.

However, we will highlight what we believe are the

important findings and key relevant studies in the

following paragraphs with an emphasis on the

genetic and epigenetic aspects of the central question.

Evidence from twin studies

Much can be learned from observations made in

pairs of identical (monozygotic) and fraternal

(dizygotic) twins. Quite informative are the studies

in which such observations were made on twin

brothers or sisters who were separated for a variety

of reasons early in life and who have lived apart ever

since. Unfortunately no such studies have been

reported for physical inactivity or level of physical

activity. On the other hand, more than a dozen

studies have been conducted with pairs of twin raised

together and the findings from these studies have

been reviewed elsewhere4. To illustrate the major

findings from these twin observational studies, we

will rely on the one performed with the largest

sample size. 

In a large cohort of monozygotic and dizygotic male

twin pairs over 18 years of age from the Finnish

Twin Registry, information on intensity and duration

of activity, years of participation in a given activity,

2
Evidence from animal models

Experimental studies in informative animal models

provide several examples of how naturally occurring

DNA mutations and laboratory-induced changes in

key genes may affect physical activity levels and

patterns. For example, mice lacking the dopamine

transporter gene exhibit marked hyperactivity10,

whereas dopamine receptor D2-deficient mice are

characterized by reduced physical activity levels11.

Likewise, disruption of genes within the melaninconcentrating hormone pathway leads to

hyperactivity12, 13.

An intriguing example of the strong effect of a

mutation in a single gene on physical activity

regulation comes from the fruit fly. In two

populations of flies, each exhibiting a distinct

activity pattern in term of food-search behavior,

those defined as rovers move about twice the

distance while feeding compared to those qualified

as sitters. This activity pattern is genetically

determined and is regulated by a single gene, dg2,

which encodes a cGMP-dependent protein kinase.

The activity of this gene product is significantly

higher in wild-type rovers than in wild type and

mutant sitters, and activation of this gene reverts

foraging behavior from the sitter to rover phenotype.

Furthermore, overexpression of the gene in sitters

changed their behavior and made them behave more

like rovers14.

Evidence from genome-wide

explorations

The only genome-wide linkage scan for physical

activity traits available to date was carried out in the

Québec Family Study cohort15. The scan was based

on 432 DNA markers across the human genome

(except the sex chromosomes) that were genotyped

in 767 subjects from 207 families. Physical activity

measures were derived from a 3-day activity diary

which yielded three traits of interest: total daily

activity, inactivity, moderate to strenuous activity,

and from a questionnaire used to assess weekly

physical activity during the past year. The strongest

evidence for the presence of a gene influencing

physical inactivity scores was detected on

chromosome 2. Suggestive linkages with physical

inactivity were also reported with markers on

chromosomes 7 and 20. Several regions of the

genome were linked with indicators of physical

and physical activity on the job was obtained from a

questionnaire5. A physical activity score was

generated from these variables, which was then used

to compute correlations within pairs of brothers of

each twin type. The correlation for the physical

activity score reached 0.57 in 1,537 pairs of

monozygotic twins and 0.26 in 3,507 pairs of

dizygotic twins. The results indicated that heritability

accounted for 62% of the physical activity score.

Other twin studies have generated higher heritability

estimates for indicators of physical activity levels but

many more have yielded heritability values in the

40% to 50% range.

Evidence from family studies

Physical activity levels and patterns in children and

their parents tend to be similar. A good number of

studies have been reported on the relationships

between the level of physical activity and a few on

the level of sedentarism in parents and their

offspring. Only a few examples will be mentioned

here.

Detailed analyses of the questionnaire on physical

activity habits available on 18,073 individuals living

in households from the 1981 Canada Fitness Survey6

and from a 3-day diary obtained in 1610 subjects

from 375 families in Phase 1 of the Québec Family

Study generated familial correlations that ranged

from 0.2 to 0.3 for various7 indicators of physical

activity. More recently, it was reported that maximal

heritabilities reached 25% for an indicator of

physical inactivity and 19% for a total physical

activity score8.

In an interesting study, 100 children, aged 4 to 7

years, and 99 mothers and 92 fathers from the

Framingham Children’s Study9 were monitored with

an accelerometer for about 10 hours per day for more

than one week in children and parents over the

course of one year. Active fathers were 3.5 times

more likely to have active offspring and active

mothers were 2.0 times more likely to have active

offspring than inactive fathers or mothers,

respectively. When both parents were active, the

children were 5.8 times more likely to be active as

children of two inactive parents. These results are

thus compatible with the notion that genetic or other

factors transmitted across generations predispose a

child to be active or inactive.

3
4

activity, including regions on chromosomes 4, 9, 11,

13 and 15. 

Evidence for a role of specific genes

Up till now, only a few genes have been specifically

associated with physical inactivity or physical

activity traits in human studies focusing on this

specific issue. These genes are the following:

dopamine receptor D2 (DRD2), angiotensinconverting enzyme (ACE), leptin receptor (LEPR),

and melanocortin 4 receptor (MC4R). 

The associations between physical activity

phenotypes and DNA sequence variation in the

DRD2 gene locus in the Québec Family Study (QFS)

and the HERITAGE Family Study subjects were

investigated15. In both studies, a change of cytosine

to thymidine (C/T) in codon 313 of the gene was

associated with physical activity levels in White

women. The QFS women with two copies of the

thymidine (T) allele (the “T” form of the gene on

both chromosomes) reported less weekly activity

during the previous year than women with only one

copy (C/T heterozygotes) or no copies (C/C

homozygotes) of the “T” allele. Similarly, among the

White women of the HERITAGE Family Study, the

T/T homozygotes showed lower sports and work

indices derived from a questionnaire than the other

genotypes. Also in the QFS cohort, significant

associations between a polymorphism located

adjacent to the MC4R gene and physical activity

phenotypes were reported16, with one set of

homozygotes having significantly lower moderateto-strenuous physical activity levels and higher

inactivity scores than the other genotypes (Figure 1).

In Pima Indians, a common glutamine (Gln) to

arginine (Arg) change of amino acid 223 in the leptin

receptor gene was associated with total physical

100

200

300

400

500

600

100

200

300

400

500

600

C/C

C/T

T/T

p=0.005

p=0.01

360 231 51 360 231 51

Figure 1

Moderate-to-strenuous physical activity and physical inactivity levels according to a melanocortin

4 receptor (MC4R) genotype in the Quebec Family Study cohort. The MC4R polymorphism 

involves two alleles, C and T, generating three genotypes: C/C, C/T, or T/T. Based on data from 

Loos et al.,16.

Moderate-to-Strenuous Activity Inactivity

I

n

a

ctivity

S

c

o

r

e

A

ctivity

S

c

o

r

e
activity, with the

Arg/Arg

homozygotes

showing 5% lower

physical activity

level than the

Gln/Gln

homozygotes17.

Winnicki et al.

investigated the

determinants of

habitual physical

activity level in a

group of nevertreated stage I

hypertensive

individuals18.

Physical activity

was assessed by a

questionnaire; the

subjects were

classified as

sedentary or

exercisers (leisure

or sports activities

at least once a week

during the previous

two months). ACE

genotype, age, sex,

marital status, profession, and coffee and alcohol

consumption were included as predictors of physical

activity level in the regression model. ACE genotype

and marital status were the strongest contributors to

physical activity status, with the frequency of one

gene variant being significantly higher in the

sedentary group. Approximately 76% of individuals

in the homozygotes for one allele were sedentary,

whereas the corresponding frequency was 48% in the

other homozygotic group18.

Are there epigenetic effects?

In recent years, a growing body of evidence has

emphasized that DNA sequence variation is

extremely important in accounting for individual

differences in behavior, physiology and response to

drugs or lifestyle interventions. More recently,

another and very significant line of evidence

indicates that chemical modification of DNA and

histone proteins could translate in non-genetic

phenotypic differences that often remarkably mimic

those associated with DNA sequence variants. These

DNA and nucleoprotein alterations have been

collectively referred to as “epigenetic events.” They

begin to occur early after fertilization, are thought to

take place in utero and even throughout the lifespan,

are typically stable, and influence gene expression. Is

there any evidence for a contribution of epigenetics

to human variation in physical activity levels or

physical inactivity?

No direct evidence exists for a contribution of any

epigenetic alterations to physical activity level for

the simple reason that the issue has not been

considered yet. However, there are experimental data

which are highly compatible with the hypothesis that

epigenetics can influence the spontaneous level of

physical activity. For instance, in one such

experiment, performed in a leading New Zealand

laboratory, maternal undernutrition throughout

pregnancy resulted in differences in postnatal

locomotor behavior19. Female Wistar rats received

5

Dista

n

c

e (c

m)

0

1500

2000

2500

3000

3500

4000

Female

Male

Normal Undernourished

Figure 2

Locomotor activity in 14-month old offspring of normally fed and undernourished 

(30% of normal intake) rat mothers. Effects of fetal maternal nutrition and gender 

are statistically significant (p<0.005 for both). From Vickers et al., 200319.
physical activity-related traits are characterized by

familial aggregation and influenced by genetic

factors. Results from animal model studies indicate

that single genes can markedly influence physical

activity-related behavior. 

The first molecular genetic studies on physical

activity traits in humans have been published during

the last few years. They support the notion that it is

possible to detect relatively small, yet biologically

important genetic effects impacting the tendency to

be sedentary or physically active at the molecular

level. We are beginning to appreciate that the in utero

environment and epigenetic events may play a role in

postnatal physiology and behavior, but their impact

on physical inactivity or physical activity level

remains to be determined.

Glossary

Phenotype: It is simply a measured trait. The

measured value or level of a particular character

(biochemical, physiological or behavioral, e.g.,

physical activity level). 

Genotype: The genetic constitution of an individual

at the whole genome level or at a specific locus.

Allele: One of several alternative forms of a gene or

DNA sequence at a specific chromosomal location

(locus). At each autosomal (non-sex chromosomes)

locus an individual possesses two alleles, one

inherited from the father and one from the mother,

and they may be the same or different.

Epigenetic: Chemical modifications superimposed

on the DNA sequence. It does not change the

genotype but it may influence gene expression in a

stable way. 

6

only 30% of the ad libitum intake of the control

females during pregnancy. The offspring of restricted

mothers were significantly smaller at birth. At ages

35 days, 145 days and 420 days, the voluntary

locomotor activity of the offspring of the two groups

were assessed. At all ages, the offspring of the

undernourished mothers were significantly less

active, and the findings are illustrated in Figure 2 for

the 420 days time point. These results suggested that

the effects of undernutrition during pregnancy

persisted during postnatal life. This effect persisted

even when offspring were overnourished during

postnatal life. One possible mechanism for such an

effect of maternal undernutrition is via alterations in

either the level of production or the sensitivity to

endogenous hormones or other secreted factors

during pregnancy. It is not unreasonable to

hypothesize that chemical modifications

superimposed on the DNA, without altering its

sequence, could have played a role in the lower

spontaneous physical activity level and its

persistence throughout the life of the animal exposed

to severe undernutrition during fetal life. 

Other lines of research suggest that high-fat diets,

protein restriction and other maternal dietary

manipulations before and during pregnancy also have

considerable consequences on the physiology and

behavior of the offspring. The implications of fetal

life exposures and epigenetic events on the

propensity to be sedentary or physically active

remain to be understood.

Summary

Research indicates that the inclination to be

physically active or sedentary has a biological

foundation. Twin and family studies confirm that
7

Please Post

President’s Council on Physical Fitness & Sports

200 Independence Avenue, S.W., Washington, DC 20201

(202) 690-9000 • FAX (202) 690-5211

Research indicates that the inclination

to be physically active or sedentary

has a biological foundation. Twin and

family studies confirm that

physical activity-related traits are

characterized by familial aggregation and

influenced by genetic factors. Results from

animal model studies indicate that

single genes can markedly influence

physical activity-related behavior.

Claude Bouchard, PhD

Human Genomics Laboratory

Pennington Biomedical Research Center

6400 Perkins Road

Baton Rouge, LA 70808
8

12. Zhuo QY, Palmiter RD: Dopamine-deficient

mice are severely hypoactive, adipsic, and

aphagic. Cell 1995, 83:p. 1197-1209.

13. Marsh DJ, Weingarth DT, Novi DE et al.:

Melanin-concentrating hormone 1 receptordeficient mice are lean, hyperactive, and

hyperphagic and have altered metabolism.

Proc Natl Acad Sci USA 2002, 99:p. 3240-

3245.

14. Osborne KA, Robichon A, Burgess E et al.:

Natural behavior polymorphism due to a

cGMP-dependent protein kinase of

Drosophila. Science 1997, 277:p. 834-836.

15. Simonen RL, Rankinen T, Perusse L et al.: A

dopamine D2 receptor gene polymorphism

and physical activity in two family studies.

Physiol Behav 2003, 78:p. 751-757.

16. Loos RJ, Rankinen T, Tremblay A, Perusse L,

Chagnon Y, Bouchard C: Melanocortin-4

receptor gene and physical activity in the

Quebec Family Study. Int J Obes (Lond) 2005,

29:p. 420-428.

17. Stefan N, Vozarova B, Del Parigi A et al.: The

Gln223Arg polymorphism of the leptin receptor

in Pima Indians: influence on energy

expenditure, physical activity and lipid

metabolism. Int J Obes Relat Metab Disord

2002, 26:p. 1629-1632.

18. Winnicki M, Accurso V, Hoffmann M et al.:

Physical activity and angiotensin-converting

enzyme gene polymorphism in mild

hypertensives. Am J Med Genet A 2004,

125:p. 38-44.

19. Vickers MH, Breier BH, McCarthy D,

Gluckman PD: Sedentary behavior during

postnatal life is determined by the prenatal

environment and exacerbated by postnatal

hypercaloric nutrition. Am J Physiol Regul

Integr Comp Physiol 2003, 285:p. R271-R273.

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