How Important is the Role of Genetics in Common Obesity

Frequently characterised by a body mass index greater than 30kg/m^2, obesity is rapidly becoming a serious problem for not just high-income countries, but also middle-income countries, with trends predicting that by 2025, 21% of women and 18% of men will be obese. Even in lower-income countries where under-nutrition is still common, prevalence of obesity has risen- in some countries up to 20% between 1990 and 2015, with the percentage of overweight children doubling in regions such as southern and western Africa between 1990 and 2010. In 2015, high body mass index was a factor in 4 million deaths, an increase of 28.3% since 1990. Cardiovascular disease was a leading cause, accounting for 2.7 million of these deaths. Obesity also brings other health concerns including diabetes, stroke, dyslipidaemia, some types of cancer, and in some cases mental health issues.

A variety of methods have been used to investigate the effect of genetics in common obesity. Pedigree studies such as twin and adoptive studies have been used to great success for over 40 years, and suggest that anywhere between 40% and 70% of inter-individual variability of body mass index is caused by genetics, but heritability estimates vary, differing from study to study. More recently, gene technology advancements have led to techniques such as genome wide association studies (GWAS) and candidate gene studies being used to identify specific loci that may be associated with obesity. These methods have been partially successful in that while they have been able to pinpoint over 97 loci that are associated with high body mass index, common obesity is a multifactorial (and multigenic) disease and its heritability can therefore not be reduced to the action of a limited number of genes, unlike Mendelian diseases. However GWAS and candidate gene studies have been able to provide information about the effect of genetics on obesity that is independent to evidence from pedigree analyses.

Twin Studies

Twin studies have indicated that 50-70% of variance in body mass index can be explained by genetic factors. In 1990, a study was conducted on twins that lived apart versus twins that lived together. Of the monozygotic twins that were part of the experiment, 93 pairs were reared apart and 154 were reared together. The experiment also included 218 pairs of dizygotic pairs that grew up apart, and 208 pairs that grew up together. Although the study contained very few twins that were obese (had a body mass index >30kg^m2), it looked into the intrapair correlation of BMI, which provides a valuable insight into the relative importance of the role of genes in body mass index as a whole. The study found that the intrapair correlation coefficient for twins that grew up apart was 0.70 for men and 0.66 for women, which is only slightly lower than coefficients obtained from twins that were raised together. The similarity between correlation coefficents of pairs that were raised together and pairs that were raised apart suggests that, during childhood at least, an individual's genetic makeup has a greater effect than environmental factors. This indicates that genetics play a major role in determining an individual's body mass index, while the environment (in this case, that the twins grew up in) has a lesser effect. Other larger and more recent twin studies appear to support this early data; a twin study of 12,000 monozygotic & dizygotic twin pairs was carried out from birth until 19 years of age. The study found that while environmental factors were hugely important at birth and heritability was relatively low, after 5 months the effect of genetics accounted for over 50% of the variance of weight and BMI in both sexes. In this study it was shown that while environmental influences have the strongest influence during pre-adolescent years, during adulthood genetics play a much larger role. This supports the evidence from previous twin studies, including the study by Stunkard et al. in 1986. It also supports a longitudinal twin study carried out in 2007 that showed that BMI at the age of 1 year correlates with BMI at the age of 18, with the correlation coefficient increasing steadily until 17 years of age. It was found that a major part of this correlation was attributable to correlate additive genetic factors, but environmental factors were present and having an effect throughout.The neonatal environment appears to be particularly important in determining adult body mass index, while environmental influences after this time period became much less important. This is important to consider as the environmental factors experienced at birth may have a knock on effect on genetic predisposition to obesity.

Adoption Studies

Adoption studies have also been used to estimate heritability. In 1992, a study of 269 Danish adoptees was carried out, which found that the body mass index of the adopted child had a high correlation with that of their biological family; the correlation coefficients were 0.16 with biological fathers, 0. 17 with biological mothers, and 0.59 with biological siblings. The correlation with their adopted families was much lower; 0.03 with adoptive fathers, 0.1 with adoptive mothers, and 0.14 with adoptive siblings. The correlation coefficient was over 5 times greater between the adopted child and their biological father than their adoptive father, 4 times greater between the adoptee and their biological siblings than it was with their adoptive siblings, and almost twice as great between the child and their biological mother than with their adoptive mother. The study was carried out over the ages of 7 to 13 look into the effect that the rearing environment of a family can have on body mass index. In this case, it was shown that the rearing environment has little effect on the development of obesity during childhood. Contrastingly, at the age of 7, genetic influences are already exerting their full effect and will continue to do so into adulthood. This corroborates the findings of the twin study carried out in 2012, which found that after 5 months of age genetics accounted for over half of variance in body mass index, and of previous twin studies. Because the adoptive study only used height and weight measurements from age 7 upwards, the earliest age that can be proved to be when the genetic influences are exerting their full force is 7; however, when considered in conjunction with the twin study it is likely that genetics were exerting their full force much before this age.

Family Studies

Family studies confirm the intergenerational transmission of body mass index between biological parents and their offspring. A study of 2,560 mothers and their 4,748 children found that there was a correlation coefficient of body mass index of 0.38 between daughters and their mothers and 0.32 between sons and their mothers. This study was particularly interesting in that it showed that intergenerational transmission was stronger between families with high body mass index than families with low body mass index, meaning that mothers with high susceptibility to obesity were more likely to pass down their traits to their children than mothers with low susceptibility. This is evidence that genetic influences are particularly important in cases of obesity, rather than being equally important for all body weights.

Candidate Gene Studies

The first studies to be used for identifying specific gene loci that may play a role in common obesity were candidate gene studies. They were first used in the mid 1990s-before this point, there was no way of determining which parts of the genome were associated with obesity. Pedigree studies were only able to determine whether or not the genome has an effect, and to what extent. In candidate gene studies, genes that are already suspected of having a role in the development of a common disease are examined to see if variation in that specific gene is associated with the disease- in this case, common obesity. Many candidate genes have been identified for obesity-susceptibility but they only account for around 1% of the total genetic variation observed in obesity. Candidate gene studies have been shown to be likely to miss many effects on obesity-related traits by non-candidate genes, as they rely on a previous hypothesis that a certain gene is associated with the disease. For example, many candidate gene studies have been carried out on genes involved in the leptin-melanocortin pathway as it has been known to play a large role in obesity; other genes that are involved in obesity may have been missed as there was no previous evidence to link them to obesity. They have also proved to be hard to replicate.

Genome Wide Association Studies

Genome wide association studies are a relatively new technique of looking into the role that genetic factors play in common obesity-they have only been used for just over ten years. In this decade, understanding of the genetics of human disease has increased exponentially. Genome wide association studies have been carried out using the whole genome of thousands of individuals with the aim of to finding out if any genetic variants are associated with a trait; such as common obesity. The difference between candidate gene analysis and genome wide association studies is that while candidate gene studies require a hypothesis that a certain gene is linked to obesity, genome wide association studies can be used to identify unknown genes that may be associated with the disease, and therefore don't require previous knowledge on the gene/genetic pathway. A study of 249,796 subjects in 2010 confirmed 14 loci that are known to increase obesity susceptibility and identified 18 previously unknown loci that are associated with BMI. However, while pedigree studies have shown that between 40% and 80% of variance in body mass index is caused by genes, the total contributions of loci that have been found using genome wide association studies amounts to ~1.45% of total inter-individual body mass index variance. This seems to indicate that the importance of the role of genetics in common obesity is negligible, but, as obesity is a complex multigenic & multifactorial disease. Genome wide association studies have also been instrumental in building up a picture of obesity-related gene networks. A study was carried out in 2008 of the adipose tissue and blood samples of 1,675 Icelandic individuals from ages 18 to 85. Adipose tissue was collected from 1,002 individuals and blood samples were collected from 673 individuals. Analysis of the adipose tissue showed strong correlations between the genes that were expressed and the phenotypes of obesity-body mass index, percentage body fat and waist to hip ratio. 72% of the 23,720 genes expressed in the adipose tissue correlated with BMI and percentage body fat, and 63% correlated with waist to hip ratio. In comparison 9% of the genes analysed in the blood samples correlated with body mass index, 5% with percentage body fat and 3% with waist to hip ratio. Identifying gene networks in adipose tissue that are associated with obesity shows that genetics play a major role in common obesity. Because all subjects were selected as families, most individuals in the study had at least 2 generations of their family also participating in the study. This meant that heritability could also be analysed; obesity and altered gene expression were found to have a strong association. This reinforces the findings of the pedigree studies that genetics play a very important role in common obesity.

Epigenetics

More recently, epigenetics have been looked into as a way in which genetics play a role in complex diseases, including common obesity. The epigenome may be important in obesity because although changes are not expressed in the DNA sequence, they are heritable and can affect phenotype. This means that epigenetic mechanisms inherited from parents or acquired during early childhood can have an effect on an individuals susceptibility to obesity throughout their entire life. Methylation is the addition of a methyl group to a nucleotide, usually at the 5' carbon in CpG bases, which are frequently found in 'CgP islands' in the promotor regions or first exons of genes. It affects transcriptional regulation, alternative splicing and how alternative promoters are controlled. This means that changes in the epigenome can affect gene expression- which can have a knock on effect on complex disease such as common obesity. A study of 479 individuals was undertaken in 2014 that looked into the effect that methylation at various CgP sites sites may have on body mass index. Sites that were found to be associated with a high body mass index were then tested in two separate replication cohorts. A gene locus was found in blood cells and adipose tissue that is associated with increased body mass index. While this, like using candidate gene analysis to identify gene loci that may be associated with obesity, is not able to pinpoint the cause of obesity due to the complex nature of the disease, in conjunction with research into other factors it can help to build a bigger picture of some of the ways in which genetics may play a role in obesity. The changes in the epigenome are heritable, and can therefore be passed on to offspring, but the epigenome can also be affected by environmental factors. This means that while there may be an association between an epigenetic feature such as methylation and high body mass index, the original cause of the epigenetic change may be environmental. Copy number variation is a structural variation of the genome where sections are either duplicated or deleted. While this causes necessary variation within the human species, it has been suggested that it might also play a role in the cause of diseases such as obesity. However, a genome wide association study undertaken by the Wellcome Trust Case Control Consortium of associations between copy number variations and common human diseases in 19,000 individuals found only 3 loci where CNVs were associated with a disease; none of them were associated with obesity. This led the researchers to conclude that common CNVs that can be looked into using current technology are unlikely to contribute a great deal to the genetic basis of common disease.

Conclusion

There is no doubt that genetic factors have played and will continue to play a very important role in the current 'obesity crisis'. Estimates of heritability from pedigree studies show that a person's genetic makeup is very important in determining whether or not they will become obese. Candidate gene studies and genome wide association studies have identified many loci that are associated with obesity, but this provides weaker evidence for the importance of the role of genetics in obesity due to the fact that common risk variants are only able to explain a tiny percentage of inter-individual body mass index variance. Studies of the epigenome have also shown that epigenetic variation may be a factor in obesity, and while this type of variation cannot be ascribed to changes in the primary DNA sequence, it is still a major genetic influence. However, it is also clear that the current obesogenic environment is having a huge effect on obesity rates, affecting those with a genetic susceptibility to obesity. This indicates that while genetics may predispose certain individuals to obesity, the reason that there has been such a surge in obesity in recent years is due to the coupling between the obesogenic environment and genetic predisposition. The interaction between environmental and genetic factors is important when assessing the role of genetics, as both are heavily intertwined in the aetiology, and both exert their effects in the development of common obesity.