Genetics of obesity

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A 1680 painting by Juan Carreno de Miranda of a girl presumed to have Prader-Willi syndrome La monstrua desnuda (1680), de Juan Carreno de Miranda..jpg
A 1680 painting by Juan Carreño de Miranda of a girl presumed to have Prader-Willi syndrome

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]

Contents

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 (weight gain) or leptogenic (weight loss) genes may influence the obese individual's response to weight loss or weight management. [9]

Specific genetic mechanisms

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
Ghrelin 605353 3p25.3
Ghrelin receptor 601898 3q26.31
prohormone convertase-1 deficiency 600955 5q15-q21
proopiomelanocortin deficiency 609734 2p23.3
melanocortin-4 receptor polymorphism (MC4R [15] ) 155541 18q22
BMIQ1 7q32.3near D7S1804 [16]
BMIQ2 13q14near D13S257 [16]
BMIQ3 6q23-q25near D6S1009, GATA184A08, D6S2436, and D6S305 [17]
BMIQ4 11q24near D11S1998, D11S4464, and D11S912 [17]
BMIQ5 16p13near ATA41E04 [18]
BMIQ6 20pter-p11.2near D20S482 [18]
INSIG2 [15] 2q14.1
FTO [15] 16q12.2Adults 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] 19q13.12KCTD15 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 1q41Disputed metabolic function of being either a lipase [26] or a short-chain carboxylesterase. [27]
CB1 [28] 114610 6q15
NPY5R [29] 602001 4q32.2

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. [30]

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. [31] 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. [32]

Numerous studies of laboratory rodents provide strong evidence that genetics play an important role in obesity. [33] [34]

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. [35]

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. [36] [37] Other candidate anti-obesity-related genes include ALK, [38] TBC1D1, [39] and SRA1. [40]

Genetic syndromes

The term "non-syndromic obesity" is sometimes used to exclude these conditions. [41] 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. [42]

See also

Related:

Related Research Articles

The thrifty gene hypothesis, or Gianfranco's hypothesis is an attempt by geneticist James V. Neel to explain why certain populations and subpopulations in the modern day are prone to diabetes mellitus type 2. He proposed the hypothesis in 1962 to resolve a fundamental problem: diabetes is clearly a very harmful medical condition, yet it is quite common, and it was already evident to Neel that it likely had a strong genetic basis. The problem is to understand how disease with a likely genetic component and with such negative effects may have been favoured by the process of natural selection. Neel suggested the resolution to this problem is that genes which predispose to diabetes were historically advantageous, but they became detrimental in the modern world. In his words they were "rendered detrimental by 'progress'". Neel's primary interest was in diabetes, but the idea was soon expanded to encompass obesity as well. Thrifty genes are genes which enable individuals to efficiently collect and process food to deposit fat during periods of food abundance in order to provide for periods of food shortage.

<span class="mw-page-title-main">FTO gene</span> Protein-coding gene in the species Homo sapiens

Fat mass and obesity-associated protein also known as alpha-ketoglutarate-dependent dioxygenase FTO is an enzyme that in humans is encoded by the FTO gene located on chromosome 16. As one homolog in the AlkB family proteins, it is the first messenger RNA (mRNA) demethylase that has been identified. Certain alleles of the FTO gene appear to be correlated with obesity in humans.

<span class="mw-page-title-main">Mevalonate kinase</span> Mammalian protein found in Homo sapiens

Mevalonate kinase is an enzyme that in humans is encoded by the MVK gene. Mevalonate kinases are found in a wide variety of organisms from bacteria to mammals. This enzyme catalyzes the following reaction:

<span class="mw-page-title-main">NPC1</span> Protein-coding gene in the species Homo sapiens

Niemann-Pick disease, type C1 (NPC1) is a membrane protein that mediates intracellular cholesterol trafficking in mammals. In humans the protein is encoded by the NPC1 gene.

<span class="mw-page-title-main">Genome-wide association study</span> Study of genetic variants in different individuals

In genomics, a genome-wide association study, is an observational study of a genome-wide set of genetic variants in different individuals to see if any variant is associated with a trait. GWA studies typically focus on associations between single-nucleotide polymorphisms (SNPs) and traits like major human diseases, but can equally be applied to any other genetic variants and any other organisms.

<span class="mw-page-title-main">Melanocortin 4 receptor</span> Mammalian protein found in Homo sapiens

Melanocortin 4 receptor (MC4R) is a melanocortin receptor that in humans is encoded by the MC4R gene. It encodes the MC4R protein, a G protein-coupled receptor (GPCR) that binds α-melanocyte stimulating hormone (α-MSH). In mouse models, MC4 receptors have been found to be involved in feeding behaviour, the regulation of metabolism, sexual behaviour, and male erectile function.

<span class="mw-page-title-main">Cell adhesion molecule 1</span> Protein involved in attachment of cells

Cell adhesion molecule 1 is a protein that, in humans, is encoded by the CADM1 gene.

<span class="mw-page-title-main">MKKS</span> Protein-coding gene in the species Homo sapiens

McKusick–Kaufman/Bardet–Biedl syndromes putative chaperonin is a protein that in humans is encoded by the MKKS gene.

<span class="mw-page-title-main">TFAP2B</span> Protein that in humans and is encoded by the TFAP2B gene

Transcription factor AP-2 beta also known as AP2-beta is a protein that in humans is encoded by the TFAP2B gene.

RPGRIP1L is a human gene.

<span class="mw-page-title-main">TMEM18</span> Protein-coding gene in the species Homo sapiens

Transmembrane protein 18 also known as TMEM18 is a protein which in humans is encoded by the TMEM18 gene.

<span class="mw-page-title-main">GNPDA2</span> Protein-coding gene in the species Homo sapiens

Glucosamine-6-phosphate deaminase 2 also known as GNPDA2 is an enzyme that in humans is encoded by the GNPDA2 gene.

<span class="mw-page-title-main">NEGR1</span> Protein-coding gene in the species Homo sapiens

Neuronal growth regulator 1 also known as NEGR1 is a protein which in humans is encoded by the NEGR1 gene.

<span class="mw-page-title-main">KCTD15</span> Protein-coding gene in the species Homo sapiens

Potassium channel tetramerisation domain containing 15 also known as BTB/POZ domain-containing protein KCTD15 is protein that in humans is encoded by the KCTD15 gene.

<span class="mw-page-title-main">MTCH2</span> Protein-coding gene in the species Homo sapiens

Mitochondrial carrier homolog 2 also known as MTCH2 is a protein which in humans is encoded by the MTCH2 gene.

<span class="mw-page-title-main">IRX3</span> Protein-coding gene in the species Homo sapiens

Iroquois-class homeodomain protein IRX-3, also known as Iroquois homeobox protein 3, is a protein that in humans is encoded by the IRX3 gene.

<span class="mw-page-title-main">Monocarboxylate transporter 9</span> Protein-coding gene in the species Homo sapiens

Monocarboxylate transporter 9 is a protein that in humans is encoded by the SLC16A9 gene.

Most cases of type 2 diabetes involved many genes contributing small amount to the overall condition. As of 2011 more than 36 genes have been found that contribute to the risk of type 2 diabetes. All of these genes together still only account for 10% of the total genetic component of the disease.

Karen L. Mohlke is a biologist at University of North Carolina, Chapel Hill. She is known for her work in human genetics, especially in the area of diabetes research. She was one of the first researchers to use exome array genotyping.

Eleftheria Zeggini is a director of the institute of translational genomics in Helmholtz Zentrum München and a professor at the Technical University of Munich (TUM). Previously she served as a research group leader at the Wellcome Trust Sanger Institute from 2008 to 2018 and an honorary professor in the department of health sciences at the University of Leicester in the UK.

References

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