British Medical Bulletin, 2017, 123:159–173

doi: 10.1093/bmb/ldx022
Advance Access Publication Date: 7 July 2017

Invited Review

The contribution of genetics and environment

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to obesity
David Albuquerque†,‡,*, Clévio Nóbrega§,**,††, Licínio Manco†,‡‡,
and Cristina Padez†,‡‡
†
Research Center for Anthropology and Health (CIAS), Department of Life Sciences, University of
Coimbra, Coimbra, Portugal, ‡Fundación Investigación Hospital General Universitario de Valencia,
Genomics group, Valencia, Spain, §Department of Biomedical Sciences and Medicine (DCBM), University
of Algarve, Faro, Portugal, **Centre for Biomedical Research (CBMR), University of Algarve, Faro,
Portugal, ††Algarve Biomedical Center (ABC), University of Algarve, Faro, Portugal, and ‡‡Faculty of
Sciences and Technology, Department of Life Sciences, University of Coimbra, Coimbra, Portugal
*Correspondence address. Research Center for Anthropology and Health (CIAS), Department of Life Sciences,
University of Coimbra, Calçada Martim de Freitas (edifício de São Bento), 3000-456 Coimbra, Portugal.
E-mail: dav.albuquerque@gmail.com/daal@fct.uc.pt
Editorial Decision 21 June 2017; Accepted 23 June 2017

Abstract
Background: Obesity is a global health problem mainly attributed to life-
style changes such as diet, low physical activity or socioeconomics factors.
However, several evidences consistently showed that genetics contributes
significantly to the weight-gain susceptibility.
Sources of data: A systematic literature search of most relevant original,
review and meta-analysis, restricted to English was conducted in PubMed,
Web of Science and Google scholar up to May 2017 concerning the contri-
bution of genetics and environmental factors to obesity.
Areas of agreement: Several evidences suggest that obesogenic environ-
ments contribute to the development of an obese phenotype. However, not
every individual from the same population, despite sharing the same obe-
sogenic environment, develop obesity.
Areas of controversy: After more than 10 years of investigation on the genet-
ics of obesity, the variants found associated with obesity represent only 3%
of the estimated BMI-heritability, which is around 47–80%. Moreover, genetic
factors per se were unable to explain the rapid spread of obesity prevalence.

© The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
160 D. Albuquerque et al., 2017, Vol. 123

Growing points: The integration of multi-omics data enables scientists having

a better picture and to elucidate unknown pathways contributing to obesity.
Areas timely for developing research: New studies based on case–control
or gene candidate approach will be important to identify new variants asso-
ciated with obesity susceptibility and consequently unveiling its genetic
architecture. This will lead to an improvement of our understanding about
underlying mechanisms involved in development and origin of the actual
obesity epidemic. The integration of several omics will also provide

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insights about the interplay between genes and environments contributing
to the obese phenotype.
Key words: obesity, genetics, gene–environment interactions, heritability, BMI, omics

Introduction than one hundred loci associated with the common

The prevalence of obesity and related co-morbidities
has reached in the last four decades epidemic propor-
tions in many populations, becoming one of the
major public health concerns throughout the world.1
This epidemic cannot be solely explained by sudden
changes in our genetic background, and has been
mainly attributed to lifestyle modifications. Some
scientists consider it as the result of a ‘social global-
ization’.2 In fact, this recent trend toward increasing
obesity prevalence has been mostly attributed to
over-nutrition and sedentary behaviours as product
of the industrialization of societies. Other factors
including societal, economics, cultural, etc., have also
been considered as significant contributions to the
spread of obesity. Nevertheless, in populations shar-
ing the same obesogenic environment, and despite
different prevalence rates of obesity, there are both
obese and normal weight individuals. This might sug-
gest that some individuals are more susceptible to
weigh gain than others, when exposed to the same
obesogenic environment. This difference could be the
result of the individual genetic profile. Over the last
two decades, and with the progress on molecular
technologies, several studies have been performed
within families, twins and adopted children identify-
ing several genes associated with obesity.3 In 1997,
Montague and colleagues4 identified the leptin (LEP)
gene as the first gene associated with a Mendelian
non-syndromic form of obesity. Since 2007, genome-
wide scans have been successful in identifying more
(polygenic) form of obesity.3 However, while genetic
factors undoubtedly contribute to individual weight
gain susceptibility, the obesity-associated single
nucleotide polymorphisms (SNPs) that have been
identified to date explain less than 3% of the inher-
ited susceptibility to develop an obese phenotype.
This result is very far from the heritability estimates
of body mass index (BMI) rounding 47–80%.5 This
situation suggests that additional genetic loci (includ-
ing low/rare frequency alleles), or other genetic var-
iants such as copy number variations (CNVs)
predisposing to weight gain remain to be discovered.
The interaction between gene–environment by epi-
genetics mechanisms is another approach that needs
to be further investigated. Moreover, the integration
of multi-omics analysis is now seeing as an important
issues to unravel the obesity condition.
In this review, we aim to cover what is already
known about the influence of genetic factors in the
susceptibility risk to develop an obese phenotype.
Regarding environmental factors, we focus our
attention on how socioeconomic conditions might
influence food choice in children. We will also briefly
refer other factors influencing the susceptibility to
weight gain, and the new promising approach based
on multi-omics studies to unravel new mechanisms
underpinning the development of obesity.
Literature selection was performed between
December and May 2017, focusing on the most rele-
vant articles published in English in peer-reviewed
Gene–environment interactions to obesity, 2017, Vol. 123
journals. For this purpose, a search of the literature
was conducted using the online databases PubMed,
Web of Science and Google scholar. Further relevant
articles were hand-searched based on the references
of the selected studies.
Genetic influences on obesity
Within any given environment, there is a certain
variation regarding body size and shape among indi-
viduals. Part of this variation result from genetic fac-
tors. To think that obesity could have a genetic
component is not surprising, given that is known for
long that obesity often runs in families. Effectively,
familial studies showed that BMI is highly correlated
with parental obesity. Children whose both parents
are obese, have higher risk of being obese when com-
pared with children from non-obese parents.6
Nonetheless, in familial studies is difficult to distinct
if this correlation result from genetic or environmen-
tal factors. This question could be in part addressed
by studying twin pairs or adopted children providing
evidence about genetic influences on BMI. A meta-
analysis of 31 twin studies showed that for adults,
the BMI variation explained by genetic difference
ranged from 47% to 80%.7 More recently, a study
conducted by Silventoinen and colleagues,5 analysing
87 782 twin pairs from 45 cohorts also concludes
the important role of genetic factors in the variation
of BMI. In line with this data, adoption studies
showed evidences of the contribution of genetics on
BMI.8 These studies demonstrated that the BMI of
adopted children correlates strongly with biological
parents, and less with adoptive parents.9,10
It is now perfectly established that genes contrib-
ute to differences in body weight within a given
population. Interestingly, some genes identified as
causing obesity in rodents models,11 have also been
identified as contributors to severe human obesity.3
Non-syndromic monogenic forms of obesity result
from mutations in a single gene and affect ~5% of
the population. These loss-of-function mutations are
rare and generally cause deficiencies in food intake,
and energy homoeostasis. The major parts of these
mutations have been identified in LEP, leptin recep-
tor (LEPR), melanocortin 4 receptor (MC4R), and
161
pro-opiomelanocortin (POMC) genes. Interestingly,
a recent study found a deletion in POMC gene with
an allele frequency of 12% in Labrador retriever,
affecting their body weight and food motivation12
showing the importance of the overall leptin/melano-
cortin pathway on the obese phenotype.
Polygenic obesity is the most common form of
obesity in modern societies where the environment
favours weight gain due to food abundance and lack
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of physical activity. With the advance of technology
and the completion of Human genome project our
knowledge on the genetic basis of obesity increased
drastically in the last years. Several studies emerged
identifying more than 100 BMI-associated loci when
comparing a sample composed by normal weight
and obese individuals (Table 1).3 The first locus
undoubtedly associated with obesity using a
genome-wide association (GWA) approach, was the
fat-mass and obesity associated gene (FTO).13
Subsequent GWA studies and meta-analysis identi-
fied numerous variants associated with common
obesity.3 The most recent GWAS meta-analysis iden-
tified 97 BMI-associated loci (56 of which were
novel) in a study involving 339 224 European adults,
accounting to 2.7% of BMI variation (Table 1).14
It is still difficult to explain the rapid spread of
obesity worldwide based only in our genetic back-
ground. Understanding how genes influence mechan-
isms of energy homoeostasis, causing variation on
body weight within any given environment is essen-
tial. However, genes rarely have by itself the power
to determine an individual’s anatomy, physiology or
behaviour. It is the interaction between genes and
environment at all stages of the life cycle, which can
influence and activate weight gain.
Environmental influences on obesity
Several authors suggest that the global rise of obesity
is being driven largely due to environmental factors
such as high food consumption, high sweetened bev-
erages, less activity, television watching, etc. rather
than biological ones. Nowadays, as a result of social
globalization, we are everyday exposed to images and
offers of high fat/caloric, palatable and inexpensive
foods. Furthermore, our physical requirements have
162 D. Albuquerque et al., 2017, Vol. 123

Table 1 List of some genes and SNPs associated with body mass index (BMI) from genome-wide association
studies (GWAS) using European populations

Chr. Gene symbol SNPs Position Alleles EAF References

1 AGBL4 rs657452 49124175 A/G 0.39 Locke et al.14

1 ELAVL4 rs11583200 50094148 C/T 0.39 Locke et al.14
1 IArs2 rs1465816 220116461 T/C 0.28 Hägg et al.15
1 LRP1B rs1890652 31482730 C/T 0.18 Speliotes et al.16
1 NAV1 rs2820292 201815159 C/A 0.55 Locke et al.14

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1 NEGR1 rs2815752 72346757 A/G 0.62 Speliotes et al.16
1 rs2568958 72299433 Willer et al.17, Thorleifsson et al.18
1 PTBP2 rs1555543 96479241 C/A 0.59 Speliotes et al.16
1 SEC16B rs543874 177920345 G/A 0.19 Speliotes et al.16
rs10913469 177944384 Thorleifsson et al.18
1 TAL1 rs977747 47219005 T/G 0.40 Locke et al.14
1 TNNI3K rs1514175 74525960 A/G 0.43 Speliotes et al.16
1 TXNDC12 rs2809930 51981596 T/C 0.00 Hägg et al.15
2 ADAM23 rs13387838 206416723 A/G 0.04 Felix et al.19
2 CREB1, KLF7 rs17203016 207390794 G/A 0.20 Locke et al.14
2 EHBP1 rs11688816 62825913 G/A 0.52 Locke et al.14
2 ERBB4 rs7599312 212548507 G/A 0.72 Locke et al.14
2 FANCL rs887912 59075742 T/C 0.29 Speliotes et al.16
2 FIGN rs1460676 163711179 C/T 0.18 Locke et al.14
2 KCNK3 rs11126666 26705943 A/G 0.28 Locke et al.14
2 USP37 rs492400 218485029 C/T 0.42 Locke et al.14
2 ADCY3 rs713586 24935139 C/T 0.47 Speliotes et al.16
2 SSFA2 rs17456481 181934548 G/C 0.07 Hägg et al.15
2 TMEM18 rs2867125 622827 T/C 0.17 Speliotes et al.16
rs6548238 634905 C/T 0.84 Willer et al.17
rs7561317 644953 Thorleifsson et al.18
2 UBE2E3 rs1528435 180686235 T/C 0.63 Locke et al.14
3 CADM2 rs13078807 85835000 G/A 0.20 Speliotes et al.16
3 ETV5 rs7647305 186116501 Thorleifsson et al.18
rs9816226 186116710 T/A 0.82 Speliotes et al.16
3 FHIT rs2365389 61250788 C/T 0.58 Locke et al.14
3 GBE1 rs3849570 81742961 A/C 0.35 Locke et al.14
3 RARB rs6804842 25064946 G/A 0.57 Locke et al.14
3 RASA2 rs16851483 141556594 T/G 0.06 Locke et al.14
4 GNPDA2 rs10938397 45180510 G/A 0.43 Speliotes et al.16, Willer et al.17
4 HHIP rs11727676 144737912 T/C 0.91 Locke et al.14
4 SCARB2 rs17001654 76208415 G/C 0.15 Locke et al.14
4 SLC39A8 rs13107325 102267552 T/C 0.07 Speliotes et al.16
5 FLJ35779 rs2112347 75719417 T/G 0.63 Speliotes et al.16
5 ZNF608 rs4836133 124996410 A/C 0.48 Speliotes et al.16
6 C6orf106 rs205262 34595387 G/A 0.27 Ahmad et al.20
6 FOXO3 rs9400239 108656460 C/T 0.68 Locke et al.14
6 NUDT3 rs206936 34335092 G/A 0.21 Speliotes et al.16
6 IFNGR1 rs13201877 137354404 G/A 0.14 Locke et al.14
6 LOC285762 rs9374842 119864519 T/C 0.74 Locke et al.14
Continued
Gene–environment interactions to obesity, 2017, Vol. 123 163

Table 1 Continued

Chr. Gene symbol SNPs Position Alleles EAF References

6 MTFR2 rs9494464 136187778 C/T 0.01 Hägg et al.15

6 PARK2 rs13191362 162612318 A/G 0.87 Locke et al.14, Ahmad et al.20
6 TDRG1, LRFN2 rs2033529 40380914 G/A 0.29 Locke et al.14
6 TFAP2B rs987237 50835337 G/A 0.18 Speliotes et al.16
7 ASB4 rs6465468 95540202 T/G 0.31 Locke et al.14
7 CALCR rs9641123 93568420 C/G 0.43 Locke et al.14

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7 HIP1 rs1167827 75533848 G/A 0.55 Locke et al.14
7 PMS2L11 rs2245368 76978826 C/T 0.18 Locke et al.14
8 ELP3 rs13253111 28204457 A/G 0.57 Felix et al.19
8 PEX2 rs6981577 76961693 G/A 0.41 Hägg et al.15
8 RALYL rs2033732 84167474 C/T 0.75 Locke et al.14
8 ZBTB10 rs16907751 80463222 C/T 0.14 Locke et al.14
9 C9orf93 rs4740619 15634328 T/C 0.54 Locke et al.14, Ahmad et al.20
9 EPB41L4B, C9orf4 rs6477694 109170062 C/T 0.36 Locke et al.14
9 LMX1B rs10733682 126698635 A/G 0.47 Locke et al.14
9 LRRN6C rs10968576 28414341 G/A 0.31 Speliotes et al.16
9 NTRK2 rs1211166 84671077 G/A 0.18 Guo et al.21
9 TLR4 rs1928295 117616205 T/C 0.54 Locke et al.14
10 GRID1 rs7899106 85651147 G/A 0.05 Locke et al.14
10 HIF1AN rs17094222 100635683 C/T 0.21 Locke et al.14
10 NT5C2 rs11191560 103109281 C/T 0.08 Locke et al.14
10 TCF7L2 rs7903146 112998590 C/T 0.71 Locke et al.14
11 BDNF rs17309930 27726946 A/C 0.21 Locke et al.14
rs10767664 27704439 A/T 0.78 Speliotes et al.16
rs925946 27645655 Thorleifsson et al.18
11 CADM1 rs12286929 115151684 G/A 0.52 Locke et al.14
11 CEP295 rs12801458 93709816 T/A 0.07 Hägg et al.15
11 HSD17B12 rs2176598 43842728 T/C 0.25 Locke et al.14
11 MTCH2 rs10838738 47641497 G/A 0.34 Willer et al.17
11 rs3817334 47629441 T/C 0.41 Speliotes et al.16, Thorleifsson et al.18
11 RPL27A, TUB rs4929949 8583046 C/T 0.52 Speliotes et al.16
12 CLIP1 rs11057405 122297350 G/A 0.90 Locke et al.14
12 FAIM2 rs7138803 49853685 A/G 0.38 Speliotes et al.16
13 MIR548A2 rs1441264 79006784 A/G 0.61 Locke et al.14
13 MIR548X2, PCDH9 rs9540493 65631572 A/G 0.45 Locke et al.14
13 MTIF3 rs4771122 27446043 G/A 0.24 Speliotes et al.16
13 OLFM4 rs12429545 53528071 A/G 0.13 Locke et al.14
14 NRXN3 rs10150332 79470621 C/T 0.21 Speliotes et al.16
14 PRKD1 rs11847697 30045906 T/C 0.04 Speliotes et al.16
rs12885454 29267632 C/A 0.64 Locke et al.14
14 STXBP6 rs10132280 25458973 C/A 0.68 Locke et al.14
15 LOC100287559, BBS4 rs7164727 72801650 T/C 0.67 Locke et al.14
15 MAP2K5, LBXCOR1 rs2241423 67794500 G/A 0.78 Speliotes et al.16
15 DMXL2 rs3736485 51456413 A/G 0.45 Locke et al.14
16 CBLN1 rs2080454 49028679 C/A 0.41 Locke et al.14
16 FTO rs1558902 53769662 A/T 0.42 Speliotes et al.16, Willer et al.17
16 FTO rs9939609 53786615 A/T 0.41 Frayling et al.13, Scuteri et al.22
Continued
164 D. Albuquerque et al., 2017, Vol. 123

Table 1 Continued

Chr. Gene symbol SNPs Position Alleles EAF References

16 GPRC5B rs12444979 19922278 C/T 0.87 Speliotes et al.16

16 KAT8 rs9925964 31118574 A/G 0.62 Locke et al.14
16 INO80E rs4787491 30004016 G/A 0.51 Locke et al.14
16 NLRC3 rs758747 3577357 T/C 0.26 Locke et al.14
16 SBK1 rs2650492 28322090 A/G 0.30 Locke et al.14
16 SH2B1 rs7498665 28871920 G/A 0.41 Willer et al.17

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rs7359397 28874338 T/C 0.40 Speliotes et al.16, Thorleifsson et al.18
17 RABEP1 rs1000940 5379957 G/A 0.32 Locke et al.14
17 SMG6 rs9914578 2101842 G/C 0.23 Locke et al.14
18 GRP rs7243357 59216087 T/G 0.81 Locke et al.14
18 LOC284260, RIT2 rs7239883 42567706 G/A 0.39 Locke et al.14
18 MC4R rs571312 60172536 A/C 0.24 Speliotes et al.16
rs17782313 60183864 C/T 0.21 Willer et al.17, Loos et al.23
18 RAB27B rs8092503 54812256 G/A 0.27 Felix et al.19
19 PGPEP1 rs17724992 18344015 A/G 0.75 Locke et al.14
19 QPCTL rs2287019 45698914 C/T 0.80 Speliotes et al.16
19 KCTD15 rs11084753 33831232 G/A 0.67 Willer et al.17
rs29941 33818627 G/A 0.67 Speliotes et al.16, Thorleifsson et al.18
19 TOMM40 rs2075650 44892362 A/G 0.85 Guo et al.21
19 ZC3H4 rs3810291 47065746 A/G 0.67 Speliotes et al.16
21 ETS2 rs2836754 38919816 C/T 0.60 Locke et al.14

Chr., chromosome; SNPs, single nucleotide polymorphisms; EAF, effect allele frequency.
SNP positions are reported according to Build 38 (GRCh38.p10) and their alleles are coded based on the positive strand. Effect allele is based
on the meta-analysis of GWAS association data.

changed resulting in an imbalance in energy intake
and expenditure. The modern lifestyle places indivi-
duals to live in an obesogenic environment, encour-
aging us to eat more and exercise less. For example,
several studies found association between obesity and
time spent watching television in both adults24 and
children.25 From an evolutionary perspective, is
totally the opposite to the time where humans were
more actives and had limitations on food intake.
Several reviews on obesity point to the potential con-
tribution of environments factors that promote exces-
sive food consumption and discourage physical
activity. Recently, there has been a growing recogni-
tion of socioeconomic factors contributing to obesity.
Regarding, for example, children, several factors
have been considered to explain the current epidemic
of childhood obesity. However, the pathways to
childhood obesity are very complex and still unclear.
Obesity reflects complex interactions among genetic,
metabolic, behavioural, cultural and environmental
factors.26 The majority of the works rely on child
and parent characteristics and has not considered
family system or the multilevel context in which
child risk factors emerge.27 It is necessary to consider
both biological and social determinants of childhood
obesity at three levels (individual, family and com-
munity) and across early childhood.26
Among numerous factors that underlie child-
hood obesity parental and family history of obesity
can have strong influences through genetic as well
as environmental factors. Family factors play a
huge role because family members are likely to have
similar diets, screen time and physical activity beha-
viours as well as a major influence by perceptions
and attitudes concerning diet and activity that leads
to obesity.28 Behind these factors and behaviours,
the socioeconomic status (SES) of the family plays a
decisive role in the aetiology of childhood obesity.
Studies have showed a socioeconomic gradient
in childhood obesity.29,30 Parental education as an
Gene–environment interactions to obesity, 2017, Vol. 123
indicator of socioeconomic position (SEP) has the
most consistent, inverse association with childhood
obesity.30,31 Other SEP indicators such as parental
occupation and family income were more inconsist-
ent. In a meta-analysis, Wu and colleagues32 found
that low SEP is associated with a 10% higher risk for
overweight and 41% higher risk of obesity in chil-
dren aged 0–15 years in high-income countries more
specifically in North America, Europe and Oceania.
Earlier studies in this topic presented results that
showed that obesity is higher in people from a low
socioeconomic status in developed countries rather
than in developing economies.33 Socioeconomic fac-
tors are likely to be associated with child adiposity
through a number of pathways, including knowl-
edge, attitudes, financial and other constraints on
nutrition and physical activity patterns. Higher risks
of obesity in children with lower SEP in developed
countries may be related to less access to healthy
food and safe exercise, less interest in weight control,
cultural standards of physical effectiveness, and dis-
crimination against socioeconomic advancement.34
However, a different picture can be found in devel-
oping countries and less economic developed areas,
where malnutrition and opulence co-exist, food
availability remains a daily challenge in populations
with low SEP and obesity is subsequently perceived
as a sign of wealth.35 Parental educational level is
more consistently inversely associated with child-
hood obesity than other indicators. As an important
socioeconomic indicator, parental educational level
influences the family’s knowledge and beliefs, and
these are considered important for healthy lifestyles
and the development of obesity. Moreover, higher
educational achievement may facilitate better under-
standing and utilization of available nutrition infor-
mation that assists individuals’ decisions on dietary
practice and tend to follow recommendations for
health behaviours36 and respond more actively to
health-related media messages37 than lower socio-
economic groups. Children from more educated par-
ents are more likely to eat breakfast and consume
fewer snacks, and they are less likely to eat foods
with high-energy content, such as sweetened bev-
erages38 and more fruit and vegetable intake39 con-
trary to children from low SES that tend to have
165
diets rich in low cost energy dense food,40,41 partici-
pated less in physical activity sports,42 and have low-
er awareness of weight control.43 The environment
where families live can also contribute to a less
healthy eating diet. Children living in more deprived
places tend to eat less fruit and vegetables but more
sugar and sweets, fats processed meats, salty snacks
and soft drinks compared with those from higher
income households.44 Excessive food intake is a
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major contributor to obesity. Another large con-
tributor to obesity is the lack of physical activity45
and sedentary behaviour measured by screen time.25
Sallis and colleagues46 found a social gradient in sed-
entary, physical activity and access to physical activ-
ity facilities in young people.
Families living in poverty have different prior-
ities than those with a stable SEP. Those facing pov-
erty are more likely to unintended disinvestment in
health and healthy behaviours.47 The social gradi-
ent in childhood obesity in some populations may
partly be due to healthy eating and physical activity
being considered a low priority in deprived house-
holds.36 This problem is still more complex when
we take a contextual vision of our world. Modern
food environments are filled with nutrient-poor and
energy-dense foods. These foods are highly palat-
able and processed in ways that make it difficult for
the body to regulate intake and weight.48 This bio-
logical vulnerability to ultra-processed foods is
especially problematic for children because they
have a stronger preference for sweet foods than
adults.49,50 Childhood is a period of a person’s life
when industries work to develop brand loyalty.
Marketing and early exposure at a young age to
ultra-processed foods shape children’s taste expecta-
tions and preferences for unhealthy products.49
Gene–lifestyle interactions in obesity
Gene–environmental (G × E) interactions do exist
when the risk conveyed by a specific genotype
depends on one or more environmental exposure
levels.51 Although since 2007 many genetic var-
iants detected by GWAS have been associated with
obesity or obesity-related traits, those variants,
individually or in combination by calculating a
166
genetic risk score (GRS), only explain small frac-
tions of phenotypic variations.
It is hypothesized that interaction effects between
genes and environmental factors may account for
some of this ‘missing heritability’ in obesity, with
multiple known obesity-predisposing gene variants
interacting with lifestyle to modify the obesity risk.
In the present review, we will focus our attention
in two major factors contributing to body weight
regulation, which are physical activity and diet, and
how they mediate the association between genetic
variants and obesity.51 However, there are other
environmental factor exposures that can play a role
on obesity susceptibility interacting with genetic, epi-
genetic or other molecular mechanisms. For example,
respiratory disorders (e.g. obstructive sleep apnoea)
or sleep disturbance (e.g. sleep duration, insomnia or
excessive daytime sleepiness) have been identified
influencing obesity.52,53 These traits are heritable and
there are some evidence of a genetic component
involved on sleep disturbances.52,53 Smoke has been
also implicated as one of these potential contributors
to increase weight gain. For example, a recent meta-
analysis involving 51 080 smokers (predominantly
from European descent) identified 23 novel genetic
loci, with nine of them showing a clear evidence of
gene–smoking interaction on obesity-related traits.54
It was also documented that the genetic association
with BMI was strengthened with increased hours of
TV watching55 or with educational level.56
Gene–physical activity interactions
Modulation of FTO–obesity associations by self-
reported physical activity is one of the most replicated
gene–environmental interactions in obesity. While evi-
dence work showed that the ‘at risk’ alleles of the FTO
single nucleotide polimorfisms are not associated with
altered resting energy expenditure or physical activity
in humans, many individual observations in European
ancestry populations suggests that moderate to vigor-
ous physical activity attenuates the effect of FTO gen-
etic susceptibility to obesity.57,58 A meta-analysis by
Kilpeläinen and colleagues59 showed that the effect of
FTO rs9939609 on BMI, waist circumference, body
fat percentage and obesity risk is ~30% lower in
D. Albuquerque et al., 2017, Vol. 123
physically active than in sedentary adults. Although
the meta-analysis of Kilpeläinen and colleagues59
showed no interaction between FTO and physical
activity in children and adolescents, some individual
studies suggest that low physical activity seems to
accentuate the effect of FTO on risk of obesity also
among this age group.58,60 Most recent additional
individual studies for the FTO rs9939609 variant
endorsed similar GxE observations for obesity indi-
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ces in adults,61 young adults62 or adolescents.63
Interaction effects between other obesity-related loci
and physical activity in relation to obesity-related traits
were also documented. The same pattern suggesting
that higher physical activity may attenuate adverse
effects of the obesity-related loci was shown for other
variants in different genes.63–65 Moreover, the meta-
analysis of 111 421 adults of European ancestry con-
ducted by Ahmad and colleagues65 showed a statistical
significant GRS (calculated by summing the BMI-
associated alleles of each one of 12 genetic variants)
and physical activity interaction effect in BMI (p inter-
action = 0.015). Consistent with the observations in
European populations, Zhu and colleagues66 found in
Chinese adults that the effect of a GRS based on 28
single nucleotide polimorfisms on obesity susceptibility
was more pronounced in individuals with low physical
activity than in those with high physical activity levels.
Although the mechanisms behind the observa-
tion that physical activity attenuate the influence of
obesity-loci in weight gain remain to be explained,
the fact that physical activity can lead to temporary
appetite suppression,67 suggests some biologically
plausible support for the observed attenuation of
obesity risk allele associations.63
Gene–diet interactions
The role for FTO risk alleles in the regulation of
food intake was evidenced by several works support-
ing for the association with increased appetite,
energy, dietary fat or protein intake and reduced sati-
ety.68 Additionally, evidences for a gene–diet inter-
action has also come from studies on the FTO locus
suggesting that dietary habits and energy intake
might also attenuate the effects of FTO on obesity
susceptibility (Table 2). Several studies observed for
 Gene–environment interactions to obesity, 2017, Vol. 123
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Table 2 A summary of some significant studies on gene–diet interactions on BMI or obesity

Gene/SNP ID Study design Population ancestry Main findings References

FTO/rs9939609 Cross-sectional European (Swedish)

Significant interactions were observed between energy-adjusted fat Sonestedt et al.69
intake and FTO genotype and between carbohydrate intake and
FTO genotype on BMI.
FTO/rs9939609 Case–control European (Spanish) Influence of dietary fatty acid distribution on the effect of the Moleres et al.72
rs9939609 polymorphism of the FTO gene on children and
adolescents’ obesity risk.
FTO/rs9939609 Case–control European (French) High dietary saturated fat intake accentuates obesity risk associated Phillips et al.70
with the FTO gene.
FTO/rs1121980 Cross-sectional European (USA) High intake of saturated fatty acids strengthens the association Corella et al.73
rs9939609 Hispanics (USA) between the FTO and BMI.
FTO/rs8050136 Cross-sectional European (USA) Lifestyle factors modified the genetic risk of FTO on obesity Ahmad et al.74
phenotypes, particularly among women who were both inactive
and had high intake.
FTO/rs1558902 Two-years intervention Several Carriers of the risk allele had a greater reduction in weight, body Zhang et al.71
composition, and fat distribution in response to a high-protein
diet.
ADRB2/rs1042714 Case–control European (Spanish) High carbohydrate consumption increase risk of obesity among Martinez et al.75
(Gln27Glu) ADRB2 27Glu genotypes.
LIPC/rs1800588 Case-only European An interaction between fibre intake and LIPC gene, and dietary fat Santos et al.76
ADIPOQ/rs266729 (several countries) intake and ADIPOQ or PPARG3 genes, to modify the
PPARG3/rs10865710 association with obesity.
GRS Three-year follow-up European (Finnish) A diet low in fibre appeared to have a BMI-increasing effect in those Jääskeläinen et al.77
who carried large numbers of obesity-predisposing variants.
GRS Cohort (NHS, HPFS, WGHS) European (USA) Genetic association with adiposity was stronger among participants Qi et al.78
with higher intake of sugar-sweetened.
GRS Cohort (NHS, HPFS, WGHS) European (USA) Genetic association with adiposity was stronger among participants Qi et al.79
with higher consumption of fried food.

Abbreviations: SNP ID, single nucleotide polymorphism identification; GRS, genetic risk score.

167
168
risk allele carriers of FTO gene polymorphisms that
a high-fat diet further accentuated the obesity
risk.59,69,70 Also, for the FTO rs1558902 poly-
morphism, a high-protein diet was found to facilitate
weight loss and improvement of body composition
in individuals with the risk allele, whereas an oppos-
ite genetic effect was observed on changes in fat dis-
tribution in response to a low-protein diet.71
Other loci have also been implicated in gene–diet
interactions (Table 2). For example, a case–control
study found that the high carbohydrate consumption
increase risk of obesity among ADRB2 genotypes.75
A case-only study in adult obese women observed an
interaction between fibre intake and LIPC gene, and
dietary fat intake and ADIPOQ or PPARG3 genes,
to modify the association with obesity.76 Also
Jääskeläinen and colleagues77 in a 3-year follow-up
study observed that a diet low in fibre appeared to
have a BMI-increasing effect in those who carried
large numbers of obesity-predisposing variants.
Cohort studies calculating genetic risk scores have
demonstrated that the genetic association with adi-
posity was stronger among participants with higher
intake of sugar-sweetened78 or higher consumption
of fried food.79 Several intervention studies demon-
strated gene–diet interaction on obesity documented
for variants in genes including IRS, TCF7L2, GIPR,
PPM1K, ADIPOQ, FAAH, FTO or Visfatin (see
review by Huang and Hu51).
Although these evidences that various nutrients
modulate gene expression influencing the impact of
genetic variants on obesity, the mechanisms behind
the present observation remain to be explained.77
For the FTO locus, that is associated with methyla-
tion capability,80 some investigators speculate that
the intron-1 obesity-associated region might be sen-
sitive to epigenetic effects.
Other players contributing to obesity
susceptibility
Epigenetics refers to a set of mechanisms regulating
gene expression without alteration of the DNA
sequence, and involves DNA methylation, histone
modifications and the microRNAs role in gene
expression.3 From these mechanisms, the most
D. Albuquerque et al., 2017, Vol. 123
studied to assess the epigenetic component in the
context of obesity is DNA methylation. Briefly, it
consists of the introduction of methyl groups at the
carbon-5 of cytosine, usually at the CpG dinucleo-
tides position. Through epigenome-wide studies
(EWAS), which allow collection of information
about DNA methylation variations throughout the
epigenome, was possible to identify methylation pro-
files in different genes associated with obesity.81
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Moreover, several studies also pointed to an interest-
ing observation linking alterations in methylation
marks of in utero environment with the development
of adult obesity.3 However, the knowledge of
mechanisms by which maternal nutritional environ-
ment induces such changes remains largely
unknown.
DNA is wrapped in proteins called histone, which
undergoes several types of modifications (e.g. acetyl-
ation, methylation, phosphorylation, among others).
These modifications were shown to be important in
the regulation of gene expression. In the context of
obesity they were linked to adipogenesis and thus
might play an important role in obesity onset and
development.82
MicroRNAs are endogenous short single-stranded
non-protein-coding RNAs with ~21–25 nucleotides
in length, which are involved in post-transcriptional
regulation of gene expression. They have been impli-
cated in obesity, namely by acting in different path-
ways of the metabolic function or in the adypocytes
differentiation.3,83 For example miR-21 is strongly
expressed in human adipose tissue and positively cor-
related with BMI.84
Another player that recently emerged accounting
for obesity development is the gut microbiota,
which comprises a complex community of bacteria
living in the human gastrointestinal tract.85 Several
evidences suggest that diet alters gut microbiota,
and this is reflected by differences observed between
obese and lean individuals. Furthermore, other
studies pointed to the importance of gut microbiota
in modulating the energy intake.
The implication of epigenetic profiles and gut
microbiota in obesity is much more complex than
this brief description. Indeed, there are growing evi-
dences from several studies and reviews that highlight
Gene–environment interactions to obesity, 2017, Vol. 123 169

the importance of these players in obesity. Neverthe-
less, more controlled and standardized studies are
needed to access the real impact of these players in
the obesity.
Integration of multi-omics data
on obesity
The genomics era yielded several advances on the
how to analyse all these information together.
These new data mostly results from new scientific
fields designed by adding omics suffix (Fig. 1), such
as genomics, epigenomics, transcriptomics, proteo-
mics and metabolomics. Integrative omics analyses
refer to the combination of at least two different
types of these omics, and appear essential to under-
stand the underlying mechanisms and to discover
new pathways involved in obesity and other condi-

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understanding of the genetic susceptibility to obes-
ity. However, despite the huge advances on this
field there is still a missing gap between the previous
heritability studies (~47–80% of BMI) and BMI-
associated loci identified until now (<3% of BMI).
Generally, these genomic studies are based on single
genetic association and are not looking at the
whole-exome/genome level. The recent advance on
technology resulted in a growing number of bio-
logical data, and from now on the main issue is
tions affecting human health. There are still few
studies based on this approach regarding the obes-
ity condition. However, some studies could be
found reporting the integration of two sets of omics
data such as the expression of quantitative trait loci
(eQTL) or the methylation-QTL (meQTL). Using
this approach, Smemo and colleagues86 found that
variants within introns of FTO gene are function-
ally connected with the homeobox 3 gene (IRX3)
expression. In mouse, Irx3-deficiency reduce body

Fig. 1 Schematic representation of an integrated multi-omics approach, which combine genom-

ics (access to DNA sequence), epigenomics (access to DNA methylation, histone modifications
and microRNA), transcriptomics (access to mRNA sequence and level of expression), proteomics
(access to protein sequence), and metabolomics (access to metabolites). All the data need to be
analysed using a bioinformatics tools. Inter-individual variations along any of these omics levels
contribute to the wide range of phenotype variability observed in human subjects.
170
weight of 25–30%.86 Another study analysing 52
known obesity-associated polymorphisms, identi-
fied alleles at 28 of these polymorphisms associated
with methylation levels at 107 proximal CpG sites
regulation in peripheral blood.87 The interaction
between polymorphisms and methylation mechan-
isms is very important to understand the overall
molecular basis associated with a trait. Individual’s
carrying the TT genotype for the rs17782313 poly-
morphism near MC4R gene has been identified as
having promotor hypermethylation and decreased
expression of MC4R.88
Our diet compositions changed drastically from
the time humans were hunter-gatherers. The indus-
trialized food brought new bioactive molecules of
determinant nutrients that may influences tran-
scripts, proteins or metabolites. Several obesity sus-
ceptibility genes were found to interact with dietary
carbohydrates increasing BMI when one or more
servings are consumed per day.78
The integration of several multi-omics datasets
might lead to the detection of new obesity-related
genes and the molecular pathways underlying this
condition. A recent study using a porcine model
identified several pathways and potential causal
genes for obesity integrating genomics and tran-
scriptomics data.89 Further validation is needed,
including a human sample to investigate how these
genes could be used as biomarkers for obesity.
Conclusions
There is an increasing idea that obesity arises beyond
a simple imbalance between energy intake and
expenditure. It is also very clear the important role of
genetics and lifestyle factors in the development of
obesity. The heritability studies point to a high genetic
component of obesity, nevertheless until now only a
small portion of that component was unravelled. On
the other hand, the western societies promote the
development of obesity making available highly cal-
oric diets and sedentary behaviours. However, there is
also a growing awareness to a healthy lifestyle. This
review focused on two major environmental factors,
nonetheless, other factors such as stress, alcohol and
various industrial chemicals may also contribute to
D. Albuquerque et al., 2017, Vol. 123
obesity by epigenetic mechanisms. Thus, the underlying
causes for obesity are far more complex, involving
social and cultural aspects, and at a more biological
context involving epigenetics mechanisms, regulation
of food intake, and even the contribution of the gut
microbiota.
Future studies focusing on gene–lifestyle interac-
tions, genetics or environment factors will defini-
tively help to understand the complex architecture
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of obesity onset and development.
Acknowledgements
This study was performed in part with the support of
Fundação para a Ciência e a Tecnologia (FCT) (UID/
ANT/00283/2013). David Albuquerque as a Post-
Doc fellowship (SFRH/BPD/109043/2015) from
FCT. Clévio Nóbrega is funded by FCT, Portugal,
the French Muscular Dystrophy Association, France.
Conflict of interest statement
The authors have no potential conflicts of interest
to declare.
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