Elsevier

Appetite

Volume 115, 1 August 2017, Pages 71-79
Appetite

Two novel candidate genes identified in adults from the Newfoundland population with addictive tendencies towards food

https://doi.org/10.1016/j.appet.2017.01.004Get rights and content

Abstract

Food addiction (FA) is a distinguished clinical feature affecting about 5% adults of the general population in Canada. FA contributes to obesity, however, the underlying genes in FA are largely unknown. The aim of the current study was to search for FA candidate genes using an exome sequencing followed by a verification study using the most significantly associated identified genes. From a total of 752 adults, 24 subjects were selected including 8 obese with high and 8 obese with low/zero FA clinical symptom score (FAO, NFO), and 8 healthy controls with normal BMI and low/zero FA symptom score (Ctrl). Exome sequencing was completed in all three groups. The top 100 SNPs identified were categorized into 5 subgroups based on gene functions: addiction (Ad), psychological disorders, energy metabolism and obesity, and cancer, unknown function or with other diseases. In the verification study, the top 19 SNPs in the Addiction subgroup were genotyped in the entire 752 subjects using Sequenom iPLEX Gold genotyping technology. Comparison of NFO with Ctrl, and FAO with NFO, Ctrl and the combined group of NFO + Ctrl revealed 19 SNPs associated with Ad genes including, TIRAP, MMADHC, ERAP1, NTM, MYPN, GRID1, ITPR2, GPSM1, ZCCHC14, TNN, PPARD, CACNA1C, SIM1, and DRD2. Genetic association analysis was performed. The major allele A of rs2511521 located in DRD2 (OR = 3.1(95% CI 1.1–8.2)) and the minor allele T of rs625413 located in TIRAP (OR = 2.5(95% CI 1.1–5.8)) in NFO subjects significantly associated with increased risk of food addiction.

Using a combination of exome sequencing method and a candidate gene association approach two new FA candidate genes are identified. Further study on the rest of the genes in the other four categories will be warranted.

Introduction

Over the past 3 decades, the global prevalence of obesity, defined by a body mass index (BMI) of 30 or higher, has increased substantially. By 2019, it is estimated that 55.4% of the Canadian adult population will be categorized as overweight or obese (Twells, Gregory, Reddigan, & Midodzi, 2014). Obesity is a multifactorial disease and the etiology is not completely understood (“Obesity and overweight,” 2016). It has been well documented, however, that genetics (Huang et al., 2015, Qi et al., 2012), endocrine function (Roman et al., 2012, Tang-Péronard et al., 2011), behavioral patterns (Farooqi, 2014, Murray et al., 2014) and environmental determinants (Kershaw, Albrecht, & Carnethon, 2013) play fundamental roles in the development of obesity. Genetic predisposition might be a key factor responsible for the large individual difference in body weight, body fat and other obesity-related aspects (Barsh et al., 2000, Gesta et al., 2006). Estimates of the heritable variation contributing to obesity range from 30 to 60% in family studies to 60–80% in twin studies (Fawcett et al., 2010, Rankinen et al., 2006). In a previous study, we discovered that chronic compulsive overeating, defined as food addiction by the Yale Food Addiction Scale (YFAS), significantly contributes to the common form of human obesity (Pedram et al., 2013). Additionally, the clinical symptom count of food addiction defined by the YFAS is highly associated with the severity of obesity (Pedram et al., 2013). Furthermore, one study has reported that the prevalence of food addiction in obese individuals seeking weight loss treatment was 15.2%, while in another study, the prevalence of food addiction in obese subjects not seeking weight loss was 25% (Davis et al., 2011, Eichen et al., 2013). These studies suggest that food addiction with co-morbid obesity may represent an important subgroup of the obese population with a distinctive etiology.

Accumulating evidence has demonstrated the neurobiological and behavioral similarities between food addiction and substance dependence in both human and animal studies (Blumenthal and Gold, 2010, Davis and Carter, 2009, Fortuna, 2012, Smith and Robbins, 2013, von Deneen and Liu, 2012). In animal models, foods high in sugar and fat are particularly associated with addiction-like behavior (Avena, Bocarsly, & Hoebel, 2012, pp. 351–365; Avena et al., 2008, Avena et al., 2009). In human studies, it has also been suggested that the pattern of food intake in food addiction may parallel substance dependence and this phenomenon might share the same neurobiological, behavioral and clinical framework as conventional drug dependence (DiLeone et al., 2012, Gearhardt et al., 2011, Meule and Kübler, 2012). Data from family, twin, and adoption studies across several drug classes (opioids, cocaine, cannabis, nicotine, alcohol) strongly implicates the role of genetic factor involved in each aspect of addiction development including vulnerability to initiation, continued use, and propensity to become dependent (Li and Burmeister, 2009, Spanagel, 2013, Wang Yang et al., 2014). There also exists a genetic overlap between drug and behavioral addictions like gambling (Spanagel, 2013). Studies have discovered many genes that increase the vulnerability in the development of substance dependence (Crabbe, 2002, Kreek et al., 2005, Noble, 2000, Reed et al., 2014, Shi et al., 2002, Weiss et al., 2008, Zucker, 2014, pp. 51–69). For instance, twin studies have shown that the heritability of addictions ranges from 39% (hallucinogens) to 72% (cocaine) (Ducci & Goldman, 2012). Importantly, however, the predisposition to addiction may be caused by genetic variants that are common to all addictions and by those specific to a particular addiction (Kreek et al., 2005). However, to the best of our knowledge, there is little information regarding genes associated with an addictive tendency toward food measured by YFAS. A few studies were reported including a genome-wide investigation of food addiction (Cornelis et al., 2016), an evaluation of potential involvements in dopaminergic reward pathways in the brain (Davis et al., 2013) or mu-opioid receptor gene (Davis & Loxton, 2014). Exome sequencing is a powerful genome-wide screening method and is an effective way to discover disease causing mutations and genes. (Kiezun et al., 2012). Candidate gene-based association study is the most common method for discovering the link between complex disease and genes that are suspected to be associated with phenotypes of interest (Zhu & Zhao, 2007).

In the current study which was the first of its kind in the field, we employed a two-stage approach: an exome sequencing technology as a screening stage followed by a genetic association study to discover and verify genes related to food addiction.

Section snippets

Ethics statement

This study was approved by the Health Research Ethics Authority (HREA), Memorial University of Newfoundland, St. John's, Canada, with project identification code: #10.33, (latest date of approval: February 10, 2016). All participants provided written and informed consent.

Study sample

The current study was designed and performed in two stages. Stage I, included a genome-wide screening study using a whole-exome sequencing method on selected samples, and stage II was a verification study using a candidate gene association method on the genes related to addiction found in stage I, in the entire study population.

Physical characteristics of subjects in stages I and II

Demographic and physical characteristics of the participants in the three groups based on adiposity and food addiction symptom counts are presented in Table 1 (adiposity was based on BMI).

Comparison between FAO and NFO

Among the 100 SNPs with the most significant allele frequency differences between two groups of FAO and NFO, 7 SNPs located in 7 different genes were discovered that are associated with addiction (Table 2). All the SNPs had significantly higher minor allele frequencies in FAO than NFO. In the case of minor

Discussion

As the first exome study on food addiction, the unique study design with two equally obese groups but different in food addiction symptom counts, plus a healthy control group was likely the key for us to identify food addiction-related genes in a relatively small study. Several hundreds of genes have been linked to the development of the common form of human obesity (Rankinen et al., 2006). It has been well documented that human obesity is a complex disease with multiple routes of etiology. One

Conclusion

In the current study we employed the exome sequencing technology combined with a genetic association study, two genes related to addictive tendencies towards food were identified and validated: the DRD2 and TIRAPgenes in the Newfoundland population. This is the first time that TIRAP has been reported as to be associated with addictive tendencies towards food.

Acknowledgments

We highly appreciated the contributions of all participating volunteers. The study has been funded by a Canadian Institutes of Health Research (CIHR) operating grant to Dr. Sun [grant numbers MOP192552, 2009].

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