Genetics of obesity

Like many other medical conditions, obesity is the result of an interplay between environmental and genetic factors.[2][3] Studies have identified variants in several genes that may contribute to weight gain and body fat distribution; although, only in a few cases are genes the primary cause of obesity.[4][5]

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A 1680 painting by Juan Carreño de Miranda of a girl presumed to have Prader-Willi syndrome[1]

Polymorphisms in various genes controlling appetite and metabolism predispose to obesity under certain dietary conditions. The percentage of obesity that can be attributed to genetics varies widely, depending on the population examined, from 6% to 85%,[6] with the typical estimate at 50%. It is likely that in each person a number of genes contribute to the likelihood of developing obesity in small part, with each gene increasing or decreasing the odds marginally, and together determining how an individual responds to the environmental factors. [7] As of 2006, more than 41 sites on the human genome have been linked to the development of obesity when a favorable environment is present.[8] Some of these obesogenic or leptogenic genes may influence the obese individual's response to weight loss or weight management.[9]

Genes

Although genetic deficiencies are currently considered rare, variations in these genes may predispose to common obesity.[10][11][12] Many candidate genes are highly expressed in the central nervous system.[13]

Several additional loci have been identified.[14] Also, several quantitative trait loci for BMI have been identified.

Confirmed and hypothesized associations include:

Condition OMIM Locus Notes
leptin deficiency 164160 7q31.3
leptin receptor deficiency 601007 1p31
prohormone convertase-1 deficiency 600955 5q15-q21
proopiomelanocortin deficiency 609734 2p23.3
melanocortin-4 receptor polymorphism (MC4R[15]) 155541 18q22
BMIQ1 7q32.3 near D7S1804[16]
BMIQ2 13q14 near D13S257[16]
BMIQ3 6q23-q25 near D6S1009, GATA184A08, D6S2436, and D6S305[17]
BMIQ4 11q24 near D11S1998, D11S4464, and D11S912[17]
BMIQ5 16p13 near ATA41E04[18]
BMIQ6 20pter-p11.2 near D20S482[18]
INSIG2[15] 2q14.1
FTO[15] 16q12.2 Adults who were homozygous for a particular FTO allele weighed about 3 kilograms more and had a 1.6-fold greater rate of obesity than those who had not inherited this trait.[19] This association disappeared, though, when those with FTO polymorphisms participated in moderately intensive physical activity equivalent to three to four hours of brisk walking.[20]
TMEM18[15] 2p25.3
GNPDA2[15] 4p13
NEGR1[15] 1p31.1
BDNF[15] 11p13
KCTD15[15] 19q13.12 KCTD15 plays a role in transcriptional repression of AP-2α, which in turn, inhibits the activity of C/EBPα, an early inducer of adipogenesis.[21]
KLF14[22]  ? Although it does not play a role in the formation of fat itself, it does determine the location on the body where this fat is stored.
SH2B1[23] 16p11.2
MTCH2[23] 11p11.2
PCSK1[23] 5q15-q21
NPC1[24] 18q11-q12
LYPLAL1[25] 616548 1q41 Disputed metabolic function of being either a lipase[26] or a short-chain carboxylesterase.[27]

Some studies have focused upon inheritance patterns without focusing upon specific genes. One study found that 80% of the offspring of two obese parents were obese, in contrast to less than 10% of the offspring of two parents who were of normal weight.[28]

The thrifty gene hypothesis postulates that due to dietary scarcity during human evolution people are prone to obesity. Their ability to take advantage of rare periods of abundance by storing energy as fat would be advantageous during times of varying food availability, and individuals with greater adipose reserves would more likely survive famine. This tendency to store fat, however, would be maladaptive in societies with stable food supplies.[29] This is the presumed reason that Pima Native Americans, who evolved in a desert ecosystem, developed some of the highest rates of obesity when exposed to a Western lifestyle.[30]

Numerous studies of laboratory rodents provide strong evidence that genetics play an important role in obesity.[31][32]

The risk of obesity is determined by not only specific genotypes but also gene-gene interactions. However, there are still challenges associated with detecting gene-gene interactions for obesity.[33]

Genes protective against obesity

There are also genes that can be protective against obesity. For instance, in GPR75 variants were identified as such alleles in ~640,000 sequenced exomes which may be relevant to e.g. therapeutic strategies against obesity.[34][35] Other candidate anti-obesity-related genes include ALK,[36] TBC1D1,[37] and SRA1.[38]

Genetic syndromes

The term "non-syndromic obesity" is sometimes used to exclude these conditions.[39] In people with early-onset severe obesity (defined by an onset before 10 years of age and body mass index over three standard deviations above normal), 7% harbor a single locus mutation.[40]

See also

Related:

  • Human genetic variation

References
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